SNDA 20-509

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SNDA 20-509

• Gemzar plus Carboplatin Treatment of Late
  Relapsing Ovarian Cancer

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Proposed Indication

• Gemzar in combination with carboplatin is
  indicated for the treatment of patients with
  advanced ovarian cancer that has relapsed at
  least 6 months after completion of platinum-
  based therapy

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Pivotal Trial

• A Randomized Open Label Phase 3 Study Comparing
  Gemcitabine Plus Carboplatin Versus Carboplatin
  Monotherapy in Patients with Advanced Epithelial
  Ovarian Carcinoma Who Failed First-Line
  Platinum-Based Therapy

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Dosing

• -Gemzar plus Carboplatin
• Gemzar 1000 mg/m2 on Days 1 and 8 and
  carboplatin AUC 4
• -Carboplatin Alone
• Carboplatin AUC 5 administered on Day 1
• Cycles are repeated every 21-days.

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Regulatory Background

• -Study was not conducted under an IND.
• -Protocol had not been reviewed by DODP
• -Pre NDA Meeting 12/21/04.
• Issue Is PFS an appropriate endpoint
• -Pre NDA Meeting 3/23/05.
• Further discussion of PFS and a sensitivity
  analysis plan

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Submitted Clinical Studies

• Phase 3 - Pivotal trial
• Phase 2 - Gemzar carboplatin in identical dose
  and schedule in an identical patient population.
  40 patients. Investigator reported response rate
  62.5
• Phase 1/2 - Varying gemzar and carboplatin doses.
  Identical patient population. 25 patients.
  Response rate 40.0

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Participating groups

• -AGO
• -EORTC
• -NCIC-CTG
• -14 sites in China, India, Italy, Venezuela and
  Peru
• - No U.S. sites

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Main Inclusion Criteria

• -Females ³18 years old with ovarian cancer not
  amenable to curative surgery or radiation therapy
  
• -Relapsed disease gt 6 months after
  discontinuation of 1st line platinum-containing
  therapy
• -ECOG PS lt 2
• -Adequate marrow reserve
• -Measurable or evaluable disease

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Study Plan

• -Treatment continues for 6 cycles until disease
  progression, intolerable toxicity, or other
  relevant reason to discontinue treatment.
• -Diagnostic studies (radiology, physical exam or
  ultrasound) every other cycle.
• -30 day poststudy follow-up disease evaluation.
• -Independent review of CT scans and MRIs

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Efficacy Endpoints

• Primary
• - PFS
• Secondary
• - Survival
• - RR Duration
• Q of L

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Patient and Disease Characteristics

• Patient Groups were comparable for
• Age
• Ethnicity
• Performance status
• Platinum-free interval
• Ovarian Cancer Histology
• Tumor Differentiation
• Stage at Diagnosis
• Pretreatment Tumor Burden

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Prior Chemotherapy
GCb n178 n () Cb N178 n ()
Platinumpaclitaxel others 122 (68.5) 120 (67.4)
Platinumdocetaxel others 3 (1.7) 7 (3.9)
Platinum Non-taxane 51 (28.7) 49 (27.5)
Carboplatin only 2 (1.1) 2 (1.1)
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PFS Primary Analysis

• Scans were not routinely performed after a single
  post-study evaluation.
• Investigator clinical judgment determined the
  timing of progression assessment.
• Non-progressors were censored at last visit
  date.
• New therapy did not always imply progression.
• Missing studies did not affect progression date.

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PFS Sponsor Primary Analysis
GC (N178) C (N178)
Censored 13 13
Median (mo) (95 CI) 8.6 (8.0, 9.7) 5.8 (5.2, 7.1)
HR 0.72 (0.57, 0.90) p0.0038 HR 0.72 (0.57, 0.90) p0.0038 HR 0.72 (0.57, 0.90) p0.0038
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PFS Sponsor Primary Analysis

• HR 0.72 (0.57, 0.90) p0.0038

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Sensitivity Analysis for PFS

• Non-progressing patients, patients with missing
  scans prior to progression and patients who died
  after an extended lost to follow up time were
  censored at their last complete diagnostic
  evaluation.
• Patients who began a new therapy prior to
  progression were censored on the day that the
  therapy was initiated.

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PFSSponsor Sensitivity Analysis
GC (N178) C (N178)
Censored 74 57
Median (mo) (95 CI) 6.9 (6.3, NE) 5.6 (5.0, 5.9)
HR 0.47 (0.32, 0.68) p0.001 HR 0.47 (0.32, 0.68) p0.001 HR 0.47 (0.32, 0.68) p0.001
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PFS FDA Analysis
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Response Rate
GC (N178) C (N178) p
RR CR PR 47.2 14.6 32.6 30.9 6.2 24.7 0.0016
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Post Study Chemotherapy
GC 178 pts C 178 pts
Post-study Chemo 75.8 72.5
Specific Drugs Known 41 40
Post study Gemzar 0 10.1
Denominator 129 patients Denominator 129 patients Denominator 129 patients
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Survival

• HR 0.98 (0.78, 1.24) p0.898

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Treatment Dose Intensity
Treatment Arm Percent () of Planned Mean Dose
Gemcitabine Day 1 Gemcitabine Day 8 Carboplatin Day 1 93 63 96
Carboplatin 98
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Grade 3/4 Hematologic Toxicity
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Grade 3/4 Non-laboratory toxicity
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Efficacy Conclusions

• Gemcitabine plus carboplatin treatment
  significantly prolonged PFS and increased
  response rate compared to carboplatin alone.
• Caveat Progression was not independently
  reviewed. Also response was not completely
  independently reviewed.
• There was no significant increase in survival.
• Caveat Post-study chemotherapy may confound
  survival interpretation.

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Safety Conclusions

• Grade 3 and 4 toxicities were primarily
  hematologic and were more frequent with G/C
  treatment.
• Toxicities were consistent with the single agent
  toxicity of each drug.
• No new safety concerns

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ODAC Question

• Is a significant improvement in PFS and RR, with
  no increase in overall survival, at the cost of
  some additional toxicity, an adequate basis for
  drug approval for treatment of patients with
  advanced ovarian cancer who have relapsed at
  least 6 months after completion of platinum-based
  therapy?

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