Clinical Trials for Pancreatic Cancer by krs20830

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									        Clinical Trials for
   Pancreatic Cancer

         Vincent J Picozzi MD MMM

        Virginia Mason Medical Center
                  Seattle WA




         Dr. Picozzi Schedule
                   June 1 2005
840A          6055339    Pan        CDDP/5FU/IFN
900A          6086310    Pan        CDDP/5FU/IFN
920A          0639538    Bre        F/U
940A          6085141    Pan        CDDP/5FU/IFN
1000A         0409252    Col        FOLFOX
1020A         4659055    Pan        F/U
1040A         0719890    Pan        Gem/Ox
1100A         1820797    CLL        F/U
1120A         6029083    Pan        Gem/Tax
1121A         2813430    Pan        Gem/Tax
1140A         0798636    MDS        F/U
1200P         3837035    Bla        F/u-restage
1220P         1378648    Mel        F/U
1240P         6026589    Pan        F/U-restage
0100P         6069597    Pan        Gem
0120P         1048800    Cho        F/U-restage
0140P         0661971    Pan        Gem/Tax




                                                   1
     Pancreatic cancer:
   Why so difficult to treat?
1) Hard to diagnose / discovered in advanced form

2) Drugs not as effective as desired

3) Lack of sophisticated/integrated multidisciplinary
   care
4) Patients a little older, sometimes hard to use
   intensive treatments

5) PESSIMISM




                                                        2
              Pancreatic cancer:
            Optimism for the future
Late diagnosis                    Earlier diagnosis/prevention

Ineffective drugs                 Better drugs

Lack of integrated care           Integrated multidisciplinary care

Older patients / other problems   Personalized medical approach


PESSIMISM                         OPTIMISM!!!!!




         Pancreatic cancer:
        Prevention and Early
             Diagnosis




                                                                      3
       Pancreatic cancer:
Possible chemoprevention agents
  •   Smoking cessation (e.g. varenicline)
  •   ETOH abstinence
  •   oral hypoglycemics (e.g.metformin)
  •   ASA / NSAIDS
  •   atorvastatin
  •   ursodiol
  •   interferon
  •   IGF -1R inhibitors, ..etc.




         Pancreatic cancer :
       Basis of prevention and
              detection

 • Epidemiology           ( Who is at risk )

 • Imaging               ( X Ray)

 • Biomarker             ( blood or other
                         biochemical tests)
 • + AWARENESS !!!!



                                               4
Pancreatic cancer:
     Causes

         10%


                     Genetic

               30%   Environmental
   60%
                     Unknown




 Pancreatic cancer:
 Genetic syndromes




                                     5
        Pancreatic cancer and
           Family history




   Pancreatic cancer and Age

•Median age 64


•< 1% under age 40


•2-3 X rise with each decade of life until age 80


•>75% of cases in patients between 60- and 80 years old




                                                          6
     Pancreatic cancer:
Important environmental risks

      • Cigarette smoking

      • Diabetes Mellitus

      • Pancreatitis

      • Abdominal surgery




                                7
  Pancreas cancer prevention:
         CAPS 3 Trial
• Epidemiology- Peutz Jegher, BRCA2,
                FAMM/p16, (+)FHx

• Imaging-     EUS, High resolution CT,MRI



• Biomarker-   secretin induction pancreatic
               juice ( CA 19.9, DNA
               hypermethylation, MIC-1,k-ras)




                                                8
    Pancreatic cancer:
     Early diagnosis

Any combination of the cardinal symptoms….

         1) ABDOMINAL PAIN
         2) WEIGHT LOSS
         3) JAUNDICE, plus……

         4) NEW ONSET DIABETES or
         5) PANCREATITS……

 THINK PANCREATIC CANCER!!!!!




Pancreatic cancer:
  Better drugs




                                             9
    Localized pancreatic cancer
is a systemic disease,

   thus it is not if systemic
therapy should be given….

                      ...but how




   What is better than
   gemcitabine? ? ? ?




                                   10
        Pancreas Cancer:
      Types of clinical trials
• Phase I         Safety

• Phase II        Effect ( does it work ?)

• Phase III       Efficacy ( is it better ?)

• Phase IV        Effectiveness ( does it
                  work in a community
                  practice ?)




                                               11
              Pancreas cancer
                New drugs
           Over 190 in clinical trial!!!
•   Anti IGF-1R inhibitor      •   Nimotuzumab
•   Bevacizumab                •   Opioid growth factor
•   Curcumin                   •   PX-12
•   Dalteparin                 •   QS21
•   Enzastaurin                •   Ras peptide cancer vaccine
•   F                          •   S-1
•   GVAX vaccine               •   TNFerade
•   HDAC inhibitor MG-CD0103   •   U
•   Ixabepilone                •   Volociximab
•   J                          •   W
•   K                          •   X
•   Lapatinib                  •   Yttrium 90 DOTA MoAbHuPAM4
•   MUC-1 antigen              •   Z-360




                                                                12
   Pancreatic cancer:
   Types of new drugs
• Chemotherapy
• Targeted Therapy
• Endotherapy
• Immunotherapy
• Stem cell therapy
• soon…………….Personalized therapy




                                   13
Randomized phase III trial

                                         Gemcitabine +
                                         abraxane


Metastatic pancreatic cancer
                                         Gemcitabine




      Pancreatic cancer:
Key molecular signaling pathways
           (Jones et.al. Science 2008)

           •   EGFR / k-RAS
           •   TGF-β / SMAD4
           •   JNK
           •   Integrin
           •   Hedgehog
           •   WNT/Notch
           •   G1/S phase transition
           •   apoptosis
           •   DNA damage control
           •   small GTP-ase signaling
           •   Invasion
           •   Homophilic cell adhesion




                                                         14
Randomized phase III trial

                               Gemcitabine +
                               placebo


Metastatic pancreatic cancer   Gemcitabine +
                               AMG 479


                               Gemcitabine +
                               AMG 655




                                               15
Endotherapeutic phase III trial


                XRT / 5FU +
            2                 Gemcitabine
                TNFerade
Randomize
            1
                XRT / 5FU     Gemcitabine




                                            16
    GlobeImmune randomized
          phase II trial

                             Gemcitabine +
                             GI 4000

Resected pancreatic cancer


                             Gemcitabine




                                             17
                p-
        K-ras, p-53 mutant
 mouse model of pancreas cancer
(Hingorani , et.al Cancer Cell 2004)




                                       18
                Pancreas Cancer:
                 Integrated Care




                               ACOSOG Z05031
                                Study schema

    Z 05031
                                         I                   C Y C LE 1
                                         N              C on ve ntion ally
                                         F     R           fractio na ted
                                         O     E          radiothe ra py,
                                         R     G   C I 5 -F U , C is pla tin , a nd
                                         M     I          IN F -a lph a-2b            F
     P atien ts w ith                    E     S                                      O
        re sec te d                      D     T                  +                   L
       pa nc re atic                           R                                      L
   ad en oc arcin om a                   C     A            C Y C LE 2                O
                                         O     T             C I 5-FU                 W
                                         N     I
                                         S     O                  +
                                         E     N
                                         N                  C Y C LE 3
                                         T *                 C I 5-FU

*In clud ing H IP A A A uth oriza tion




                                                                                          19
                  XRT

                  IFN

CDDP                                   5-FU




          Radiation field design
          Standard vs. ACOSOG

 CTV                    PTV



                              ACOSOG     STD
       ACOSOG   STD




                                               20
         ACOSOG Z05031
   Survival results compared to
            major trials
          Median      2-Yr OS 5-Yr OS
GITSG     21 mo       43%      19%
EORTC     17.1 mo     37%      20%
ESPAC-1   20.1 mo     39%      21%
RTOG 9704 20.6 mo     41%       --
CONKO-001 22.8 mo     48%      21%
ACOSOG    27.1 mo     58%       --




                ACOSOG Z05041




Gemcitabine                       Gemcitabine
+ erlotinib x       Surgery       + erlotinib x
2 cycles                          2 cycles




                                                  21
       VMMC staging laparoscopy results:
          localized pancreas cancer
                 60
                                    53%
                 50

                 40                           34% Overall
    % positive




                          28%
                 30
                                                Liver +
                 20                             Cytology +
                                                Peritoneum +
                 10                             Total + findings

                 0
                      Head N=57 Body/Tail
                                  N=17




                         Pancreas cancer:
                      “downstaging” borderline
                         resectable disease
                         VM phase II trial

Laparoscopic                      Drug therapy
staging                       Gemcitabine / Docetaxel       Follow-
                                                            Follow-up




                                                        Novel
                 Surgery                                CRT




                                                                        22
Personalized Therapy for
    Pancreas Cancer


   Molecular profiling?

       Biomarkers?

 In vitro/vivo drug testing?




                               23
           Pancreas cancer:
Dr.James trends
MajorFarrell UCLA in gastroenterology




                    Dr.James Farrell UCLA




                                            24
                Phase III trial

                               Gemcitabine +RP101


Metastatic pancreatic cancer


                               Gemcitabine




                                                    25
    Pancreas cancer:
  The future of treatment
                Endodiagnostic
                  (re)staging;
                    Fusion
                   Radiology

           Precancer         Cancer
           Personalized drug therapy



Advanced                               Novel
Surgery                                CRT




                                               26
              Pancreatic cancer:
            Optimism for the future
Late diagnosis                    Earlier diagnosis/prevention

Ineffective drugs                 Better drugs

Lack of integrated care           Integrated multidisciplinary care

Older patients / other problems   Personalized medical approach


PESSIMISM                         OPTIMISM!!!!!




            THANK YOU!!!!




                                                                      27

								
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