Targeted therapy in relapsed Hodgkins Disease

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Targeted therapy in relapsed Hodgkins Disease

• Tanya Wildes, M.D.
• February 9, 2007

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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 therapy.

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Hodgkins LymphomaRelapse
J Clin Oncol 20221-230
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Hodgkins LymphomaRelapse

• 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 2005106657
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Current Opinion in Investigational Drugs 2004
5(12)1262-1267
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Targets for therapy

• Ferritin
• Synthesized and secreted by Hodgkins tumor
  infiltrates
• 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

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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 system
• Expressed by a number of hematologic
  malignancies, including NHL, MM, B cell ALL and
  HD

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RadioimmunotherapyAntiferritin

• 131I-labelled antiferritin antibody
• Phase II trial N37 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 198531296-1300
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RadioimmunotherapyAntiferritin

• 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 19919918-928
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RadioimmunotherapyAntiferritin

• 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 19919918-928 J Clin Oncol
1995132394-2400
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RadioimmunotherapyAnti-CD30

• 131I 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 weeks
• 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 2005234669-4678
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Haematologica 2005 901680-1692
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Current Opinion in Investigational Drugs 2004
5(12)1262-1267
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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 gt20months of follow-up

Blood 2003101420-424
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Rituximab in LPHDAnother 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 20031014285-4289
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SGN30

• 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 2002623736-3742 ASH Annual Meeting
Abstracts 20041042639 Leukemia 2005191648-55
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SGN-30

• 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 20021403a Abstract
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SGN-30

• 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 2003102Abstract
2390
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SGN-30

• Phase II study
• 15 patients with relapsed HD enrolled
• Subjects received SGN-30 6mg/kg IV weekly for 6
  weeks.
• Of the initial 12 patients evaluable for
  response, 6 had stabilization of disease for a
  mean duration of 4.8 months
• 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 20041042635 ASCO
Annual Meeting Proceedings 2005232553Abstract
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MDX-060

• 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 20031023737-3742 J Immunother
200427347-53 Blood 20051061839-1842
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MDX-060

• 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 mg/kg
• 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 tolerated
• 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 2003102Abstract
632 ASH Annual Meeting Abstracts
2004104Abstract 2636
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XmAb2513

• 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
  MDX-060

ASH Annual Meeting Abstracts 20051061470
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SGN40

• 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 20051061476 2006
ASCO Annual Meeting Proceedings 2006247534
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Current Opinion in Investigational Drugs 2004
5(12)1262-1267
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ImmunoconjugatesSGN-35

• SGN-35
• a synthetic anti-mitotic agent monomethyl
  auristatin E (MMAE) conjugated to the anti-CD30
  antibody murinehuman 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 2005106610
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Bortezomib

• 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 days
• 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 2004103207-15 ASH Annual
Meeting Abstracts 20041042638 Blood
20061071731a-1732
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Conclusions

• Hodgkins Disease has a poor prognosis with
  limited therapeutic options when relapsed after
  transplant
• New targeted therapies hold promise for relapsed
  disease

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Haematologica 2005 901680-1692