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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 trialPhase 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 18 years old with ovarian cancer not amenable to curative surgery or radiation therapy

-Relapsed disease > 6 months after discontinuation of 1st line platinum-containing therapy

-ECOG PS < 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 MRI’s

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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 n=178

n (%)

Cb N=178

n (%)

Platinum+paclitaxel + others 122 (68.5) 120 (67.4)

Platinum+docetaxel + 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 (N=178) C (N=178)

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)

p=0.0038

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PFS – Sponsor Primary Analysis

HR 0.72 (0.57, 0.90) p=0.0038

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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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PFS–Sponsor Sensitivity Analysis

GC (N=178) C (N=178)

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)

p=0.001

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PFS – FDA Analysis

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Response Rate

GC (N=178)

C (N=178)

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

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Survival

HR 0.98 (0.78, 1.24) p=0.898

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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

GC n=175 C n=174

Anemia 28% 11%

Neutropenia 71% 12%

Thrombocytopenia 35% 1%

Red cell transfusion 38 11

Platelet transfusion 9 3

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Grade 3/4 Non-laboratory toxicity

GC n=175 C n=174 Nausea 4% 2% Vomiting 3% 2% Fatigue 3% 2% Neuropathy-Sensory 1% 2% Diarrhea 3% 2% Anorexia 1% 0% Stomatitis 1% 0%

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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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