# Presentation: 590217

## Agency Review of sNDA 50-718 SE-006

**DOXIL for Ovarian Cancer**
- Division of Oncology Drug Products
- Office of Drug Evaluation 1
- Center for Drug Evaluation and Research

**Notes:**
Good afternoon.  Dr. Dutcher, members of the advisory committee, Dr. Temple, my colleagues at the FDA, ladies and gentlemen.  Today I am presenting the FDA review of clinical data on the two pivotal trials for the efficacy supplement 20-262 on taxol.  

## REVIEW TEAMsNDA 50-718, SE-006

**Notes:**

 Before I proceed, I would like to acknowledge the members of the FDA Review team ...

## PROPOSED INDICATION

- “DOXIL is indicated for the treatment of patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regimens [and who may also be refractory to topotecan.]”
*Refractory* is defined as a patient having progressive disease while on treatment, or within 6 months of completing treatment.

**Notes:**
This application seeks approval to market taxol in the United States  / for  second-line systemic chemotherapy of patients with AIDS-related kaposis sarcoma. The proposed dosing schedule is 135 mg/m2 intravenously over three hours every three weeks.

## Requirements for Accelerated Approval

- Treatment provides benefit over “available therapies.”
- The definition of “available therapies” will be clarified soon in a guidance document.
- For this application, available therapies are drugs labeled for, or with a large body of literature supporting, efficacy for ovarian cancer refractory to platinum and paclitaxel. The FDA has determined that for this indication there are no “available therapies.”

## Requirements for Accelerated Approval (cont.)

- Approval may be based upon a surrogate endpoint that is reasonably likely to predict clinical benefit.
- For this application, that surrogate is objective tumor response.

## Question to the Committee

- Do these data on Objective Response indicate that DOXIL is “reasonably likely” to be associated with clinical benefit in this population?

## CLINICAL PROTOCOLS

**Notes:**
Between September 1993 and January 1995, the first study was undertaken in order to address the efficacy of taxol in AIDS-related Kaposi’s sarcoma.  This study was performed at the National Cancer Institute/National Institutes of Health (NIH), in Bethesda, Maryland and designated as BMS 139-174.  Between February 1995 and December 1995 the second study was initiated in order to confirm the results of the first study.  The confirmatory trial was conducted at two study sites:  the Kenneth Norris Cancer Hospital and County Hospital, Los Angeles, California, and at The New England Deaconess Hospital and Massachusetts General Hospital, Boston, Massachusetts.  This study was designated as BMS 139-281.

Both are open label phase II studies with tumor response as the primary endpoint.  The secondary efficacy endpoints for study 174 were not defined in the protocol; while for study 281, they were defined as time to tumor response duration of response and survival.  Two different dosing regimens were utilized.  For study 174, patients received 135 mg/m2 as a three hour infusion every three weeks while patients enrolled in study 281 received 100 mg/ m2 every two weeks.  A total of 85 patients were enrolled in both studies; however, there were only 59 patients who were previously treated; 40 from study 281 and 19 from 174.   The emphasis of the efficacy review will be on these 59 previously treated patients.

## Study 30-22 Design and Conduct

- Phase II, single-arm, open-label, 2-stage
- Objectives: PK, RR, safety and tolerance
- Two centers
- Study population: platinum and paclitaxel       			      failures
- 50 mg/m2 i.v. every **three** weeks x 3 cycles
- Study enrollment: 35

## Study 30-22 Efficacy Review

- Each patient’s case reviewed to determine platinum- and paclitaxel-refractoriness
- Patients meeting these criteria: 27 of 35
- Serial tumor measurements reviewed to determine _confirmed_ responses
- Patients meeting PR or CR criteria: 6/27 or  22.2% (exact 95% CI 8.6 - 42.3%)

## Slide 10

## Study 30-47 Design and Conduct 

- Phase II, single-arm, open-label, 2-stage
- Objectives: RR, TTP, DOR, survival, safety and pilot HQL questionnaire
- Patient population:  platinum- and taxane- 				        refractory
- Multicenter - United States
- 50 mg/m2 i.v. every **four** weeks x 6 cycles
- Study population: 89

## Study 30-47 Efficacy Review

- Each patient’s case reviewed to determine platinum- and paclitaxel-refractoriness
- Patients meeting these criteria: 82/89
- Serial tumor measurements reviewed to determine objective responses
- Patients meeting PR or CR criteria: 14/82 or  17.1% (exact 95% CI 9.7 - 27.0%)

## Slide 13

## Study 30-47E Design and Conduct

- Phase II, single-arm, open-label, 2-stage
- Objectives: RR, TTP, DOR, survival, safety
- Multicenter - Europe
- 50 mg/m2 i.v. every **four** weeks x 6 cycles
- Study population: 52+

## Study 30-47E Efficacy Review

- Applicant’s findings:  36/52 met platinum- and paclitaxel-refractoriness criteria
- Applicant’s efficacy findings:  Patients meeting PR or CR criteria: 0/36 or  0.0% (exact 95% CI 0.0 - 9.7%)

## Slide 16

## Study 30-49 Design

- Phase III randomized, open-label, comparative against topotecan
- Study population: failure of first-line platinum-based chemotherapy
- Duration of therapy: 1 year
- Primary Endpoints:  TTP, RR

## Study 30-49 Efficacy Review

- Patients enrolled: 241 (237 received Tx)
- 118 to DOXIL arm
- 119 to topotecan arm
- Patients meeting platinum- and paclitaxel-refractoriness criteria:  81
- 44 in DOXIL arm
- 37 in topotecan arm
- Patients meeting PR or CR criteria:
- 6/44 or 13.6% (95% CI 5.2 - 27.4%) DOXIL
- 3/37 or 8.1% (95% CI 1.7 - 21.9%) topotecan

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## sNDA 50-718 SE-006 SummaryEfficacy

- 3 Phase 2 trials; 1 ongoing Phase 3 trial
- 13.8% response rate in platinum- and 	paclitaxel-refractory ovarian cancer
- 1 Phase 2 trial with no responses

## sNDA 50-718 SE-006 SummarySafety

- At 50 mg/m2, four-week schedule less toxic than three-week schedule
- Adverse events attributable to DOXIL; some serious:
- cutaneous
- mucocutaneous
- asthenia
- hematologic
- gastrointestinal

## Question to the Committee

- Do these data on Objective Response indicate that DOXIL is “reasonably likely” to be associated with clinical benefit in this population?