Ixabepilone and Liposomal Doxorubicin in Advanced Ovarian Cancer

Study Overview
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Brief Summary
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This trial is studying the side effects and best dose of ixabepilone when given together with pegylated liposomal doxorubicin hydrochloride and to see how well they work in treating women with advanced ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer or metastatic breast cancer. Drugs used in chemotherapy, such as ixabepilone and pegylated liposomal doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose and recommended phase II dose of ixabepilone when combined with pegylated doxorubicin hydrochloride (HCl) liposome (pegylated liposomal doxorubicin hydrochloride) in women with previously treated advanced ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer or metastatic breast cancer. II. To determine the safety profile of this regimen in these patients. III. To determine the clinical efficacy of this regimen in patients with platinum- and taxane-resistant advanced ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer. OUTLINE: This is a phase I, multicenter, open-label, dose-escalation study of ixabepilone followed by a phase II study. Patients receive ixabepilone intravenously (IV) over 3 hours and pegylated liposomal doxorubicin hydrochloride IV over 30-60 minutes on day 1. Courses repeat every 21-28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for up to 2 years.

Official Title
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A Phase I/II Study of BMS-247550 and Pegylated Liposomal Doxorubicin (Doxil®) in Patients With Advanced Epithelial Ovarian Cancer or Primary Peritoneal Cancer Who Have Been Previously Treated With a Platinum and a Taxane

Conditions
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Fallopian Tube Cancer, Female Reproductive Cancer, Recurrent Breast Cancer, Recurrent Ovarian Epithelial Cancer, Stage III Ovarian Epithelial Cancer, Stage IV Breast Cancer, Stage IV Ovarian Epithelial Cancer

Intervention / Treatment
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* Drug: ixabepilone
* Drug: pegylated liposomal doxorubicin hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of 1 of the following: advanced ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer (phase I and II) or metastatic breast cancer (phase I only). Platinum- and taxane-resistant disease, defined as a disease-free interval of < 6 months after completion of platinum- and taxane-based chemotherapy. Disease progression during the regimen (phase II) or previously treated with >= 2 prior regimens for metastatic breast cancer, including 1 taxane-based regimen in the adjuvant or metastatic setting (phase I). Meets 1 of the following criteria: Previously treated with a standard course of taxane- and platinum-based chemotherapy for ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer, that is platinum-refractory or -sensitive disease (phase I ); Measurable or evaluable disease, meeting 1 of the following criteria: unidimensionally measurable lesion, known disease and CA 125 > 50 U/mL on 2 occasions >= 1 week apart or known disease and CA 27-29, CA 15-3, or CA 125 > 50 U/mL on 2 occasions >= 1 week apart (for breast cancer patients) ECOG 0-2 or Karnofsky 60-100% At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered. At least 1 week since prior chemotherapy if given on a daily or weekly schedule and recovered. At least 3 weeks since prior radiotherapy and recovered. Recovered for more than 4 weeks from all adverse events related to prior agents. Normal organ function including: Normal bilirubin WBC >= 3,000/mm3 Absolute neutrophil count >= 1,500/mm3 Platelet count >= 100,000/mm3 AST and ALT =< 2.5 times upper limit of normal (ULN) Creatinine =< 1.5 times ULN or Creatinine clearance ≥ 60 mL/min Exclusion criteria: No other concurrent investigational agents. No concurrent combination antiretroviral therapy for HIV-positive patients. No other concurrent anticancer therapy. Has received a previous chemotherapy regimen for this cancer that included drugs such as docetaxel or paclitaxel. Life expectancy of more than 3 months No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Fertile patients must use effective contraception No history of allergic reaction attributed to compounds of similar chemical or biological composition to Cremophor® or study drugs No neuropathy >= grade 2 No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance. No other uncontrolled illness. No active brain metastases, including any of the following: evidence of cerebral edema by CT scan or MRI, evidence of disease progression on prior imaging studies, requirement for steroids or clinical symptoms of brain metastasis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ixabepilone and doxorubicin)<br>Ixabepilone IV over 3 hours and pegylated liposomal doxorubicin hydrochloride IV over 30-60 minutes on day 1. | Drug: ixabepilone<br>* Given IV<br>* Other names: Ixempra;Drug: pegylated liposomal doxorubicin hydrochloride<br>* Given IV<br>* Other names: LipoDox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose-limiting Toxicity (DLT), Graded Using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 4.0 (Phase I) | Dose-Limiting Toxicities are assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification and usually encompasses all grade 3 or higher toxicities | 28 days | 
| Maximum Tolerated Dose | The phase I component of the study included 30 patients with breast and ovarian cancer. A protocol amendment was made during phase I trial from a treatment regimen of Schedule A (ixabepilone every 3-4 weeks) to Schedule B (ixabepilone every week). The maximum tolerated dose was determined to be the preceding dose of any dose that resulted in 2 DLT events. Schedule B was carried forward to the phase II trial. The Maximum Tolerated Dose for Schedule B is reported. Please see (Chuang et al., 2010) for additional details | Once 2 DLT events occur in patients during the first 28 days of treatment (cycle 1), the preceding dose will be designated the maximum tolerated dose (MTD). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Responding to Therapy (Complete Response [CR], Partial Response [PR], or Stable Disease [SD]), Assessed According to Response Evaluation Criteria in Solid Tumors (RECIST) and Cancer Antigen-125 (CA-125) Response Criteria (Phase II) |  | Up to 2 years | 
| Progression-free Survival | We will summarize progression-free survival by Kaplan-Meier survival analysis. | The time from start of treatment to time of progression or death, assessed up to 2 years |