Hedy Kindler - Oncologist Perspective.TextMark

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The Present and Future of
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Mesothelioma Treatment:
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 Medical Oncologist and
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 Researcher Perspective
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       Hedy Lee Kindler, MD

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  Associate Professor of Medicine

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  Director, Mesothelioma Program

                                                              em
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       University of Chicago

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    Present and future of

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chemotherapy treatment for MM
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• Where are we now?
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  – Current standard chemotherapies for MM

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  – Key questions about these treatments

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• Where are we going?

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  – Novel agents in development

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  – Some obstacles for moving forward

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  What is “chemotherapy”?
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• Chemotherapy is “cytotoxic”

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   – Chemotherapy kills cancer cells

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     indiscriminately, usually by interfering

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     with their DNA

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   – Chemotherapy exploits the fact that

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     cancer cells usually grow faster than

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     normal cells

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• This differs from “targeted therapy” which

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  targets specific growth factors or

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  signaling pathways that may be increased

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  or turned on in the cancer cell
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        Systemic therapy for MM
          before pemetrexed
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                  l
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Many single-agents were evaluated

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• Trials were small


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• The primary endpoint was usually response

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   – Assessment criteria were not standardized

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   – Monitoring was often done by CXR


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• Minimal to very modest activity was observed for

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  many drugs, including:


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   – Capecitabine, carboplatin, cisplatin, DHAC,

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     docetaxel, doxorubicin, edatrexate, epirubicin,

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     gemcitabine, ifosfamide, irinotecan,

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     mitomycin, paclitaxel, topotecan, trimetrexate
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    Chemotherapy for MM in 2010:
         Where are we now?
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• Cytotoxic drugs with single-agent activity

                 l
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                      a
  (<25% response rate):


                      Ap
                          pl
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   – pemetrexed, raltitrexed, vinorelbine, vinflunine


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                                  R
                                  es
• To prolong survival (by 3 months or less):

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   – add pemetrexed or raltitrexed to cisplatin

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• To increase response rate (by about 10-20%):


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   – add a platinum to pemetrexed, raltitrexed,


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     irinotecan, vinorelbine, or gemcitabine


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• In preclinical models, many novel agents seem

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  ‘promising’


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                                                                           or
   – few have activity in clinical trials


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         Activity of selected drugs
          and drug classes in MM

         M
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      Agent                        # trials               # pts            Response


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                       a
Alkylating agents                           7             194                      4.6%


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 Anthracyclines                         10                319                      6.1%

                              d
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                                   es
                                       ea
Antimetabolites                             8              319                      9%


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  Carboplatin                               3              89                      10.1%

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    Cisplatin                               5             108                      20%

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  Gemcitabine                               3              72                      6.7%

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     Taxanes                                4             111                      5.1%

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Topo I inhibitors                           4             117                      4.9%

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                                                                         o.
                                                                            or
                                                                               g
 Vinca alkaloids                            5             115                      3.6%
Adapted from Ellis, JTO 2006 and Fennell, Nat Pract Clin Oncol 2008
                    www.ifitlist.com
   The anthracyclines: The original
    “gold standard” drugs for MM

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   Agent                        # Trials               # Pts            Response

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 Doxorubicin                             1              51                      14%

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 Epirubicin                              2              68                      12%

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Mitoxantrone

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                                         2              62                      5%

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  Liposomal                              3             109                      5%

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 doxorubicin

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 Liposomal                               1              14                      0%

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daunorubicin

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                                                                   es
                                                                      o.
 Doxorubicin                             1              10                      0%

                                                                         or
                                                                            g
+ dexrazoxane
                     www.ifitlist.com
The current “gold standard” for MM:
                     The antifolates
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   Agent                     # Trials                   # Pts          Response

                 m
                     a
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   DHAC                               3                  128                     11%


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Trimetrexate                          1                  52                      12%


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 Edatrexate                           1                  20                      25%

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Edatrexate/LV                         1                  40                      16%


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Methotrexate                          3                  78                      41%


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Pemetrexed                            1                  62                      14%

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Pralatrexate                          1                  16                      0%


                                                                       o.
                                                                          or
                                                                             g
 Raltitrexed                          1                  24                      21%
                                                                                                           g
                                                                                                        or
                                                                                                     o.
                                                                                                es
                                       Pemetrexed




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                                                                                         w
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                                         (Alimta)


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       Cell membrane transport of folates

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    Reduced folate carrier (RFC)



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    – facilitated diffusion                                                             Pemetrexed: more


                                lio
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    Low affinity – high capacity                                                        active in MM than in


                                      a
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                                                                                        other tumors:


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    PCFT: Pemetrexed-



                                             d
                                                                                        •The proton-


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    selective transporter - high



                                                  es
                                                                                        coupled folate


                                                      ea
    capacity*




                                                       rc
                                                                                        transporter is


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    Lipid soluble drugs - Free                                                          highly specific for


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    diffusion but no concentration                                                      pemetrexed


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                                                                                        •Folate receptor α


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                                                                                        is highly activated


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     Folate Receptor (FR-



                                                                            w
     α) – podocytosis


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     High affinity – low




                                                                                      es
     capacity




                                                                                         o.
                                                                                            or
                                                                                               g
•    Wang, Ca Res2002
                                                                         Efflux by MRP
•    Chattopadhyay , Mol Cancer Ther 2007
               www.ifitlist.com
      Pemetrexed mechanism of action


                         M
                                                                                                         AMP



                         es
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                                                            PRPP + Gln                                      RNA &
                                                                                  GARFT            IMP



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                                                                                                         DNA synthesis




                                   m
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              Cell

                                                                                                     GMP



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                                                                              10-CHO-FH4




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                                                            h
                                                             Fo
              Folate
                                  Pemetrexed



                                                               un
Pemetrexed   Carriers




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                                                                          5, 10-CH2-FH4
             (mainly




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              RFC)
                              FPGS




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                                                                                                     FH4



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                                                                      dUMP




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                                                                          0
                                                                           w
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              membrane




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                             Pemetrexed-GluN                                                DHFR


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                                                                     TS

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                                                                                           FH2




                                                                                         o.
                                                                                            or
                                                                                               g
                                                            dTMP
                                                             DNA synthesis
                    www.ifitlist.com

  Phase II trial of pemetrexed
      M
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   (Alimta) in mesothelioma
          ot
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Patients:                     64

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Dose:                     500 mg/m2 q 21D

                                es
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Partial Response Rate:        14%

                                         h
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Median time to progression:   4.7 months

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Median survival:              10.7 months

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1 year survival:              47.8%

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Grade ¾ neutropenia:          23%

                                                                   es
                                                                      o.
                                                       Scagliotti, JCO 2003



                                                                         or
                                                                            g
                       www.ifitlist.com
 The trial that changed our outlook
on the role of chemotherapy for MM
        M
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                           Pemetrexed 500 mg/m2 q 21D

                       Ap
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                           Cisplatin 75 mg/m2 q 21D


                              d
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  456


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                                             Fo
patients                   Primary objective: survival (HR= .67)


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                                                        01
                           Placebo q 21D


                                                          0
                                                          w
                                                              w
                           Cisplatin 75 mg/m2 q 21D

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                                                                  .c
                                                                    ur
                                                                    em
                                                                      es
 Stratification: Performance status, histology, gender,



                                                                         o.
                                                                            or
 WBC, disease measurability, baseline homocysteine


                                                                               g
                                                              Vogelzang, JCO 2003
          www.ifitlist.com
       Pemetrexed + cisplatin:
The benchmark regimen for mesothelioma

       M
       es
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                                                    PC                  C    p


               lio
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                                                Pts 226                222

                     a
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                         pl
                                                RR 41%                 17% <0.001

                            ie
                            d
                                 R
                                                MST 12.1 M             9.3 M 0.020

                                 es
                                     ea
                                      rc
                                                TTP 5.7 M              3.9 M 0.001

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                                                            Vogelzang, JCO 2003
                                   www.ifitlist.com
       Alimta/cisplatin improves

                     M
quality of life in mesothelioma patients
                     es
                         ot
                          he
                             lio
                               m
                                                                           Pem + Cis


                                   a
                                   Ap
                80


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                                                                           Cis


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                                                   ea
                60
 % Target AUC




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                              p=0.012                                 p=0.009



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                                                                                           or
                          Global QoL                        Symptom distress


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                                       www.ifitlist.com
            Alimta/cisplatin improves fatigue,
                appetite, and activity level
                         M
                         es
                             ot
                               he
                                  l
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                                   m
                                       a
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                                           pl
                    80                                                        Pem + Cis


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                                              d
                                                   R
                                                                              Cis


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                                                       ea
     % Target AUC




                    60


                                                        rc
                             p=0.010                        p=0.017                 p=0.059



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                                                            52



                                                                 da
                    40       46                                  46



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                                      40


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                    20


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                                                                                         o.
                             Fatigue                    Anorexia          Activity level


                                                                                            or
                                                                                               g
*Includes all data up to 18 weeks; 100% = best score
                            www.ifitlist.com
      Alimta/cisplatin improves shortness of
               breath in MM patients

            M
               es
     40     Pem/Cis




                  ot
                                                                                    p =0.004



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            Cis




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                                  p =0.476



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                                                               p =0.344



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     35


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           0                            2                         4                     6
                                                 Cycle
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                  Alimta/cisplatin improves
                lung function in mesothelioma

                 M
                     es
         2.70                                                                                p=0.006


                      ot
                          Pem/Cis
                          Pem/Cis




                          he
                                                                    p=0.034


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                          Cis
                          Cis




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                                                                                es
         2.40


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                                                                                      or
                                                                                         g
                 0                           2                       4                         6
                                                      Cycle
                      www.ifitlist.com

 FDA Approval of Pemetrexed
        M
         es
          (Alimta)
            ot
              he
                 l
                 io
                  m
                      a
                      Ap
• On the basis of these data, the FDA approved


                          pl
                             ie
                             d
  pemetrexed for the treatment of mesothelioma in


                                  R
                                  es
  2003

                                      ea
                                       rc
                                           h
• This is the first and only drug ever FDA approved

                                            Fo
                                              un
  for this disease

                                                da
                                                  tio
                                                     n
• Pemetrexed with cisplatin is thus a standard

                                                     -2
                                                       01
  treatment option for patients with mesothelioma.

                                                         0
                                                         w
                                                             w
                                                             w
• There are other drugs with activity, however,

                                                                 .c
                                                                   ur
                                                                   em
  which may be more appropriate for an individual


                                                                     es
                                                                        o.
  patient


                                                                           or
                                                                              g
                      www.ifitlist.com

   A few things we don’t really know

        M
        es
            ot
     about pemetrexed + cisplatin

             he
                lio
                  m
                      a
• When to start it:


                      Ap
                          pl
   – timing of therapy

                             ie
                             d
                                  R
                                  es
• When to stop it:


                                      ea
                                       rc
   – maintenance

                                           h
                                            Fo
                                              un
• The optimal dose of folic acid


                                                da
                                                  tio
• When to give something other than cisplatin:

                                                     n
                                                     -2
                                                       01
   – special populations: elderly, frail


                                                         0
                                                         w
                                                             w
• When to give something other than pemetrexed:


                                                             w
                                                                 .c
                                                                   ur
   – after all, other drugs have activity

                                                                   em
                                                                     es
                                                                        o.
                                                                           or
                                                                              g
            www.ifitlist.com
         What is the optimal
        duration of treatment?
        M
        es
            ot
             he
• In the pivotal randomized study, pts received no


                lio
                  m
  more than 6 cycles of Pemetrexed-Cisplatin

                      a
                      Ap
                          pl
• What is the optimal treatment duration:

                             ie
                             d
                                  R
                                  es
   – 4-6 cycles?


                                      ea
                                       rc
                                           h
   – 4-6 cycles Pem-platin then Pem until PD?


                                            Fo
                                              un
   – 4-6 cycles Pem + platin then novel agent?

                                                da
                                                  tio
                                                     n
• In a small, non-randomized feasibility study:

                                                     -2
                                                       01
                                                         0
   – Maintenance pemetrexed following


                                                         w
                                                             w
                                                             w
     pemetrexed-platin was well-tolerated


                                                                 .c
                                                                   ur
                                                                   em
   – Responses occurred after 6 cycles


                                                                     es
                                                                        o.
                                                                           or
• The CALGB is running a randomized study to


                                                                              g
  address this question
         www.ifitlist.com
     CALGB 30901: A study of
     pemetrexed maintenance
      M
       es
          ot
            he
               l
               io
                                             Pemetrexed

                m
90 patients


                    a
                    Ap
                          R
                                             until progression

                        pl
                           ie
                           d
Pemetrexed                A


                                R
                                es
                                    ea
      +                   N                  Stratification:


                                     rc
                                         h
Cisplatin or              D                  •Cisplatin vs. carboplatin


                                          Fo
                                            un
                                             •Epithelial vs. other
Carboplatin

                                              da
                          O


                                                tio
                                                   n
 X 4 cycles


                                                   -2
                          M


                                                     01
                                                       0
                       Observation
                          I

                                                       w
                                                           w
    SD


                                                           w
                                                               .c
                          Z
                       until progression

                                                                 ur
    PR


                                                                 em
                          E


                                                                   es
    CR


                                                                      o.
                                                                         or
                                                                            g
 Primary endpoint: progression-free survival
                            PI: Arek Dudek
                      www.ifitlist.com
            Alimta, Folate and B12

        M
         es
Supplementation with dietary levels of folate + B12


            ot
              he
                 l
• significantly decreases side effects of Alimta,

                 io
                  m
                      a
   including: diarrhea, rash, fatigue, low blood

                      Ap
                          pl
                             ie
   counts (white cells and platelets) and mouth


                             d
                                  R
                                  es
   sores


                                      ea
                                       rc
• allows more chemotherapy cycles to be given

                                           h
                                            Fo
                                              un
In laboratory models, however, too much folic acid

                                                da
                                                  tio
   blocks the activity of Alimta1.

                                                     n
                                                     -2
                                                       01
How much is just right?

                                                         0
                                                          w
                                                             w
                                                              w
• Folic acid: 350 to 600 mcg orally daily. Most


                                                                 .c
                                                                   ur
                                                                   em
   multivitamin pills have 400 mcg


                                                                     es
                                                                        o.
• B12 : 1000 mcg shot every 9 weeks

                                                                           or
                                                                              g
                                  1Chattopadhyay,        Oncologist 2007; 12:80815
                    www.ifitlist.com

Special populations: the elderly
      M
       es
          ot
            he
               l
               io
                m
                    a
• In the United States, mesothelioma is
                    Ap
                        pl
                           ie
  a disease of the older patient:
                           d
                                R
                                es
                                    ea
   – median age 74
                                     rc
                                         h
                                          Fo
                                            un
   – 72% of MM pts are > 65 years

                                              da
                                                tio
                                                   n
• Many older MM pts have medical co-

                                                   -2
                                                     01
                                                       0
  morbidities and cannot tolerate

                                                       w
                                                           w
                                                           w
                                                               .c
  cisplatin (which causes fatigue, and

                                                                 ur
                                                                 em
  affects the kidneys and hearing)
                                                                   es
                                                                      o.
                                                                         or
                                                                            g
           www.ifitlist.com
          Phase II trials of
       pemetrexed + carboplatin
         M
             es
              ot
                  he
      Author                                  Ceresoli1                    Castagneto2

                     l
                    io
                     m
                         a
                         Ap
     Patients

                             pl
                                                   102                                76


                                ie
                                d
                                     R
                                     es
    Response                                       19%                            25%

                                         ea
                                          rc
                                              h
                                               Fo
     Survival                                  12.7 mo                          14 mo

                                                 un
                                                   da
                                                     tio
                                                        n
        TTP                                       6.5 mo                       8.0 mo


                                                        -2
                                                          01
                                                            0
                                                            w
In a pooled subset analysis, the elderly patients in


                                                                w
                                                                w
                                                                    .c
these 2 studies had comparable outcomes to their

                                                                      ur
                                                                      em
younger counterparts, although the older patients

                                                                        es
                                                                            o.
                                                                               or
     experienced greater hematologic toxicity3


                                                                                  g
1Ceresoli,   JCO 2006 2Castagneto, Ann Oncol 2008 3Ceresoli, Br J Ca 2008
                     www.ifitlist.com
  What if standard Alimta-based
 chemotherapy stops working, or
       M
        es
           ot
             he
  the patient cannot tolerate it?
                l
                io
                 m
                     a
                     Ap
                         pl
                            ie
                            d
                                 R
• A clinical trial is optimal, but often these

                                 es
                                     ea
                                      rc
  are not readily available

                                          h
                                           Fo
                                             un
• What are the other drugs off the shelf the

                                               da
                                                 tio
                                                    n
  doctor can give? What are their risks and

                                                    -2
                                                      01
  benefits?

                                                        0
                                                        w
                                                            w
                                                            w
                                                                .c
                                                                  ur
                                                                  em
                                                                    es
                                                                       o.
                                                                          or
                                                                             g
                                                                                                           g
                                                                                                        or
                                                                                                     o.
                                                                                                es
                                       Gemcitabine




                                                                                              em
                                                                                            ur
                                                                                          .c
www.ifitlist.com




                                        (Gemzar)


                                                                                         w
                                                                                      w
                                                                                     w
                                                                                 0
                                                                               01
                                                                             -2
                                                                         n
                                                                      tio
                                                                    da
                                                                  un
                                                                Fo
                                                            h
                                                       rc
                                                     ea
                                                  es
                                                 R
                                             d
                                           ie
                                        pl
                                      Ap
                                  a
                                m
                            lio
                         he
                       ot
                    es
                   M
                         www.ifitlist.com

    Single-agent Gemcitabine
           M
           es
               ot
                he
                   lio
                     m
                         a
                         Ap
                              Dose                    #     Response Survival


                             pl
                                ie
                             (mg/m2)

                                d
                                     R
                                     es
                                         ea
Gemcitabine                    1500                  13               0%               4.7 mo1

                                          rc
                                              h
                                               Fo
                                                 un
                                                   da
                                                     tio
Gemcitabine                    1250                  28               7%               8.0 mo2


                                                        n
                                                          -2
                                                            01
                                                              0
                                                              w
                                                                  w
Gemcitabine                    1250                  16           31%                   NR3


                                                                  w
                                                                      .c
                                                                        ur
                                                                        em
                                                                          es
                                                                             o.
                                                                                or
                                                                                   g
1Kindler Lung Ca 2001; 2 van Meerbeeck Cancer 1999;
3 Bischoff Proc ASCO 1998
                           www.ifitlist.com
    The activity of gemcitabine +

             M
    cisplatin varies between trials
             es
                 ot
                  he
                     lio
                       m
                           a
 Author          #       Gemcitabine                      Cisplatin               RR   MS


                           Ap
                               pl
                                  ie
                                  d
 Byrne1      21          1000 D1,8,15                  100 D1 q28D              48%    9.5


                                       R
                                       es
                                           ea
                                            rc
                                                h
 Nowak2      53          1000 D1,8,15                  100 D1 q28D              33% 11.2

                                                 Fo
                                                   un
                                                     da
                                                       tio
Castagneto   35            1250 D1,8                    75 D1 q21D              26%    12

                                                          n
     3




                                                          -2
                                                            01
                                                              0
                                                              w
vanHaarst4   25            1250 D1,8                    80 D1 q21D              16%    9.6

                                                                  w
                                                                  w
                                                                      .c
                                                                        ur
 SWOG5


                                                                        em
             50          1000 D1,8,15                 30D1,8,15 q28D 12%               10


                                                                          es
                                                                             o.
                                                                                or
                                                                                   g
1Byrne,JCO 1999 2Nowak, Br J Ca 2002 3Castagneto, Proc ASCO 2003
4van Haarst, Br J Ca 2002 5Kalmadi, Lung Ca 2007
                           www.ifitlist.com

 Other gemcitabine combinations

           M
               es
                ot
                    he
                       l
                      io
                                                              #           RR           Survival


                       m
                           a
                           Ap
Gemcitabine                Carboplatin1                   50              26%          15.1 mo

                               pl
                                  ie
                                  d
                                       R
                                       es
                                           ea
Gemcitabine                Oxaliplatin2                   25              40%           13 mo


                                            rc
                                                h
                                                 Fo
                                                   un
Gemcitabine Pemetrexed3                                   56              26%           8.1 mo


                                                     da
                                                       tio
                                                          52              17%          10.1 mo

                                                          n
                                                          -2
                                                            01
                           Epirubicin4

                                                              0
Gemcitabine                                               26              23%          12.6 mo


                                                                  w
                                                                  w
                                                                      w
                                                                      .c
                                                                        ur
*Gemcitabine *Vinorelbine5 30                                             10%          10.9 mo


                                                                          em
                                                                            es
                                                                             o.
 *second-line regimen



                                                                                or
                                                                                   g
           Cancer 2003 2Schuette, Clin Lung Ca 2003
 1Favaretto,
 3Janne, JCO 2008  4Portalone, Tumori 2005 5Zucali, Cancer 2008
                 www.ifitlist.com



   M
    es
       ot
         he
            l
            io
             m
                 a
                 Ap
Which combination is better:
                     pl
                        ie
                        d
                             R
    Alimta/Cisplatin or
                             es
                                 ea
                                  rc
                                      h
                                       Fo
  Gemcitabine/Cisplatin?
                                         un
                                           da
                                             tio
                                                n
                                                -2
                                                  01
                                                    0
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                                                            .c
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                                                                es
                                                                   o.
                                                                      or
                                                                         g
                      www.ifitlist.com
Which platinum doublet partner is better:
     pemetrexed or gemcitabine?

        M
         es
            ot
              he
                 l
                 io
                  m
                      a
                      Ap
                          pl
                             ie
                             d
                                  R
                                  es
                                      ea
                                       rc
                                           h
                                            Fo
                                              un
                                                da
                                                  tio
                                                     n
                                                     -2
                                                       01
                                                                                    C Lee,



                                                         0
                                                         w
                                                                                     Proc


                                                             w
                                                             w
                                                                 .c
                                                                                  IASLC 2007


                                                                   ur
                                                                   em
                                                                     es
                                                                        o.
         In a retrospective Canadian series,

                                                                           or
                                                                              g
 there was no difference in overall survival between
  platinum doublets of gemcitabine or pemetrexed
                                                                                                           g
                                                                                                        or
                                                                                                     o.
                                                                                                es
                                                                                              em
                                                                                            ur
                                           Vinorelbine
                                           (Navelbine)



                                                                                          .c
www.ifitlist.com




                                                                                         w
                                                                                      w
                                                                                     w
                                                                                 0
                                                                               01
                                                                             -2
                                                                         n
                                                                      tio
                                                                    da
                                                                  un
                                                                Fo
                                                            h
                                                       rc
                                                     ea
                                                  es
                                                 R
                                             d
                                           ie
                                        pl
                                      Ap
                                  a
                                m
                            lio
                         he
                       ot
                    es
                   M
                         www.ifitlist.com
  Vinorelbine in mesothelioma

           M
           es
               ot
                                                             #           RR           Survival

                he
                   lio
                     m
First-line

                         a
                         Ap
                             pl
                                ie
           Vinorelbine1                                     29           24%          10.6 mo


                                d
                                     R
                                     es
           Vinorelbine2                                     136          16%          9.4 mo

                                         ea
                                          rc
                                              h
                                               Fo
 Vinorelbine3                Oxaliplatin                    26           23%          8.8 mo


                                                 un
                                                   da
                                                     tio
 Vinorelbine4                 Cisplatin                     57           28%          11.6 mo


                                                        n
                                                        -2
                                                          01
Second-line


                                                            0
                                                                 w
                                                                 w
                                                                     w
           Vinorelbine5                                     63           16%          9.6 mo


                                                                     .c
                                                                       ur
                                                                         em
 Vinorelbine6 Gemcitabine                                   30           10%          10.9 mo

                                                                           es
                                                                            o.
                                                                               or
                                                                                  g
       JCO 2000 2Muers, Lancet 2008 3Fennell, Lung Ca 2005 4Sorensen,
1Steele,

 Proc JTO 2007 5Stebbing, Lung Ca 2008 6Zucali, Cancer 2008
                  www.ifitlist.com



    M
     es
        ot
          he
             l
             io
              m
                  a
                  Ap
    Do we really know that
                      pl
                         ie
                         d
                              R
                              es
 chemotherapy is better than
                                  ea
                                   rc
                                       h
                                        Fo
just taking care of symptoms?
                                          un
                                            da
                                              tio
                                                 n
                                                 -2
                                                   01
                                                     0
                                                     w
                                                         w
                                                         w
                                                             .c
                                                               ur
                                                               em
                                                                 es
                                                                    o.
                                                                       or
                                                                          g
                    www.ifitlist.com
Is chemotherapy better than no treatment?
     The UK MS01 Trial: A randomized

      M
       es
  phase III trial of active symptom control

          ot
            he
               l
      with or without chemotherapy

               io
                m
                    a
                    Ap
                        pl
Newly-diagnosed malignant pleural mesothelioma


                           ie
                           d
                                R
                                es
                                    ea
                                Randomization


                                     rc
                                         h
                                          Fo
                                            un
                                              da
                                                tio
                                                   n
                                                   -2
  Active                      ASC +                                      ASC +

                                                     01
                                                       0
                                                       w
 Symptom                 4 cycles of MVP                               12 weekly


                                                           w
                                                           w
                                                               .c
  Control                                                              cycles of


                                                                 ur
                                                                 em
                        Mitomycin 6 mg/m2
   (ASC)                                                              Vinorelbine

                                                                   es
                        Vinblastine 6 mg/m2


                                                                      o.
                                                                         or
                        Cisplatin 50 mg/m2


                                                                            g
                                                                        (30 mg/m2)
                          www.ifitlist.com
Overall Survival (ASC vs. ASC+ chemo)


            M
                                                 ASC   ASC+chemo


            es
 1.00




                ot
                                      Pts         136     273


                 he
                    lio
                                      Median      7.6 mo 8.5 mo


                      m
                          a
                          Ap
 0.75




                                      1 yr survival 30% 37%


                              pl
                                 ie
                                 d
                                      HR = 0.89 (0.72-1.12)


                                      R
                                      es
                                      p= 0.32


                                          ea
                                           rc
 0.50




                                               h
                                                Fo
                                                  un
                                                    da
                                                      tio
                                                         n
 0.25




                                                         -2
                                                           01
                                                             0
                                                             w
                                                                 w
                                                                 w
 0.00




                                                                     .c
                                                                       ur
                                                                       em
        0   6        12        18         24    30     36        42         48        54   60




                                                                         es
                                           Time (months)




                                                                            o.
                                                                               or
                                                                                  g
                              ASC alone                  ASC + Chemotherapy
                              www.ifitlist.com
           Overall survival (3 arms)
                                         ASC ASC+MVP ASC+Vin


           M
1.00




               es
                               Pts       136    137     136


                ot
                    he
                               Median 7.6 m 7.8 m       9.5 m


                       l
                      io
                          m
                               1 yr      30%     31%    42%


                           a
0.75




                              Ap
                               pl
                                   HR:          0.99    0.8


                                  ie
                                    d
                                       R
                                  95% CI     0.78-1.27 0.63-1.02


                                        es
                                           ea
0.50




                                  p-value      0.95      0.08


                                             rc
                                                h
                                                  Fo
                                                    un
                                                      da
0.25




                                                        tio
                                                           n
                                                           -2
                                                             01
                                                               0
                                                               w
0.00




                                                                   w
                                                                   w
                                                                       .c
                                                                         ur
       0   6         12        18          24    30     36         42         48        54   60




                                                                         em
                                            Time (months)




                                                                           es
                                                                              o.
                                                                                 or
                                    ASC alone                  ASC + MVP




                                                                                    g
                                    ASC + N
                www.ifitlist.com



  M
   es
      ot
        he
           l
           io
            m
  What are some of the
                a
                Ap
                    pl
                       ie
  challenges facing the
                       d
                            R
                            es
                                ea
development of new drugs
                                 rc
                                     h
                                      Fo
                                        un
    for this disease?
                                          da
                                            tio
                                               n
                                               -2
                                                 01
                                                   0
                                                   w
                                                       w
                                                       w
                                                           .c
                                                             ur
                                                             em
                                                               es
                                                                  o.
                                                                     or
                                                                        g
                    www.ifitlist.com

    Obstacles to progress
      M
       es
          ot
            he
               l
               io
• Why haven’t we done better?

                m
                    a
                    Ap
                        pl
  – What are some of the obstacles we’ve

                           ie
                           d
                                R
    encountered in developing new

                                es
                                    ea
                                     rc
    treatments for this disease?

                                         h
                                          Fo
                                            un
• Where do we go from here?
                                              da
                                                tio
                                                   n
                                                   -2
  – What interesting, potentially active new

                                                     01
                                                       0
                                                       w
    agents are being studied?

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                                                           w
                                                               .c
                                                                 ur
                                                                 em
                                                                   es
                                                                      o.
                                                                         or
                                                                            g
                      www.ifitlist.com
  Several factors have hampered
   the development of effective
        M
        es
            ot
             he
    regimens for mesothelioma
                lio
                  m
                      a
                      Ap
                          pl
                             ie
                             d
• Most drugs don’t work
                                  R
                                  es
                                      ea
                                       rc
• MM is uncommon

                                           h
                                            Fo
                                              un
                                                da
• MM is heterogeneous

                                                  tio
                                                     n
                                                     -2
• Staging is unreliable

                                                       01
                                                         0
                                                         w
                                                             w
• Response assessment is difficult

                                                             w
                                                                 .c
                                                                   ur
                                                                   em
                                                                     es
                                                                        o.
                                                                           or
                                                                              g
                        www.ifitlist.com
    Most drugs don’t work—why?

          M
•   We don’t understand the biology well

           es
              ot
                he
    enough to find the right drugs to test

                   l
                   io
                    m
                        a
                        Ap
    –   More research funding is needed


                            pl
                               ie
                               d
•   The right drugs may be out there, but it is

                                    R
                                    es
                                        ea
    difficult to persuade pharma to test them

                                         rc
                                             h
                                              Fo
    in an unprofitable disease

                                                un
                                                  da
                                                    tio
    –   More funding is needed


                                                       n
                                                       -2
                                                         01
•   Drugs may work in the test tube but not

                                                           0
                                                           w
                                                               w
    in the patient because the drug isn’t

                                                               w
                                                                   .c
                                                                     ur
    being delivered properly to the tumor, or

                                                                     em
                                                                       es
                                                                          o.
    is being inactivated in the patient’s body

                                                                             or
                                                                                g
    –   More research is needed
                      www.ifitlist.com
  Several factors have hampered
   the development of effective
        M
        es
            ot
             he
    regimens for mesothelioma
                lio
                  m
                      a
                      Ap
                          pl
                             ie
                             d
• Most drugs don’t work

                                  R
                                  es
                                      ea
                                       rc
• MM is uncommon

                                           h
                                            Fo
                                              un
• MM is heterogeneous

                                                da
                                                  tio
                                                     n
                                                     -2
• Staging is unreliable

                                                       01
                                                         0
                                                         w
                                                             w
• Response assessment is difficult

                                                             w
                                                                 .c
                                                                   ur
                                                                   em
                                                                     es
                                                                        o.
                                                                           or
                                                                              g
                      www.ifitlist.com
         MM is uncommon

        M
• Many clinical trials, by necessity, are small

         es
            ot
              he
  – This can lead to false + and – results

                 l
                 io
                  m
                      a
                      Ap
• Large trials are difficult to complete

                          pl
                             ie
                             d
  – May require many sites in many countries

                                  R
                                  es
                                      ea
  – Accrual may take years

                                       rc
                                           h
                                            Fo
  – They may close prematurely and be

                                              un
                                                da
    underpowered

                                                  tio
                                                     n
                                                     -2
  – A finite number of trials can be performed

                                                       01
                                                         0
                                                         w
• The potential market is small

                                                             w
                                                             w
                                                                 .c
                                                                   ur
                                                                   em
  – It’s not profitable!


                                                                     es
                                                                        o.
  – It is difficult to interest pharmaceutical

                                                                           or
                                                                              g
    companies or grant funding agencies
           www.ifitlist.com
    In the US, MM is uncommon
          and regionalized
       M
        es
• Most community and academic oncologists see

           ot
             he
                l
  very few MM

                io
                 m
                     a
                     Ap
• Several academic centers of excellence see high


                         pl
                            ie
  volumes of MM

                            d
                                 R
                                 es
                                     ea
• Principal sources of clinical trials in the US:


                                      rc
                                          h
                                           Fo
   – Cooperative groups


                                             un
                                               da
   – NCI phase II consortia

                                                 tio
                                                    n
                                                    -2
   – Pharmaceutical companies


                                                      01
                                                        0
                                                        w
• In the past, it was easier to open trials that


                                                            w
                                                            w
                                                                .c
  accrued small numbers of pts per site

                                                                  ur
                                                                  em
                                                                    es
   – increased regulatory and cost burdens make it


                                                                       o.
                                                                          or
     more and more difficult to open trials if only a

                                                                             g
     few pts are accrued
                          www.ifitlist.com
                          Slow accrual:
         Phase III ranpirnase trial took

           M
              es
        8 years to accrue 428 patients!

               ot
                   he
                      l
                     io
                      m
                          a
                          Ap
          R                   Ranpirnase 240 μg/m2 (480 μg/m2) q wk


                              pl
                                 ie
          A                     + Doxorubicin 60 mg/m2 d1 q3wk


                                 d
                                      R
          N


                                      es
428                                                     X 6 cycles


                                          ea
          D


                                           rc
pts

                                               h
          O


                                                Fo
          M


                                                  un
                                                    da
          I                           Doxorubicin 60 mg/m2 d1 q3wk


                                                      tio
                                                         n
          Z                                              x 6 cycles


                                                         -2
          E


                                                           01
                                                             0
                                                             w
                                                                 w
                                                                 w
                                                                     .c
      The standards of care changed in the interim:

                                                                       ur
                                                                       em
                                                                         es
         *Approval of pemetrexed


                                                                            o.
                                                                               or
                                                                                  g
         *Diminished role for doxorubicin
      Completing a definitive trial will be challenging
                 www.ifitlist.com
No difference in survival

   M
   es
       ot
        he
           lio
             m
                 a
                 Ap
                                           Median
                                                       1 year                           p




                     pl
                     Treatment (N)         Survival                 HR       95% CI




                        ie
                                                      survival                        value




                        d
                                          (months)




                             R
                             es
                                 ea
                   Ranpirnase /
                                            11.09       46.1%




                                  rc
                 Doxorubicin (203)                                           0.84,




                                      h
                                                                   1.023              0.825




                                       Fo
                                                                             1.25




                                         un
                 Doxorubicin (210)          10.76       42.9%




                                           da
                                             tio
                                                n
                                                -2
                                                  01
                                                    0
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                                                        w
                                                          w
                                                            .c
                                                              ur
                                                              em
                                                                es
                                                                   o.
                                                                      or
                                                                         g
                               www.ifitlist.com
MS01 trial: Non-significant survival benefit for
vinorelbine likely due to reduced sample size


                M
                es
Initial design: 840 pts in 4 yrs, 3 arms, 90% power. Accrual poor.


                    ot
                     he
                        l
Revised design: 2 arms, 420 pts, chemo arms pooled, 76% power


                         io
                          m
                              a
                               Ap
                                  pl
 1.00




                                          ASC            MVP               Vin



                                     ie
                                     d
                      Pts                 136            137               136



                                          R
                                          es
                      Median               7.6 m         7.8 m            9.5 m



                                              ea
 0.75




                                               rc
                      1 yr                29%            31%              42%             Study conclusion:


                                                   h
                                                    Fo
                         HR:                             0.99              0.8
                                                                                          Vinorelbine may


                                                      un
                        95% CI                         0.78-1.27 0.63-1.02
 0.50




                                                        da
                                                                                          improve MST by


                                                          tio
                              p-value                   0.95       0.08



                                                             n
                                                              -2
                                                                                             ~2 months


                                                                01
 0.25




                                                                  0
                                                                                            (p=0.11; NS)


                                                                      w
                                                                      w
                                                                          w
                                                                           .c
 0.00




                                                                             ur
                                                                               em
                                                                                 es
        0   6   12       18       24    30     36        42      48       54      60
                                   Time (months)




                                                                                       o.
                                                                                          or
                                                                                             g
                              ASC alone                ASC + MVP
                              ASC + N
                      www.ifitlist.com
  Several factors have hampered
   the development of effective
        M
        es
            ot
             he
    regimens for mesothelioma
                lio
                  m
                      a
                      Ap
                          pl
                             ie
• Most drugs don’t work

                             d
                                  R
                                  es
                                      ea
• MM is uncommon

                                       rc
                                           h
                                            Fo
                                              un
• MM is heterogeneous
                                                da
                                                  tio
                                                     n
                                                     -2
• Staging is unreliable

                                                       01
                                                         0
                                                         w
                                                             w
• Response assessment is difficult

                                                             w
                                                                 .c
                                                                   ur
                                                                   em
                                                                     es
                                                                        o.
                                                                           or
                                                                              g
                      www.ifitlist.com
     MM is heterogeneous

        M
        es
• There are many prognostic factors,

            ot
             he
                l
  including:

                 io
                  m
                      a
                      Ap
   – 3 pathologic subtypes—epithelial,

                          pl
                             ie
                             d
     sarcomatoid, and biphasic—that

                                  R
                                  es
                                      ea
     produce very different outcomes

                                       rc
                                           h
                                            Fo
                                              un
   – 4 different sites of disease—pleural,

                                                da
                                                  tio
     peritoneal, tunica vaginalis,

                                                     n
                                                     -2
                                                       01
     pericardial— with differing natural

                                                         0
                                                         w
                                                             w
     histories

                                                             w
                                                                 .c
                                                                   ur
                                                                   em
• No prognostic scoring system fully

                                                                     es
                                                                        o.
                                                                           or
  accounts for this heterogeneity

                                                                              g
                           www.ifitlist.com
       MM is heterogeneous

             M
             es
                 ot
•It is very difficult to make cross-trial comparisons


                  he
                     lio
                       m
•The same drugs may yield very different outcomes


                           a
                           Ap
in different trials--which makes it hard to figure out

                               pl
                                  ie
                                  d
whether a drug is really helpful, or not


                                       R
                                       es
                                           ea
                                            rc
                                                h
 Author          #         Gemcitabine                    Cisplatin               RR   MS


                                                 Fo
                                                   un
                                                     da
  Byrne      21            1000 D1,8,15                  100 D1 q28D             48%   9.5


                                                       tio
                                                          n
                                                          -2
 Nowak       53            1000 D1,8,15                  100 D1 q28D             33%   11.2


                                                            01
                                                              0
                                                              w
                                                                  w
Castagneto   35                1250 D1,8                 75 D1 q21D              26%   12


                                                                  w
                                                                      .c
                                                                        ur
                                                                        em
vanHaarst    25                1250 D1,8                 80 D1 q21D              16%   9.6


                                                                          es
                                                                             o.
                                                                                or
 SWOG        50            1000 D1,8,15                30D1,8,15 q28D            12%   10


                                                                                   g
                     www.ifitlist.com
  Several factors have hampered
   the development of effective
       M
        es
           ot
             he
    regimens for mesothelioma
                l
                io
                 m
                     a
                     Ap
                         pl
                            ie
• Most drugs don’t work

                            d
                                 R
                                 es
                                     ea
• MM is uncommon

                                      rc
                                          h
                                           Fo
                                             un
• MM is heterogeneous

                                               da
                                                 tio
                                                    n
                                                    -2
• Staging is unreliable
                                                      01
                                                        0
                                                        w
                                                            w
• Response assessment is difficult

                                                            w
                                                                .c
                                                                  ur
                                                                  em
                                                                    es
                                                                       o.
                                                                          or
                                                                             g
                       www.ifitlist.com

      Staging is unreliable
         M
          es
             ot
               he
• There are many staging systems for pleural MM

                  l
                  io
                   m
                       a
• All are surgically based

                       Ap
                           pl
                              ie
• While some may predict survival in the resected

                              d
                                   R
                                   es
  patient, none accurately selects non-surgical

                                       ea
                                        rc
                                            h
  patients with similar prognoses


                                             Fo
                                               un
• Therefore, chemotherapy trials in MM may

                                                 da
                                                   tio
  include patients with a range of stages, and

                                                      n
                                                      -2
                                                        01
  prognoses


                                                          0
                                                          w
                                                              w
   – We don’t put patients with stages I, II, III, and IV

                                                              w
                                                                  .c
                                                                    ur
     NSCLC in the same study—why do so in MM?

                                                                    em
                                                                      es
                                                                         o.
                                                                            or
                                                                               g
                         www.ifitlist.com
        Many staging systems for MM,
              none satisfactory

           M
            es
               ot
                 he
• Butchart (1976)


                    l
                    io
                     m
                         a
    – Based on only 29 surgical pts, not TNM


                         Ap
                             pl
•   Mattson (1982)

                                ie
                                d
                                     R
                                     es
•   Chahinian (1983)


                                         ea
                                          rc
    UICC-TNM Atlas 3rd Ed. (1992)

                                              h
•


                                               Fo
                                                 un
•   Boutin (1993)

                                                   da
                                                     tio
                                                        n
•   Sugarbaker et al. (1993)

                                                        -2
                                                          01
    – Based on 176 pts, single-center, surgical only, not TNM


                                                            0
                                                            w
                                                                w
                                                                w
• IMIG-TNM System (1995)


                                                                    .c
                                                                      ur
                                                                      em
    – The most widely used, current standard


                                                                        es
                                                                           o.
• IASLC-IMIG-MARF (2010)

                                                                              or
                                                                                 g
    – In development (Rusch, Proc IASLC 2009)
                      www.ifitlist.com
  Several factors have hampered
   the development of effective
        M
        es
            ot
             he
    regimens for mesothelioma
                lio
                  m
                      a
                      Ap
                          pl
                             ie
• Most drugs don’t work

                             d
                                  R
                                  es
                                      ea
• MM is uncommon

                                       rc
                                           h
                                            Fo
                                              un
• MM is heterogeneous

                                                da
                                                  tio
                                                     n
• Staging is unreliable

                                                     -2
                                                       01
                                                         0
                                                         w
• Response assessment is difficult
                                                             w
                                                             w
                                                                 .c
                                                                   ur
                                                                   em
                                                                     es
                                                                        o.
                                                                           or
                                                                              g
                     www.ifitlist.com

  Response assessment
       M
       es
           ot
       is difficult
            he
               lio
                 m
                     a
                     Ap
• Unlike others tumors, MM is not compact,

                         pl
                            ie
                            d
  intraparenchymal, or uniformly growing

                                 R
                                 es
                                     ea
                                      rc
• Thus, MM is difficult to measure

                                          h
                                           Fo
                                             un
  reproducibly

                                               da
                                                 tio
                                                    n
• The assessment of MM tumor response

                                                    -2
                                                      01
  demonstrates substantial variability

                                                        0
                                                        w
                                                            w
                                                            w
  between observers

                                                                .c
                                                                  ur
                                                                  em
• Assessment criteria vary between trials

                                                                    es
                                                                       o.
                                                                          or
                                                                             g
                  www.ifitlist.com
   The current standard for

    M
measuring MM: Modified RECIST
    es
        ot
         he
            lio
              m
                  a
                  Ap
                      pl
                         ie
                         d
                              R
                              es
                                  ea
                                   rc
                                       h
                                        Fo
                                          un
                                            da
                                              tio
                                                 n
                                                 -2
                                                   01
                                                     0
                                                     w
                                                         w
                                                         w
                                                             .c
                                                               ur
                                                               em
                                                                 es
                                                                    o.
                                                                       or
                              Byrne and Nowak. Annals of Oncology, 2004   g
                        www.ifitlist.com
 Despite these problems, there are several
advantages in developing new drugs for MM

          M
           es
              ot
                he
                   l
                   io
• It is relatively easy to get a new drug

                    m
                        a
                        Ap
  approved because:

                            pl
                               ie
                               d
  –   Nothing else works very well

                                    R
                                    es
                                        ea
  –   Survival is short, so trials complete quickly

                                         rc
                                             h
                                              Fo
  –   Trials are small, so they require less money

                                                un
                                                  da
                                                    tio
  –   Once a drug is approved for this uncommon


                                                       n
                                                       -2
      indication, it can be more readily approved for

                                                         01
                                                           0
                                                           w
      a more lucrative one (pemetrexed for NSCLC)


                                                               w
                                                               w
                                                                   .c
                                                                     ur
• The incidence is regionalized, as are the

                                                                     em
                                                                       es
  centers of excellence

                                                                          o.
                                                                             or
                                                                                g
           www.ifitlist.com
        How do we select new
        agents to test in MM?

       M
        es
           ot
Targets with ‘interesting’ preclinical data:

             he
                l
                io
                 m
                     a
  – VEGF, src, c-met, IGF-1R, AKT, aurora kinases,


                     Ap
                         pl
    ephrins, mesothelin, WT-1, TRAIL…..

                            ie
                            d
                                 R
                                 es
     • Promising preclinical data has led to many


                                     ea
                                      rc
       disappointing results in patients


                                          h
                                           Fo
                                             un
Choice of drug is based on:

                                               da
                                                 tio
                                                    n
  – Availability of agents for clinical testing against

                                                    -2
                                                      01
    a target of interest

                                                        0
                                                        w
                                                            w
                                                            w
  – Phase I single-agent and combination safety


                                                                .c
                                                                  ur
                                                                  em
    data


                                                                    es
                                                                       o.
  – Willingness of a drug company to test

                                                                          or
                                                                             g
    drugs in MM
                         www.ifitlist.com
   Given all of these hurdles, it’s remarkable
   how many new drugs are being tested in


           M
            es
     mesothelioma patients: A partial list

               ot
                 he
                    l
VEGF inhibitors: AZD2171, Bevacizumab, NGR-hTNF,


                    io
                     m
                         a
   Pazopanib, Sorafenib, Sunitinib, ZD6474


                         Ap
                             pl
Src inhibitor: Dasatinib


                                ie
                                d
                                     R
HDAC inhibitors: SAHA, PXD101


                                     es
                                         ea
Anti-mesothelin agents: MORAb009, SS1P


                                          rc
                                              h
                                               Fo
Proteasome inhibitor: Bortezomib


                                                 un
                                                   da
PDGF inhibitor: Imatinib


                                                     tio
                                                        n
                                                        -2
mTor inhibitor: RAD001



                                                          01
                                                            0
CDK inhibitor: CBP501


                                                            w
                                                                w
                                                                w
WT-1: WT-1 vaccine


                                                                    .c
                                                                      ur
                                                                      em
TGF-B inhibitor: GC1008



                                                                        es
                                                                           o.
TRAIL receptor-2 agonist: CS-1008


                                                                              or
                                                                                 g
Other targets with interesting preclinical data: c-met, IGF-1R,
   AKT, aurora kinases, ephrins, hedgehog….
                    www.ifitlist.com

          Trial design in MM:
      M
       es
             It’s a balance
          ot
            he
               l
               io
                m
                    a
                    Ap
Many questions                                Finite Resources

                        pl
                           ie
                           d
                                R
• Agent? Class?

                                es
                                              • Limited patient

                                    ea
                                     rc
• Trial design?

                                         h
                                                numbers

                                          Fo
                                            un
                                              da
• Primary endpoint?                           • Limited Funding
                                                tio
                                                   n
                                                   -2
• Line of therapy?

                                                     01
                                                       0
                                                       w
• Patient

                                                           w
                                                           w
                                                               .c
                                                                 ur
  population?

                                                                 em
                                                                   es
                                                                      o.
                                                                         or
                                                                            g
                            www.ifitlist.com
   Despite substantial pre-clinical data, phase
   II trials of EGFR and PDGF inhibitors have

              M
               es
       not demonstrated any activity in MM

                  ot
                    he
                       l
                       io
                        m
       Drug                     #       RR              SD                    PFS         MST


                            a
                            Ap
                                pl
     Gefitinib1             43          2%             49%              40% 3 m           6.8 m


                                   ie
                                    d
                                        R
                                        es
     Gefitinib2             21          5%             50%                               14.1 m


                                            ea
                                             rc
                                                 h
     Erlotinib3             64          0%             47%              28% 6 m          39% 1yr


                                                  Fo
                                                    un
                                                      da
 Imatinib 800mg4            25          0%             38%                                2m



                                                        tio
                                                           n
                                                           -2
 Imatinib 600mg5            17          0%             29%                1.8 m          14.3 m



                                                             01
                                                               0
 Imatinib 400mg6            21          0%           12% >6 m             2.1m            13 m


                                                               w
                                                                   w
                                                                   w
                                                                       .c
                                                                         ur
 Imatinib 400mg7            11          0%             36%                1.8 m           4.6 m


                                                                         em
                                                                           es
                                                                               o.
                                                                                  or
1Govindan,CCR 2005 2Lee, Proc ASCO 2008 3Garland, Proc ASCO 2004 3Millward,



                                                                                     g
Proc ASCO 2003 4Villano Proc ASCO 2004; 5Mathy Lung Ca 2005; 6Porta CCP 2006
                         www.ifitlist.com
   Antibodies against VEGF and its receptors
significantly decrease proliferation of MM in vitro


          M
           es
               ot
                he
                                         VEGF


                   lio
                     m
                                                                1 untreated MPP89

                         a
                         Ap
                             pl
     Control                                                    2 + anti-IgG1 control

                                ie
                                d
                                     R
                                                                Ab

                                     es
                                         ea
                                          rc
                                                                3 + rhVEGF

                                              h
                                               Fo
                                                 un
                                                                4 + anti-VEGF


                                                   da
                                                     tio
                                      VEGF

                                                        n
                                                                5 + anti-KDR Ab


                                                        -2
                                                          01
                                     inhibition                 6 + anti-Flt-1 Ab

                                                            0
                                                            w
                                                                w
                                                                 w
                                                                    .c
                                                                      ur
                                                                      em
                                                                        es
                                                                           o.
                                                                              or
                                                                                 g
                                                                Strizzi, J Pathol 2001
                      www.ifitlist.com
    An incomplete list of the VEGF

        M
      inhibitors evaluated in MM
         es
            ot
              he
                 l
                 io
                  m
•   AZD2171

                      a
                      Ap
                                                Is it a wise use of

                          pl
                             ie
•   Bevacizumab

                             d
                                  R
                                                  limited patient

                                  es
                                      ea
•   NGR-hTNF

                                       rc
                                                   resources to

                                           h
                                            Fo
•   Pazopanib

                                              un
                                                perform so many

                                                da
                                                  tio
•   Sorafenib

                                                     n
                                                “me too trials” in
                                                     -2
                                                       01
•   Sunitinib

                                                         0
                                                 this uncommon
                                                         w
                                                             w
                                                             w
                                                                 .c
•   SU5416

                                                                   ur
                                                     disease?

                                                                   em
                                                                     es
•   Thalidomide

                                                                        o.
                                                                           or
                                                                              g
•   ZD6474
                          www.ifitlist.com

 Phase II studies of VEGF inhibitors: Modest

            M
              es
   single-agent activity in mesothelioma

                ot
                   he
                      l
                     io
                      m
                          a
       Drug               #           RR           SD          SD            TTP        MST


                          Ap
                              pl
                                 ie
                                                             > 6 mo          mo         mo


                                 d
                                      R
                                      es
     SU54161              22          11%          38%                        2        12.4 mo


                                          ea
                                           rc
                                               h
  Thalidomide2            40          0%                      28%                      7.5 mo


                                                Fo
                                                  un
                                                    da
                                                      tio
  Thalidomide3            22          6%           50%        25%             2        11 mo


                                                         n
                                                         -2
                                                           01
    Vatalinib4            39          11%          66%                                 10.0 mo


                                                             0
                                                               w
                                                                 w
                                                                   w
   Sorafenib5             39          4%           39%                      2.3/4.1    5.2/14.3


                                                                     .c
                                                                       ur
                                                                       em
    Sunitinib6            23          18%          55%                       3.7         8.2


                                                                         es
                                                                             o.
                                                                                or
                                                                                   g
1Kindler,Proc ASCO 2001 2Baas, Lung Ca 2005 3Pavlakis, Proc IASLC 2003
4Jahan, Proc IASLC 2005 5Janne, Proc IMIG 2006 6Nowak, Proc IMIG 2008
                       www.ifitlist.com
    Randomized phase II trial of
gemcitabine/cisplatin +/- bevacizumab

         M
          es
             ot
               he
                  l
                  io
             Gemcitabine

                   m
                       a
                       Ap
             Cisplatin                                       Bevacizumab

                           pl
                              ie
                              d
                                   R
             Bevacizumab

                                   es
                                       ea
106

                                        rc
                                                            until progression


                                            h
                  X 6 cycles


                                             Fo
pts

                                               un
                                                 da
             Gemcitabine

                                                   tio
                                                      n
                                                             Placebo

                                                      -2
             Cisplatin

                                                        01
                                                          0
             Placebo

                                                             w
                                                              w
                                                                 w
                                                                  .c
                                                                    ur
                                                                     em
  Stratification:


                                                                       es
                                                             Primary endpoint:


                                                                         o.
  •Performance status: 0 vs. 1


                                                                            or
                                                          Progression-free survival


                                                                               g
  •Histology: epithelial vs. other
                                                             Kindler, Proc IASLC 2007
              www.ifitlist.com
         Overall survival

M
es
    ot
     he
        lio
          m
                                                 Bevacizumab              15.6 mo


              a
              Ap
                                                 Placebo                  14.7 mo


                  pl
                     ie
                     d
                          R
                          es
                                                   Logrank p=0.91


                              ea
                               rc
                                   h
                                    Fo
                                      un
                                        da
                                          tio
                                             n
                                             -2
                                               01
                                                 0
                                                   w
                                                     w
                                                       w
                                                         .c
                                                           ur
                                                           em
                                                             es
                                                                o.
                                                                   or
                                                                      g
           www.ifitlist.com
          Overall survival by
         baseline VEGF level

  M
   es
      ot
        he
                                                           VEGF ≤ Median


           l
           io
            m
                a
                                                           VEGF > Median


                Ap
                    pl
                       ie
                       d
                            R
                                                       Logrank p=0.014


                            es
                                ea
                                 rc
                                     h
                                      Fo
                                        un
                                          da
                                            tio
                                               n
                                               -2
                                                 01
                                                   0
                                                   w
                                                       w
                                                       w
                                                           .c
                                                             ur
                                                             em
                                                               es
Median VEGF level = 144 pg/ml


                                                                  o.
                                                                     or
                                                                        g
       www.ifitlist.com
Overall survival by treatment:
       VEGF < median

  M
   es
      ot
        he
                                                           Bevacizumab


           l
           io
            m
                a
                                                           Placebo


                Ap
                    pl
                       ie
                       d
                            R
                            es
                                                            Logrank p=0.028


                                ea
                                 rc
                                     h
                                      Fo
                                        un
                                          da
                                            tio
                                               n
                                               -2
                                                 01
                                                   0
                                                   w
                                                       w
                                                       w
                                                           .c
                                                             ur
                                                             em
                                                               es
                                                                  o.
                                                                     or
  Bevacizumab-treated pts with low baseline


                                                                        g
   VEGF levels had longer overall survival
                               www.ifitlist.com
          M.A.P.S Phase 2-3 Trial

                M
                   es
                    ot
                        he
                                    Pemetrexed


                           l
                          io
                           m
  Pleural MM                        Cisplatin                                    Bevacizumab

                               a
                               Ap
  Histologically


                                   pl
                                    Bevacizumab


                                      ie
                                      d
  proven                            15 mgkg                                      until progression


                                           R
                                           es
                                               ea
  PS: 0-2



                                                rc
                                       X 6 cycles

                                                    h
  Chemo-naive


                                                     Fo
                                                                           Primary endpoints


                                                       un
                                    Pemetrexed


                                                         da
                                                                           •Phase 2: 6 mo PFS


                                                           tio
                                    Cisplatin

                                                              n
Stratification:                                                            •Phase 3: OS


                                                              -2
                                                                01
•Center


                                                                  0
                                                                  w
•Histology (epithelioid                    Statistics


                                                                      w
                                                                      w
                                                                          .c
vs. sarcomatoid)                           Phase 2: >25/50 non-progressors at 6 mo


                                                                            ur
                                                                            em
•PS (0-1vs 2)                              to proceed to phase 3


                                                                              es
                                                                                  o.
                                           Phase 3:↑median OS 13 to 17.3 mo, 3 yr


                                                                                     or
                                                                                        g
                                           survival 14.7 to 23.6%
Zalcman, Proc ASCO 2010                    Requires 445 pts
                      www.ifitlist.com
Randomized trial of pemetrexed/cisplatin
       +/- your new drug here

        M
        es
            ot
             he
                lio
                                      Pemetrexed

                  m
                      a
                      Ap
                                      Cisplatin

                          pl
                             ie
                             d
                                  R
                                  es
                                      ea
  Randomize

                                       rc
                                           h
                                            Fo
                                      Pemetrexed

                                              un
                                                da
                                      Cisplatin

                                                  tio
                                                     n
                                                     -2
                                      Your new drug here

                                                       01
                                                         0
                                                         w
                                                             w
                                                             w
                                                                 .c
                                                                   ur
                                                                   em
 Is this the ONLY appropriate paradigm for

                                                                     es
                                                                        o.
                                                                           or
        new drug development in MM?

                                                                              g
                                   www.ifitlist.com
 Mesothelin: a target for antibody therapy


                    M
                    es
• Mesothelin:a cell surface glycoprotein expressed on


                        ot
                         he
normal mesothelial cells of pleura, pericardium and

                            lio
                               m
                                  a
peritoneum


                                   Ap
                                       pl
                                          ie
•Highly expressed in > 90% of mesotheliomas


                                          d
                                               R
                                               es
                                                   ea
                                                    rc
                                                        h
                             RR




                                                         Fo
                                                           un
                                                                      GPI




                                                             da
  Precursor protein (71 kDa)




                                                               tio
                                                                  n
                                                                  -2
                                                                    01
                                                                      GPI




                                                                      0
                                                                        w
                                                                            w
                                      Mesothelin (40 kDa)




                                                                            w
                                                                                .c
     MPF (31 kDa)




                                                                                  ur
                                                                                  em
                                                                                    es
                                                                                       o.
                                                               Membrane




                                                                                          or
             Mesothelin processing



                                                                                             g
                                                                      Hassan, Clin Cancer Res, 2004
                                                                   www.ifitlist.com
                              Marked synergy between gemcitabine plus
                              SS1P against mesothelin expressing tumor

                                                M
                                                    es
                                                     ot
                                            xenografts

                                                         he
                                                            l io
                                                               m
                        500




                                                                   a
                                                                   Ap
                        450                                                                                                                       Control




                                                                        pl
                                                                           ie
                        400                                                                                                                       SS1P




                                                                             d
                                                                                R
                                                                                                                                                  Gemcitabine
Mean tumor size (mm3)




                        350




                                                                                   es
                                                                                    ea
                                                                                                                                                  Gemcitabine + SS1P
                        300




                                                                                          rc
                                                                                            h
                        250




                                                                                               Fo
                                                                                                                                                                   60% CR




                                                                                                 un
                        200




                                                                                                   da
                        150




                                                                                                     tio
                                                                                                        n
                        100




                                                                                                               -2
                                                                                                                     60% CR




                                                                                                                 01
                        50                     60% CR 80% CR                 100% CR                     80% CR




                                                                                                                   0
                                                                                                                         w
                         0




                                                                                                                         w
                              5   7   9   11   13   15   17   19   21   23    25    27    29   31   33    35   37   39   41   43   45   47   49    51    53   55   57   59   61   63




                                                                                                                              w
                                                                                                                              .c
                                                                                                                                ur
                                                                                         Days after tum or inoculation




                                                                                                                                   em
                                                                                                                                     es
                                                                                                                                         o.
                                      Despite these data, the phase II trial

                                                                                                                                            or
                                                                                                                                               g
                                          uses a pem-cis backbone
                           www.ifitlist.com
         Anti-mesothelin therapies
             in phase I/II trials

          M
              es
               ot
                   he
    Recombinant                                         Chimeric monoclonal

                      l
                     io
                      m
                          a
  immunotoxin SS1P                                      antibody MORAb-009

                           Ap
                              pl
                                 ie
                                 d
                                      R
                                      es
                                          ea
                                            rc
                                               h
                                                 Fo
                                                   un
 VL           VH


                                                     da
                                                       tio
                      II              III


                                                          n
      -S-S-



                                                          -2
                                                            01
                                                              0
                                                              w
Anti-mesothelin               -Toxin-


                                                                  w
                                                                  w
                                                                      .c
                                                                        ur
                                                                        em
 Phase I/II trials of SS1P + pemetrexed/cisplatin


                                                                          es
                                                                             o.
    and Morab-009 + pemetrexed/cisplatin


                                                                                or
                                                                                   g
                     are ongoing
                      www.ifitlist.com
    Bortezomib for mesothelioma

        M
In preclinical models in MM, bortezomib:

         es
            ot
              he
• Induces apoptosis and cell cycle arrest

                 l
                 io
                  m
                      a
• Inhibits constitutive activation and

                      Ap
                          pl
                             ie
   nuclear translocation of NFkB

                             d
                                  R
                                  es
• Sensitizes MM cells to chemotherapy

                                      ea
                                       rc
                                           h
                                            Fo
• Has significant anti-tumor activity in


                                              un
                                                da
   mouse MM xenografts


                                                  tio
                                                     n
                                                     -2
Ongoing phase II clinical trials:


                                                       01
                                                         0
                                                         w
• Single-agent, first and second-line (ICORG/GIME)


                                                             w
                                                             w
                                                                 .c
                                                                   ur
• In combination with cisplatin (EORTC 8052)


                                                                   em
                                                                     es
                                                                        o.
                                                                           or
                                                                              g
           www.ifitlist.com
  Second-line chemotherapy in MM
                                                           #            RR              Survival


              M
               es
                  ot
  Gemcitabine/vinorelbine1                               30            10%              10.9 mo

                    he
                       l
                       io
                        m
           Imatinib2                                     17            0%               14.3 mo

                            a
                            Ap
                                pl
         Pemetrexed3                                     123           19%               8.4 mo

                                   ie
                                   d
                                        R
                                        es
   Raltitrexed/oxaliplatin4                              15            20%              10.1 mo

                                            ea
                                             rc
                                                 h
          Sorafenib5                                     39            4%               14.3 mo

                                                  Fo
                                                    un
                                                      da
          Sunitinib6                                     23            18%               8.2 mo


                                                        tio
                                                           n
                                                           -2
           Thalidomide7                                   22           6%               11 mo


                                                             01
                                                               0
                                                               w
           Vinorelbine8                                   63           16%              9.6 mo


                                                                   w
                                                                   w
                                                                       .c
                                                                         ur
             ZD04739                                      47           12%              6.7 mo


                                                                         em
                                                                           es
           Ranpirnase10                                   39           3%               7.3 mo

                                                                              o.
                                                                                 or
                                                                                    g
1. Zucali, Cancer 2008 2. Villano Proc ASCO 2004 3. Jassem, JCO 2008 4. Fizazi, JCO 2003
5. Janne, Proc IMIG 2006 6. Nowak, Proc IMIG 2008 7. Pavlakis, Proc IASLC 2003
8. Stebbing, Lung Ca 2008 9. Giaccone BJC 2002 10. Mikulski, JCO 2002
                      www.ifitlist.com

Phase I trial of SAHA (Vorinostat)

        M
         es
            ot
              he
                 l
                 io
                  m
• Inhibits class I and II HDACs

                      a
                      Ap
                          pl
• Potent inhibitor of MM in vitro

                             ie
                             d
                                  R
                                  es
• Represses the gene for TS


                                      ea
                                       rc
                                           h
Patients: 13 (10 evaluable)


                                            Fo
                                              un
Median # prior chemo tx: 1, range 0-5

                                                da
                                                  tio
                                                     n
Dose: 300 (9 pts) or 400 (2 pts) mg po bid x 3D/wk

                                                     -2
                                                       01
                                                         0
Response: 2/10 (1 unconfirmed)


                                                         w
                                                             w
                                                             w
                                                                 .c
Median TTP: 3 months


                                                                   ur
                                                                   em
All pts w/ PR/SD had ↓ dyspnea and/or pain

                                                                     es
                                                                        o.
                                                                           or
                                                   Krug, Clin Lung Ca 2006


                                                                              g
                       www.ifitlist.com
       Phase III trial of SAHA in
   previously-treated mesothelioma

         M
          es
             ot
                      Unresectable MPM


               he
                  l
                  io
                     1 or 2 prior regimens


                   m
                       a
        Stratify by: histology, PS, # prior regimens


                        Ap
                           pl
                              ie
                              d
                                   R
                                   es
                       Vorinostat

                                       ea
                                        rc
 660                   initially 300mg BID x 14 D q 21D



                                            h
                                             Fo
                       changed to 300mg BID x 3 D Q7D
 pts

                                               un
                                                 da
                                                   tio
                                                      n
                       Placebo

                                                      -2
                                                        01
                                                          0
                                                          w
10 endpoint: Overall survival


                                                              w
                                                              w
                                                                  .c
                                                                    ur
1st interim analysis: after 50 pts enrolled for futility


                                                                    em
                                                                      es
2nd interim analysis: after 220 pts enrolled for 20 endpoints


                                                                         o.
                                                                            or
                                                                               g
Correlative studies: genotyping, volumetrics, PFT,
symptom and QOL assessment
                      www.ifitlist.com
Mesothelioma

        M
represents a good

         es
            ot
              he
potential target disease

                 l
                 io
                  m
                      a
                      Ap
for gene therapy:

                          pl
                             ie
                             d
                                  R
                                  es
                                      ea
•Localized to chest cavity

                                       rc
                                           h
                                            Fo
until late

                                              un
                                                da
                                                  tio
•Easily accessible

                                                     n
                                                     -2
                                                       01
•Current therapies

                                                         0
                                                         w
                                                             w
inadequate

                                                             w
                                                                 .c
                                                                   ur
                                                                   em
•Some evidence of immune

                                                                     es
                                                                        o.
                                                                           or
responsiveness

                                                                              g
                    www.ifitlist.com
HSVtk “Suicide” Gene Therapy

      M
       es
          ot
       HSVtk                         Mammalian kinases
            he
               l
               io
                m
                    a
                    Ap
                        pl
                           ie
                           d
                                R
 GC                     GCV-                       GCV-PPP

                                es
                                    ea
                                     rc
 V                      P
                                         h
                                          Fo
                                            un
                                              da
                                                tio
 •Incorporates into growing DNA and

                                                   n
                                                   -2
                                                     01
 causes cell death.

                                                       0
                                                       w
                                                           w
                                                           w
 •Has bystander effects by intracellular

                                                               .c
                                                                 ur
                                                                 em
 transport of GCV-PPP

                                                                   es
                                                                      o.
 • ? Generates an immune response

                                                                         or
                                                                            g
 against the tumor
                      www.ifitlist.com

   Phase I trials of Ad.IFN-β
        M
         es
            ot
Single dose trial:


              he
                 l
                 io
                  m
• Intrapleural Ad.IFN-β was well-tolerated, with


                      a
                      Ap
  acceptable toxicities at the lowest dose levels

                          pl
                             ie
                             d
• Clear evidence of intrapleural transgene

                                  R
                                  es
                                      ea
  expression given elevations of soluble IFN-β on


                                       rc
                                           h
                                            Fo
  ELISA


                                              un
                                                da
• Some anecdotal clinical responses

                                                  tio
                                                     n
                                                     -2
A second trial used 2 doses of vector:


                                                       01
                                                         0
                                                         w
• Gene transfer was much lower after 2nd dose


                                                             w
                                                             w
                                                                 .c
                                                                   ur
• Anti-tumor antibodies were induced


                                                                   em
                                                                     es
• 4 pts had responses- best responses with low

                                                                        o.
                                                                           or
                                                                              g
  tumor burdens
                                          www.ifitlist.com

The effect of Ad.IFN-b Is enhanced by

                     M
                      es
  combining it with chemotherapy
                          ot
                              he
                                 lio
                                    m
                                        a
                                              Ap
                                               pl
                                                  ie
7.112 : A B 12 A d .IF N - b et a - - > C is/ Gem
                                                                                                              Experiment 2- AB12- Day 23




                                                     d
                                                        R
                                                           es
  1600                                                                                       1400




                                                               ea
  1400




                                                                rc
                                                                                             1200




                                                                       h
  1200




                                                                T u m or S iz e Cu bic m m
                                                                                             Fo
  1000
                                                                                             1000




                                                                                               un
   800




                                                                                                 da
   600                                                                                        800




                                                                                                   tio
   400
                                                                                              600




                                                                                                      n
   200




                                                                                                          -2
     0                                                                                        400




                                                                                                            01
          Contr ol    Ci s/ Gem   mu.Ad.IFN-   mu.Ad.IN-beta




                                                                                                              0
                                   beta -->                                                   200




                                                                                                              w
                                   Ci s/ Gem




                                                                                                                  w
                                                                                                0




                                                                                                                   w
                          D A Y 31




                                                                                                                      .c
                                                                                                    ctl       alimta/cis     IFNbeta       Combo -2   combo+2




                                                                                                                        ur
                                                                                                                           em
                                                                                                                             es
                                                                                                                               o.
                                                                                                                                  or
    Phase I trials are in development to combine Ad.IFN-B


                                                                                                                                     g
               with one or both of these regimens
                     www.ifitlist.com
    A New Approach for MM:

       M
        es
       Blockade of TGF−β
           ot
             he
                l
                io
                 m
                     a
•TGF-β is a cytokine (growth

                     Ap
                         pl
factor) released by tumors

                            ie
                            d
                                                                   2500




                                 R
and white blood cells within

                                 es
                                     ea
                                                                   2000




                                      rc
tumors


                                          h
                                           Fo
                                                                   1500




                                                        p g /m l
•TGF-β helps tumors grow,

                                             un
                                               da
                                                                   1000
primarily by paralyzing the

                                                 tio
                                                    n
                                                                   500




                                                    -2
body’s own immune reaction


                                                      01
                                                        0
                                                                     0
against the tumor


                                                                   w
                                                                              Mesothelioma    Breast Cancer   NSCLC




                                                                     w
                                                                          w
•(TGF-b) is made in much

                                                                          .c
                                                                            ur
                                                                                 em
larger amounts by MM than


                                                                                   es
                                                                                         o.
other tumors


                                                                                            or
                                                                                               g
                                         www.ifitlist.com
Anti TGF-β antibody markedly inhibits the

                      M
 growth of mouse mesothelioma tumors
                           es
                               ot
                                he
                                   lio
                                     m
                                             Effect of Anti-TGF B on Ab 12 tumor




                                         a
                                         Ap
                                             pl
                                                ie
                    1600




                                                d
                                                     R
                                                     es
                    1400




                                                         ea
                                                          rc
                    1200




                                                              h
                                                               Fo
     Volume (mm3)




                                                                 un
                    1000




                                                                   da
                                                                                                        Control




                                                                     tio
                    800




                                                                        n
                                                                                                        TGF-ab




                                                                         -2
                    600




                                                                           01
                                                                             0
                                                                              w
                    400




                                                                                 w
                                                                                  w
                                                                                      .c
                                                                                        ur
                    200




                                                                                        em
                                                                                          es
                      0




                                                                                              o.
                           0         5        10         15       20     25      30      35       40




                                                                                                 or
                                                                                                    g
                                                                  days
                     www.ifitlist.com

   Phase II trial of GC1008, an
       M
       es
   antibody that blocks TGF−β
           ot
            he
               lio
                 m
                     a
• A clinical trial of GC1008, a
                     Ap
                         pl
                            ie
  monoclonal antibody that blocks
                            d
                                 R
                                 es
                                     ea
  TGF-β (U Penn and U Chicago)

                                      rc
                                          h
                                           Fo
• This trial is open to patients who

                                             un
                                               da
                                                 tio
  have failed 1 or 2 other treatments

                                                    n
                                                    -2
                                                      01
  for their mesothelioma

                                                        0
                                                        w
                                                            w
                                                            w
• This trial is partly funded by a

                                                                .c
                                                                  ur
                                                                  em
  charitable foundation

                                                                    es
                                                                       o.
                                                                          or
                                                                             g
                        www.ifitlist.com

 WT-1 Heteroclitic Peptide Vaccine

          M
           es
              ot
                he
• WT-1 gene is involved in tissue development, cell

                   l
                   io
                    m
  proliferation and differentiation, and apoptosis

                        a
                        Ap
                            pl
• Over-expressed in mesothelioma

                               ie
                               d
                                    R
• 10 MM pts who have received 0-1 prior regimens and

                                    es
                                        ea
                                         rc
  are WT-1 + will be enrolled


                                             h
                                              Fo
                                                un
Dose/schedule:


                                                  da
                                                    tio
• Four WT-1 peptides in given weeks 1, 4, 6, 8, 10, 12.

                                                       n
                                                       -2
                                                         01
  Pts with immune response and no disease


                                                           0
                                                           w
  progression can get maintenance vaccinations

                                                               w
                                                               w
                                                                   .c
  monthly after that

                                                                     ur
                                                                     em
                                                                       es
Correlative studies: DTH, ELISPOT, T-cell proliferation


                                                                          o.
                                                                             or
                                                                                g
  assays, and PCR for WT-1 levels
                      www.ifitlist.com
   Where do we go from here with
    systemic therapy for MM?

        M
         es
            ot
• Better drugs


              he
                 l
                 io
   – More preclinical investigation


                  m
                      a
   – Learn to use the drugs we have: maintenance, special


                      Ap
                          pl
     populations, multimodality


                             ie
                             d
• Better choices

                                  R
                                  es
                                      ea
   – More selectivity regarding the ‘promising’ drugs we


                                       rc
                                           h
     choose to move from the bench to the clinic


                                            Fo
                                              un
   – Fewer ‘me too’ trials (why 10+ trials of VEGF inhibitors?)



                                                da
• Better designed trials

                                                  tio
                                                     n
                                                     -2
   – Otherwise we may miss an active agent, or conclude



                                                       01
     erroneously that an inactive regimen merits further


                                                         0
                                                         w
     study


                                                             w
                                                             w
                                                                 .c
   – Appropriately powered, multi-center trials, preferably


                                                                   ur
     with randomized phase II screening designs to balance


                                                                   em
                                                                     es
     heterogeneity


                                                                        o.
                                                                           or
   – Appropriate endpoints: response, PFS, OS, QOL,


                                                                              g
     correlative studies built in
                     www.ifitlist.com
Hope for the future: how can we make
   progress against this disease?

       M
        es
           ot
             he
Understanding the biology of MM


                l
                io
                 m
• More funding for basic science research

                     a
                     Ap
                         pl
Early detection


                            ie
                            d
                                 R
• Learning how to use the new biomarkers and


                                 es
                                     ea
  developing new ones


                                      rc
                                          h
Staging

                                           Fo
                                             un
• Revising how we classify tumors

                                               da
                                                 tio
                                                    n
Surgery


                                                    -2
                                                      01
• Integrating chemo and radiation


                                                        0
                                                        w
                                                            w
Chemotherapy


                                                            w
                                                                .c
                                                                  ur
• Better drugs, defining key questions, novel


                                                                  em
  approaches

                                                                    es
                                                                       o.
                                                                          or
• Commitment from pharmaceutical companies


                                                                             g
                       www.ifitlist.com
          The University of Chicago
           Mesothelioma Program
         M
          es
             ot
               he
 Medical Oncology          Imaging                                 Translational Lab


                  l
                  io
                   m
                       a
   Hedy Kindler        Samuel Armato                                   Ravi Salgia


                       Ap
                           pl
    Ravi Salgia       Heber MacMahon                                 Rajani Kanteti


                              ie
                              d
                                                                    S. Loganathan


                                   R
 Michael Maitland    William Sensakovic


                                   es
                                       ea
                                                                   S. Krishnaswamy


                                        rc
  Victoria Villaflor    Adam Starkey


                                            h
                                                                    Osvaldo Zumba


                                             Fo
   Nick Campbell          Zac Labby


                                               un
                                                                     Rabia Hassan


                                                 da
Surgical Oncology     Pulmonary/High-


                                                   tio
                                                                      V. Natarajan


                                                      n
                                                      -2
Wickii Vigneswaran      risk asbestos                             Data Management


                                                        01
                                                          0
Radiation Oncology      Kyle Hogarth


                                                          w
                                                                      Jasmin Patel


                                                              w
                                                              w
  Joseph Salama           Pathology


                                                                  .c
                                                                     Julia Melnick


                                                                    ur
                                                                    em
      Nursing            Aliya Husain                                   Lisa Lipp


                                                                      es
                                                                         o.
 Jennifer Shouldis     Thomas Krausz                                    Statistics


                                                                            or
                                                                               g
   Sylvia Watson                                                  Theodore Karrison

				
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