Ixabepilone and Liposomal Doxorubicin in Advanced Ovarian Cancer

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.

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.