Preliminary Toxicity Results of a Phase II Randomized Trial of Weekly or Every 3-Week Ixabepilone in Metastatic Breast Cancer (MBC).

Abstract

Abstract Background: Epothilones, including ixabepilone, have demonstrated antitumor activity in a wide range of chemonaïve and chemo-resistant cancer models. This study was conducted to determine efficacy and toxicity of the weekly schedule (weekly x 3 w/ no dosing in Week 4) compared to the every 3-week schedule in MBC patients.Patients and Methods: Patients with HER2-negative MBC that was measurable, or nonmeasurable with serum CA27.29 (or CA15.3) ≥50, performance status (ECOG 0-2) with no limit on prior chemotherapy were enrolled. Any existing peripheral neuropathy must have been ≤Grade 1. Treatment: Patients were randomly assigned to receive ixabepilone 16 mg/m2 IV over 1-hour on Days 1, 8, and 15 of each 28-day cycle (Arm 1), or 40 mg/m2 IV over 3-hours on Day 1 of each 21-day cycle (Arm 2). Toxicity was assessed and graded at every visit using the NCI CTCAE v3. Disease was assessed every 12 weeks during treatment.Results: 173 patients enrolled to date out of a planned accrual of 176 patients (85 in Arm 1 and 88 in Arm 2); median follow-up was 3.8 and 3.48 months, respectively. Median age [range] was 60 [37-79] in Arm 1 and 57 [39-80] in Arm 2, respectively. ECOG PS 2 was ∼7% in both treatment arms, all others were 0 or 1. Most patients had received prior chemotherapy for MBC (Arm 1/Arm 2: 1 or more prior regimens 74%/73%), and/or hormonal therapy. Prior adjuvant/neoadjuvant therapy had been received by 53% and 73% of patients in Arms 1 and 2, respectively. Prior anthracyclines had been administered to 61% and 76% in Arms 1 and 2, respectively, while taxanes had been administered to 69% and 75%, respectively. Hormone receptor status ER/PR Arm 1/Arm 2: +/+ 56.5%/44%, +/- 15%/18%, and -/- 20%/24%. Dosing: Arm 1 received a mean dose of 14.8 mg/m2, whereas Arm 2 received 37.2 mg/m2 over a median of 3 28-day cycles and 4 21-day cycles, respectively. Mean dose intensity was 93% in both arms. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 22% (Arm 1) and 57% (Arm 2) of patients; serious adverse events occurred in 28% and 36% of Arm 1 and Arm 2 patients, respectively. Grade 3-4 TR neutropenia occurred in only 5% of Arm 1 patients, but was 33% in Arm 2; febrile neutropenia was limited to 1 patient in Arm 2 (Grade 3). Other Grade 3-4 TRAEs in >5% of patients (Arm 1/Arm 2) were: fatigue (5%/16%), neuropathy (5% [4% Grade 3, 1% Grade 4]/14% [∼13% Grade 3, 1% Grade 4]), dehydration (1%/10%), and vomiting (0%/6%). Discontinuations due to TRAEs were 7% in Arm 1 and 14% in Arm 2. Growth factor use was limited to 2 patients (2%) in Arm 2, due to anemia. Most deaths were due to PD.Conclusion: Both schedules have an acceptable safety profile. Preliminary safety results show the every 3-week ixabepilone schedule resulted in more adverse events than the weekly schedule and Grade 3-4 neuropathy occurred less frequently with the weekly dosing. Preliminary ORR, PFS, and OS will be reported.Supported, in part, a research grant from Bristol-Myers Squibb, Princeton, NJ. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6099.