Genasense in RelapsedRefractory Chronic Lymphocytic Leukemia

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Genasense in Relapsed/Refractory Chronic
Lymphocytic Leukemia
update Footer w/ current v on handouts

• Oncologic Drug Advisory Committee
• September 6, 2006

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Genasense is a novel therapeutic agent that
augments the activity of chemotherapy by
stimulating apoptosis through downregulation of
Bcl-2
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Genasense Drug Substance(Oblimersen Sodium,
G3139)

• Phosphorothioate backbone

• Selectively targets Bcl-2 RNA
• Decreases Bcl-2 protein

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Genasense Indication

• Genasense in combination with Fludarabine and
  Cyclophosphamide is indicated for the treatment
  of patients with relapsed/refractory CLL

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Agenda
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Expert Advisors
Clinical Michael Keating, MB BS Professor of
Medicine Leukemia, MDACC Susan OBrien,
MD Professor of Medicine Leukemia, MDACC Kanti
Rai, MB BS Chief, Division of Hematology/Oncology,
LIJMC Clinical Pharmacology Anthony Tolcher,
MD Director, Clinical Research Cancer Therapy
Research Center Histopathology John Bennett,
MD Prof. of Pathology and Laboratory Medicine,
URCC Cell/Molecular Biology John Reed, MD,
PhD President Chief Executive Officer The
Burnham Institute Biostatistics Richard Kay,
PhD Honorary Lecturer Biostatistics
University
of Cardiff Gary Koch, PhD Professor of
Biostatistics, UNC, Chapel Hill Drug
Administration Margaret Green, RN, OCN Research
Nurse Associate Leukemia Program University of
Chicago MC
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Criteria for Accelerated Approval

• Substantial evidence from well-controlled
  clinical trials regarding a surrogate end-point
• Surrogate end-point reasonably likely to predict
  clinical benefit
• Serious or life-threatening disease
• Drug must provide benefit over available therapy
• Post-marketing studies must verify clinical
  benefit

ODAC Meeting on Accelerated Approvals, March 2003
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Relapsed/Refractory Chronic Lymphocytic Leukemia

• Michael Keating, MB, BS

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CLL Patients Express Bcl-2
ASchena et al. Blood 1992792981, BHanada et al.
Blood 1993151820, CRobertson et al. Leukemia
199610456, DZaja F, Leuk Lymphoma 199828567,
EAviram et al. Eur J Haematol 20006480,
FKlobusicka et al. Neoplasma 200249387,
GMenendez et al. Leukemia 200418491, HTracey et
al. J Pathology 2005206123
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Relapsed/RefractoryChronic Lymphocytic Leukemia

• Highly symptomatic
• Fever, night sweats, weight loss, fatigue,
  lymphadenopathy, splenomegaly
• Poor Prognosis
• Fatalities from infection or bleeding
• Limited treatment options
• Repeat Fludarabine
• Alemtuzumab
• Rituximab (unapproved for CLL)
• Investigational agents

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Relapsed/Refractory CLL Treatment
ObjectivePALLIATION IS NO LONGERTHE DESIRED
CLINICAL ENDPOINT

• Prior to 2000
• Palliation
• Partial reduction
• Tumor volume
• Symptoms
• Peripheral blood abnormalities

• Currently
• Prolonged Remission
• Complete resolution
• Tumor volume
• Symptoms
• Peripheral blood abnormalities
• Durable CR/nPR

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Prior FDA Approval Studiesin Relapsed/Refractory
CLL
Chlorambucil failure, Non NCI-WG criteria, No
CT Campath ODAC presentation No CT
Silver Bullet
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CR and nPR Require Normalization of All Disease
Parameters
NCI WG Cheson, Blood, 1996
Silver Bullet
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Bone Marrow nPR vs. CR
Baseline
nPR with Nodule
CR Clear of Nodules
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CR and nPR Correlate withIncreased Survival in
CLL
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Summary

• Relapsed/Refractory CLL
• Rapidly progressive
• Highly symptomatic
• Resistant to chemotherapy
• Fatalities due to infection and/or bleeding
• Limited medical options
• CR/nPR is the most relevant current endpoint in
  CLL
• Unmet medical need

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Clinical Efficacy Safety

• Loretta Itri, MD

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Genasense CLL Program

• Phase 1-2 Single agent (N40)
• Part A - dose finding
• Part B - efficacy and safety
• Phase 3 (N241)
• Randomized pivotal combination study with
  chemotherapy
• Safety Database (N1000)

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Genasense Phase 1-2 (Part A) Relapsed/Refractory
CLL (N14)

• Established MTD 3mg/kg/day (5-7 day CIV infusion)
• Dose limiting toxicities
• Cycle 1 infusion reactions
• High spiking fever, rigors and hypotension
• Tumor lysis syndrome
• Other side effects
• Nausea, fatigue, thrombocytopenia

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Genasense Phase 1-2 (Part B) Single Agent
Efficacy Relapsed/Refractory CLL(N26)
Median number of prior regimens 3 Genasense 3
to 7 mg/kg/d x 5-7d OBrien et al., J Clin Oncol,
2005
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GL303

• Pivotal Randomized Phase 3 Study of Fludarabine
  and Cyclophosphamide
• with or without Genasense in Relapsed/Refractory
  CLL

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GL303 Phase 3 Study Design

• 241 patients
• Relapsed/refractory 1 fludarabine regimen
• Stratification
• Fludarabine refractory vs. non-refractory
• No. of prior regimens 1-2 vs. 3
• Response to last therapy 6 vs. 6 months

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Fludarabine Sensitivity Criteria

• Refractory
• Failure to achieve at least a PR
• or
• Recurrence within 6 months of treatment
• Relapsed
• Recurrence after PR lasting 6 months

Identical to criteria employed in Alemtuzumab
BLA
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Protocol Therapy Dosing Regimens
Days
1
2
3
4
5
6
7
Genasense 3mg/kg/day CIV days 1-7
Fludarabine
Fludarabine
Fludarabine
Randomization
CTX
CTX
CTX
Fludarabine 25 mg/m2
1
2
3
Fludarabine
Fludarabine
CTX 250 mg/m2
CTX
CTX
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Protocol Endpoints

• Primary endpoint
• CR nPR
• NCI-WG criteria
• CT/US confirmation
• Central blinded expert review
• Secondary endpoints
• Response duration (CR nPR, CR nPR PR)
• Overall response (CR nPR PR)
• Time to progression
• Overall survival
• Clinical benefit
• Safety

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Central Blinded Assessment of Response and
Disease Progression

• Histopathologic review of bone marrow
• Dr. Gregory Threatte
• Clinical response assessment
• Dr. Kanti Rai
• Disease progression determination
• Dr. Kanti Rai

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Demographics and Baseline Characteristics
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Baseline Active Disease Signs and Symptoms
P 29
Stratification Factors
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Prior Chemotherapy Well Balanced
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Randomized Phase 3 Study Relapsed/Refractory
Chronic Lymphocytic Leukemia

• Efficacy

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Primary Endpoint AchievedSignificant Increase in
CR/nPR
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CR/nPR p0.025 (Chi-Square)
n11
Major Response ()
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CR
n3
nPR
n9
n5
GFC
FC
Fishers exact test CR/nPR p0.016
CR only p0.03
Silver Bullet
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CR/nPR Significantly More Durable with
Genasense/FC
GFC
FC
P0.031
From Date of Initial Response
Silver Bullet
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CR/nPR Duration of Response During Treatment and
Post Treatment
Median Duration Post Chemo GFC Not Reached
(est. 31 mos) FC 20 mos
42
36
30
24
Months
18
12
6
0
FC
GFC
Ongoing
Silver Bullet
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Four-Fold Increase in CR/nPR in Chemosensitive
Patients
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Overall Response Rate (ORR) and Response
Duration
GFC
FC
ORR CR/nPR PR
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Time to Progression Intent-to-Treat Population
GFC
FC
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TTP 2 Years Correlates with Response (CR/nPRs
Have Greatest Benefit)
Pis number with observed TTP 2 years
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Overall SurvivalIntent-to-Treat Population
GFC
FC
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Survival 3 Years Correlates with Response
(CR/nPRs Have Greatest Benefit)
Pis number with observed survival 3 years
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Durable Symptom Relief Correlates With Response
(CR/nPR Have Longest Symptom Free Duration)
For each time point, PTest of Trend
Includes B-symptoms, fatigue, symptoms due to
hepatosplenomegaly, lymphadenopathy, or other
Silver Bullet
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GL303Relapsed/Refractory Chronic Lymphocytic
Leukemia

• Safety

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Non-Hematologic Adverse Events
Silver Bullet
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Hematologic Toxicity
Silver Bullet
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PlateletsMedian and Inter-quartile Range
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Platelet Transfusions and Bleeding Events
1 grade 3, 1 grade 2 1 grade 1, 1 grade 3
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Hematologic ParametersMedian and Inter-quartile
Range
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Deaths and Discontinuations(On Study)
Silver Bullet
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Infusion Reactions

• Reaction
• Spiking fever, nausea, dehydration, rigor, back
  pain, hypotension, renal insufficiency
• Lymphoid malignancies only
• Incidence 1.7 at 3 mg/kg
• Preventive/supportive care
• Hydration, antiemetics, analgesics and observation

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Hospitalizations Grade 3-4 AEs
Gr 3-4 AEs 3
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Catheter-Related Events

• Protocol catheter requirement for Genasense
• Infection
• No grade 4 events
• Hospitalization GFC - 3, FC - 1
• Treatment interruption GFC- 1, FC - 1
• Thrombosis
• No grade 4 events
• Two Grade 3 events in GFC arm subclavian vein
  and jugular vein thrombosis

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Other Complications
Waldenstroms Macroglobulinemia AML, PTCL,
Hodgkins disease, MDS
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Summary and BenefitRisk Assessment

• Susan M. OBrien, MD

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ThrombocytopeniaPlatelet Count by Cycle
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Adverse Reactions

• Tumor lysis syndrome
• Seen with active anti-leukemia agents
• Infusion-related reactions
• Common to many CLL therapies
• 70-80 incidence with monoclonal antibodies

Silver Bullet
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Genasense Does Not Worsen Neutropenia
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Approval Studies in CLL
Non NCI-WG criteria GCSF use
Silver Bullet
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Addition of Genasense Converts PRs into Durable
CR/nPRs
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40
30
20
10
Sensitization
0
FC
GFC
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GL303 Relapsed/Refractory CLLCR/nPR Superior
to PR for TTP
CR vs PR p CR vs nPR p 0.21
Proportion of Subjects Without PD
nPR vs PR p 0.0007
Months from Randomization
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Response Considerations

• How does the pattern of response compare to that
  seen in other trials in relapsed/refractory CLL?
• How does the magnitude of improvement compare
  with other trials, and is it clinically important?

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Response and TTP in Relapsed CLLFlu/Cy vs.
Flu/Cy/Rituximab
Time-to-Progression Responders Only
FCR
No CT
FC
Months
Historical comparison of sequential
studies Adapted from Weirda et al., Cancer 2006
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Recent Randomized Studies in CLL
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GL303 Relapsed/Refractory CLL CR/nPR Duration of
Response During Treatment and Post Treatment
Median Duration Post Chemo GFC Not Reached
(est. 31 mos) FC 20 mos
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36
30
24
Months
18
12
6
0
FC
GFC
Ongoing
Silver Bullet
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Confirmatory Study in Previously Untreated CLL

• SPA requested
• Multicenter, open label study (N722)
• Primary Endpoint PFS
• Stratification
• FISH 17p- vs. 11q- vs. Other
• Rai stage
• LDH
• Investigative center

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GL303 Relapsed/Refractory CLLCriteria Met for
Accelerated Approval
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Reduction in Tumor Volume May Serve as a
Surrogate for Clinical Benefit1,2

• FDA Guidance on Surrogacy of Reduction in Tumor
  Volume3
• The association of reduction in tumor volume is
  stronger in the setting of
• Undetectable tumor volume
• 17 vs. 7 CR/nPR (p0.025)
• Reduction is durable
• GFC median duration of response estimated to
  exceed 36 months (not yet reached) vs. 22 months
• Reduction extends beyond the period of toxic
  agent administration
• GFC median duration of response estimated to
  exceed 31 months (not yet reached) vs. 20 months

1 Guidance for Industry Providing Clinical
Evidence for Effectiveness for Human Drug and
Biological Product (Oncology Supplement) May
1998 2 Reinventing the Regulation of Cancer Drugs
- March 1996 3 BLA Reference number 99-0786
(Alemtuzumab)
Silver Bullet
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