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CAMPATH ® (alemtuzumab): Status of Phase IV Post-marketing Commitments. Oncology Drugs Advisory Committee 8 Nov 2005 Cynthia Sirard, MD. Genzyme Participants. Susan Beardslee Principal Medical Writer, Scientific Reporting Stephen Eckert, Ph.D. Senior Director, Biostatistics

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campath alemtuzumab status of phase iv post marketing commitments

CAMPATH® (alemtuzumab): Status of Phase IV Post-marketing Commitments

Oncology Drugs Advisory Committee

8 Nov 2005

Cynthia Sirard, MD

genzyme participants
Genzyme Participants
  • Susan Beardslee Principal Medical Writer, Scientific Reporting
  • Stephen Eckert, Ph.D. Senior Director, Biostatistics
  • Mark Goldberg, M.D. Senior Vice President, Clinical Research
  • Mark Hayes, Ph.D. Vice President, Regulatory Affairs
  • Jeanne Jones, RN, MSN Director, Clinical Research
  • Tracie Reed Senior Associate, Regulatory Affairs
  • Cynthia Sirard, M.D. Medical Director, Clinical Research

ODAC CAMPATH Update

agenda
Agenda
  • Overview of treatment options for CLL
  • CAMPATH®: Review of data supporting approval
  • Review and status of post-approval commitments: CAM307
  • Resolving challenges in meeting post-approval commitments

ODAC CAMPATH Update

chronic lymphocytic leukemia cll
Chronic Lymphocytic Leukemia (CLL)
  • Most common form of adult leukemia in U.S.
    • Incidence: ~ 9,730 patients/year
    • Prevalence: ~ 60,000 patients
  • Progressive and often fatal disease
    • Deaths: ~4,600/year
  • No current therapy is curative
  • No therapy has demonstrated prolonged survival

ODAC CAMPATH Update

what is cll and how is it treated
What is CLL and How is it Treated?

Disease Characteristics

1st line therapy

9,730 Incidence

Evolving standards of care:

  • Alkylator-based
  • Fludarabine
  • Rituximab
  • Combination
  • Chronic disease
  • Variable clinical course
  • Often asymptomatic at dx (no treatment required)
  • Requires multiple sequential treatments
  • Treatment goal
    • Palliative
    • Curative?
    • MRD

No response

Relapsed/ refractory

therapy

60,000 Prevalence

  • Re-tx with 1st line agents
  • Fludarabine
  • Rituximab
  • CAMPATH
  • 2nd line cytotoxic
  • PBSCT/ BMT
  • Clinical trials

Response

Remission

Relapse/

progression

ODAC CAMPATH Update

campath 1h alemtuzumab
CAMPATH-1H (alemtuzumab)
  • Humanized monoclonal antibody directed against CD52 antigen
    • Expressed on B & T lymphocytes, NK cells, DCs, Mono/Mac, plasma cells, Thymocytes
    • Not expressed on bone marrow progenitor cells

Carbohydrate

Human IgG1 construct

Murine CDR’s

ODAC CAMPATH Update

mechanism of action
Complement

CAMPATH

Leukemia

Cell

CD52

FC

Receptor

Effector cell

Mechanism of action
  • Lyses lymphocytes via
    • Complement fixation
    • Antibody dependent cell mediated cytotoxicity
    • Induction of apoptosis
  • Different mechanism of action from available cytotoxic chemotherapeutic agents

ODAC CAMPATH Update

pivotal and supportive studies for approval safety
Pivotal and Supportive Studies for ApprovalSafety
  • Most common adverse events are acute infusion-related events that decline with subsequent infusions
  • Variety of opportunistic infections reported; anti-infective prophylaxis is recommended on initiation of therapy
  • Hematologic toxicity which can be severe emerges on treatment in some patients, but is usually transient
  • Reasonable and manageable safety profile in this immunocompromised, refractory disease population

ODAC CAMPATH Update

accelerated approval granted 7 may 2001
Accelerated Approval Granted 7 May 2001
  • Indication
    • CAMPATHis indicated for the treatment of B-cell chronic lymphocytic leukemia (CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy
  • Nine post-approval commitments
    • Five completed
    • Four are ongoing
      • Three will be completed in Q1 2006 at the conclusion of randomized phase III study (CAM307) initiated in 2001
      • Final commitment to be completed in a study being initiated in 2005 (CAM203)

ODAC CAMPATH Update

cam307 overview
CAM307Overview
  • Title
    • A Phase III Study to Evaluate the Efficacy and Safety of Front-Line Therapy with CAMPATH (alemtuzumab) versus Chlorambucil in Patients with Progressive B-Cell Chronic Lymphocytic Leukemia
  • Purpose
    • Verify the clinical benefit of CAMPATH therapy
  • General design
    • Open label, multi-center, randomized, active controlled trial

ODAC CAMPATH Update

cam307 objectives
CAM307Objectives
  • Primary objective
    • To demonstrate that CAMPATH is superior to chlorambucil as front-line therapy in patients with progressive B-CLL as measured by progression free survival (PFS)
  • Secondary objectives are to compare treatment arms with respect to
    • Overall survival
    • CR and overall response rates
    • Duration of response (not statistically compared)
    • Time to treatment failure
    • Time to alternative therapy
    • Safety

ODAC CAMPATH Update

cam307 inclusion criteria
CAM307Inclusion Criteria
  • Histopathologically confirmed diagnosis of B-CLL with CD5, CD19 and CD23 positive clone
  • Rai stage I through IV disease with evidence of progression
  • No previous chemotherapy for B-CLL
  • WHO performance status of 0, 1, or 2
  • Serum creatinine ≤ 2.0 X the institutional upper limit of normal
  • Adequate liver function

ODAC CAMPATH Update

cam307 exclusion criteria
CAM307Exclusion Criteria
  • ANC < 0.5 x 109/L or platelet count < 10 x 109/L
  • Autoimmune thrombocytopenia
  • Active infection
  • Serious cardiac or pulmonary disease
  • Central nervous system involvement with CLL
  • Positive quantitative CMV by PCR assay

ODAC CAMPATH Update

cam307 treatment arms
CAM307Treatment Arms
  • Patients randomized 1:1 to receive either
    • CAMPATH
      • 30 mg/day IV
      • Dosing is 3 times per week, up to 12 total weeks, inclusive of any dose escalation period

or

    • Chlorambucil
      • 40 mg/m2 PO
      • Dosing once every 28 days for a maximum of 12 months

ODAC CAMPATH Update

cam307 accrual status
CAM307Accrual Status
  • Total Enrollment = 297 patients
    • 149 patients enrolled on CAMPATH
    • 148 patients enrolled on Chlorambucil
  • Last patient enrolled 15 Jul 2004
  • Accruing / active sites
    • 45 / 68 Total
    • 9 / 20 US sites

ODAC CAMPATH Update

cam307 patient accrual distribution
Poland

Croatia

Czech Republic

Serbia

United States

Slovakia

Netherlands

Lithuania

France

Italy

United Kingdom

Estonia

Ireland

CAM307Patient Accrual Distribution

117

47

39

28

24

12

9

8

4

3

3

2

1

ODAC CAMPATH Update

cam307 statistical design
CAM307Statistical Design
  • Randomization 1:1 by Interactive Voice Response System (IVRS)
  • Primary endpoint assumption
    • 50% improvement in PFS

(21 months vs. 14 months)

  • Sample size
    • 284 patients (142 per treatment arm)

ODAC CAMPATH Update

cam307 interim and final analyses
CAM307Interim and Final Analyses
  • April 2004
    • First interim analysis (safety only) was conducted after 50 patients per arm reached 4 months following randomization
  • August 2005
    • Second interim analysis (safety and efficacy) was completed after 95 patients progressed (or died)
  • Q2 2006 (projected)
    • Final analysis planned after a total of 190 failures (progressed/died)

ODAC CAMPATH Update

cam307 status and timelines
CAM307Status and Timelines

ODAC CAMPATH Update

cam307 difficulties encountered
CAM307Difficulties Encountered
  • Initial enrollment at U.S. sites slow, likely due to alternative first-line therapeutic options for CLL patients in U.S.
  • Enrollment increased substantially following opening of sites outside United States (particularly in eastern Europe)

ODAC CAMPATH Update

cam307 difficulties encountered25
CAM307Difficulties Encountered
  • Logistical difficulties encountered in immunological function assessment cohort. Data captured for only 4 patients in CAM307.
    • In a recent discussion with the Division of Oncology Drug Products (29 July 2005), Genzyme will fulfill this commitment in a new trial CAM203

ODAC CAMPATH Update

cam203
CAM203

A Phase II, open-label, prospective, multi-center study to evaluate the efficacy and safety of subcutaneously administered CAMPATH as therapy for patients with relapsed or refractory B-CLL who have previously received treatment with an alkylating agent and failed fludarabine

ODAC CAMPATH Update

summary
Summary
  • CAMPATH has emerged as an important treatment option for CLL
  • Post-marketing commitments will be fully met following completion of CAM307 and CAM203 trials
  • These trials will further provide support for CAMPATH use in first line CLL (CAM307) and for the subcutaneous route of administration (CAM203)

ODAC CAMPATH Update

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