Targeted therapy in relapsed Hodgkins Disease by olliegoblue25


									Targeted therapy in relapsed
    Hodgkins Disease
       Tanya Wildes, M.D.
        February 9, 2007
         Hodgkins Lymphoma
• B-cell neoplasm
  characterized by sparse
  malignant cells in an
  inflammatory background.
• Upwards of 80% of patients
  achieve long term disease
  free survival.
• Trends in therapy are
  tending toward minimizing
  long term toxicities of initial
Hodgkins Lymphoma:

     J Clin Oncol 20:221-230
         Hodgkins Lymphoma:
• Prognosis
  – Depends upon duration of initial remission,
    stage at relapse and anemia at relapse
• Autologous stem cell transplant
  – 3 year EFS/FFTF is 40-75%
• Allogeneic stem cell transplant
  – Reduced intensity conditioning
     • 50% 5 year OS

               ASH Annual Meeting Abstracts 2005;106:657
Current Opinion in Investigational Drugs 2004 5(12):1262-1267
             Targets for therapy
• Ferritin
   – Synthesized and secreted by Hodgkins tumor
   – Present in the interstitium, not on the cell surface
• CD20
   – Classical HD cells are rarely CD20+
   – Malignant cells in lymphocyte predominant Hodgkin
     Disease (LPHD) all express CD20
• CD25
   – Alpha chain of the IL-2 receptor
   – Within normal tissues, the IL-2 receptor is expressed
     only on activated lymphocytes
   – CD 25 is present on nearly all H-RS cells
           Targets for therapy
• CD30
  – An integral membrane glycoprotein
  – Member of the TNF-receptor superfamily
  – In normal tissues, CD30 is restricted to activated B, T
    cells and NK cells
  – In HD cells, the CD30 ligand CD153 induces signaling
    via TNF receptor associated factors 2 and 6 (TRAF -2
    and -6) with subsequent NF-kB activation
• CD40
  – Member of the TNF receptor family
  – Present on a number of lineages in the hematopoietic
  – Expressed by a number of hematologic malignancies,
    including NHL, MM, B cell ALL and HD
•   131I-labelled   antiferritin antibody
    – Phase II trial N=37 patient with relapsed HD
    – Dosing
        • Day 0: patients received 30 mCi 131I-antiferritin
        • Day 5: 20mCi 131I-antiferritin
    – Responses
        • Overall response rate was 40%, with 1 CR and 14 PR.
        • Of the 23 patients who underwent a second cycle of therapy, only 2
          had improvement in response
    – Toxicities
        • Predominantly hematologic: leukopenia and thrombocytopenia
        • Cytopenias were of long duration and delayed the second planned
          cycle of therapy
        • No toxic deaths

                               J Clin Oncol 1985;3:1296-1300
• Yttrium-90 antiferritin
   – 90Y has advantages of higher and more uniform dose distribution
   – Protocol:
       • Patients received 111In-labelled polyclonal antiferritin for dosimetric
         calculations followed by 20-50mCi 90Y -labelled polyclonal
         antiferritin one week later
       • 19 patients received autologous bone marrow support on day 18
       • 16 were treated without bone marrow support and received the
         lower dose
   – Toxicities:
       • All patients experienced hematologic toxicity
       • 3 patients died after prolonged bone marrow aplasia
       • Autologous bone marrow infusion did not shorten the duration of
         cytopenias (median 70 days “cycle length”)

                               J Clin Oncol 1991;9:918-928
• Yttrium-90 antiferritin
   – Response:
       • 29 patients were evaluable for response; ORR was 62% with 9 CR
         and 9 PR
       • The median survival was significantly longer in responders than in
         nonresponders (177 days versus 87 days)
       • The median duration of response was 6 months
       • Responders tended to have lower serum ferritin levels, smaller
         tumors and a longer disease history than nonresponders
   – Update:
       • After additional accrual with 39 patients, ORR was 51% with 10 CR
         and 10 PR
       • Among responding patients, relapses occurred at previous bulky
         disease sites in about two-thirds of cases or at new foci in about
         one-third of cases

                              J Clin Oncol 1991;9:918-928
                            J Clin Oncol 1995;13:2394-2400
•     –Ki-4: A radioimmunoconstruct targeting the cell

  surface marker CD30 labeled with I-131
• Patients
     – 22 patients with relapsed, refractory, documented CD30+ HD
• Toxicity:
     – Hematologic toxicity was significant and prolonged, with 33%
       grade IV hematologic toxicity and a median time to nadir of 5
• Response:
     – The overall response rate was 27%, with 1 CR lasting 5 months
       and 5 PR (median duration of response 4 months)

                          J Clin Oncol 2005;23:4669-4678
Haematologica 2005; 90:1680-1692
Current Opinion in Investigational Drugs 2004 5(12):1262-1267
           Rituximab in LPHD:
 German Hodgkin Lymphoma Study Group
• 14 patients, including 10 with LPHD, 2 with
  transformed HD and 1 with CD20+
  classical HD enrolled
  – Rituximab 375 mg/m2 weekly for 4 weeks
  – Response
     • ORR 86%, with 8 CR and 4PR
     • Median duration of response had not yet been
       reached at >20months of follow-up

                      Blood 2003;101:420-424
               Rituximab in LPHD:
              Another Phase II Trial
• 22 patients with LPHD
    – 10 had recurrent disease
    – 12 were previously untreated
• Response
    – ORR was 100%; 9 patients (41%) with CR, 1 patient (5%) with CRu and
      12 patients (54%) with PR.
    – Trend toward a lower probability of CR in patients with larger lymph
      nodes, disease on both sides of the diaphragm and more than 2
      involved nodal regions.
• Duration of Response
    – Responses were shorter-lived than in the German study
    – The nine patients who relapsed did so a median of 9 months from
      initiation of therapy
• Repeat treatment with rituximab in 3 of the relapsed patients
  resulted in one CR and two with stable disease

                             Blood 2003;101:4285-4289
• Anti CD-30 chimeric monoclonal antibody
• Activity
  – In vitro, SGN-30 induces arrest of growth and
    increases the proportion of apoptotic cells
• Synergy in HD cell line
  – Combinations of SGN-30 with chemotherapeutic
    agents active in HD (including doxorubicin,
    bleomycin, vinblastine, dacarbazine, ifosfamide,
    carboplatin and etoposide) resulted in at least additive
    cytotoxicity, and synergy in some combinations

                      Cancer Res 2002;62:3736-3742
                 ASH Annual Meeting Abstracts 2004;104:2639
                        Leukemia 2005;19:1648-55
• Phase 1 single-dose study
  – Patients
     • 13 patients with CD30+ malignancies
     • 9 had relapsed HD
  – Dosing
     • The first 6 patients received a single dose of 1, 2, 4, 7.5, 10
       and 15 mg/kg
     • The next 7 patients were treated with 12.5 mg/kg
  – Responses
     • One HD patient experienced a PR
     • One ALCL patient with PR

                  ASH Annual Meeting Abstracts 2002:1403a [Abstract]
• Multi-dose Phase I dose escalation study
  – Patients
     • 24 patients were enrolled
     • 21 patients with HD
  – Dosing
     • Cohorts of six patients received 6 weekly infusions of SGN-
       30 at doses of 2, 4, 8 and 12mg/kg
  – Toxicities
     • nausea, fever, anorexia, myalgias, headache and pruritis
       occurred in less than 15% of patients
  – Responses
     • Four of the 21 HD patients had stable disease, but no
       objective responses were seen.

                 ASH Annual Meeting Abstracts 2003;102:Abstract 2390
• Phase II study
  – 15 patients with relapsed HD enrolled
  – Subjects received SGN-30 6mg/kg IV weekly for 6
  – Of the initial 12 patients evaluable for response, 6 had
    stabilization of disease for a mean duration of 4.8
  – In the 12mg/kg cohort, 7 patients had been enrolled
    with no grade 3/4 toxicities
     • The one patient in this cohort evaluable for response had
       progressive disease

                   ASH Annual Meeting Abstracts 2004;104:2635
               ASCO Annual Meeting Proceedings 2005;23:2553[Abstract]
• Anti-CD30 antibody
   – binds to a different epitope than does SGN-30
• Mouse HD model
   – MDX-060 resulted in regression of established localized tumor
• Potential synergy
   – Combinations of MDX-060 with fludarabine, gemcitabine, etoposide,
     maphosphamide (the active cyclophosphamide metabolite), and
     dexamethasone resulted in additive or even superadditive increases in
     apoptosis in some CD30+ HD cell lines
   – Treatment of several CD30+ HD cell lines with MDX-060 followed by
     bortezomib resulted in increased cell death, even in HD cell lines that
     had previously been resistant to MDX-060
   – This synergy was also seen in a mouse model of HD where the
     combination of MDX-060 and bortezomib resulted in nearly complete
     inhibition of tumor growth

                                Blood 2003;102:3737-3742
                              J Immunother 2004;27:347-53
                                Blood 2005;106:1839-1842
• Phase I study
   – 21 patients with CD30+ hematologic malignancies (16 with HD) were
     treated with MDX-060 for 4 weeks at dose levels of 0.1, 1, 5, or 10
   – Well tolerated with no significant infusional reactions, no opportunistic
     infections and no maximum tolerated dose identified
   – There was one episode of grade 3 transaminitis
• Phase II
   – 27 patients were treated with MDX-060 10mg/kg or 15 mg/kg IV weekly
     for 4 weeks
   – One patient in the phase II cohort developed grade 3/4 pulmonary
     toxicity (pneumonia/ARDS); otherwise the drug was extremely well
• Responses
   – Responses were evaluated with the combined phase I and II cohorts
   – Among the 40 HD patients, 1 CR and 2 PR

                      ASH Annual Meeting Abstracts 2003;102:Abstract 632
                      ASH Annual Meeting Abstracts 2004;104:Abstract 2636
• Hypothesis:
  – The limited clinical success of these unmodified
    antibodies may be related to the inability of the naked
    antibodies to recruit host effector functions
  – This lead to the engineering of naked antibodies to
    enhance host effector function
• XmAb2513
  – a humanized anti-CD30 antibody (hAC10) with its Fc
    region modified for enhanced cytotoxicity
  – In CD30+ HD cell lines in the presence of PBMCs,
    XmAb2513 was more potent and more efficacious
    than the chimeric anti-CD30 antibody cAC10 and
                ASH Annual Meeting Abstracts 2005;106:1470
• Humanized anti-CD40 monoclonal antibody
• In NHL cell lines, inhibits proliferation, induces antibody-dependent
  cellular cytotoxicity and apoptosis
• HD in vitro study
    – 85% of HD tumors expressed CD40+ on the Hodgkin-Reed Sternberg
      cells and on the surrounding mononuclear cells
    – 8/9 tumors evaluated by flow cytometry were positive for CD40
    – SGN-40 induced dose-dependent lysis via antibody-dependent cellular
      cytotoxicity and mediated anti-proliferative signaling
• Clinical Trials
    – Phase I trials of SGN-40 in MM or NHL are currently underway
        • Preliminary results in NHL are encouraging
        • Well tolerated
        • 3 objective responses have been observed
    – Clinical trials in relapsed HD not yet underway

                            ASH Annual Meeting Abstracts 2005;106:1476
                        2006 ASCO Annual Meeting Proceedings 2006;24:7534
Current Opinion in Investigational Drugs 2004 5(12):1262-1267
• SGN-35
   – a synthetic anti-mitotic agent monomethyl auristatin E (MMAE)
     conjugated to the anti-CD30 antibody murine:human chimeric
     antibody cAC10
• In vitro, SGN-35 is translocated into lysosomes where
  MMAE is liberated from the antibody and accumulates
  within the cell.
   – SGN-35 potently inhibits cell viability in CD30+ cell lines
• In a HD mouse model, SGN-35 induced complete tumor
  regression, and was well tolerated
• Phase I studies are currently underway for CD30+
  hematologic malignancies

                     ASH Annual Meeting Abstracts 2005;106:610
• CD30+ HD cell lines
   – bortezomib exhibited antiproliferative effects, induced
     cell cycle arrest and caused apoptosis
• Clinical trial: pilot study
   – single-agent bortezomib in 14 heavily pretreated
     patients with relapsed HD
   – Dosing: 1.3 mg/m2 IV on days 1, 4, 8, 11 every 21
   – Toxicities
      • one event of neutropenic fever and one of dyspnea
      • Thrombocytopenia was the major hematologic toxicity
   – Responses
      • 1 PR and 2 minor responses
                         Clin Cancer Res 2004;10:3207-15
                    ASH Annual Meeting Abstracts 2004;104:2638
                            Blood 2006;107:1731a-1732
• Hodgkins Disease has a poor prognosis
  with limited therapeutic options when
  relapsed after transplant
• New targeted therapies hold promise for
  relapsed disease
Haematologica 2005; 90:1680-1692

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