1. 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

2. REVIEW TEAM sNDA 50-718, SE-006

3. 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.

4. 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.”

5. 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.

6. 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?

7. CLINICAL PROTOCOLS

8. 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

9. 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%)

11. 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

12. 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%)

14. 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+

15. 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%)

17. 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

18. 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

26. 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

27. 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

28. 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?