Phase I trial of weekly and every-three-weeks ixabepilone (Ix) and sunitinib (S) in advanced solid tumors (STs).

Abstract

e13516 Background: S is a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic/antiproliferative properties. Ix is a cytotoxic microtubule-stabilizing semisynthetic epothilone also containing antiproliferative and antiangiogenic effects. IX and S combination may be synergistic, since S may increase delivery of Ix to the tumor by inducing vascular normalization, and the anti-angiogenic effects of S may be enhanced by Ix through HIF-1α regulation. Methods: Patients (pts) with advanced STs were enrolled in a phase I, dose-escalation study to assess safety, pharmacokinetics (PK), angiogenesis biomarkers (ABM) and to determine the recommended phase II dose. Eligibility criteria: age ≥ 18, ≤ 4 prior systemic therapies (tx), performance status (PS) 0-2, measurable/evaluable disease and good organ function. Treatment schedules: A (weekly Ix, 3 out of 4-weeks cycle): starting dose: 7.5 mg/m2 IV (1A), 15 mg/m2 IV (2A) and 20 mg/m2 IV (3A). Schedule B (every 3 weeks): starting dose 20 mg/m2 IV (1B), 30 mg/m2 IV (2B) and 40 mg/m2 IV (3B). In both schedules, S was given continuously starting on day 8 of cycle 1 at 37.5 mg PO per day. Pts were treated in a standard 3 + 3 design with dose-limiting toxicities (DLTs) assessed in the first cycle. Results: 18 pts enrolled to date, 17 are evaluable for toxicity and 14 for efficacy. Baseline characteristics: median age: 62 (49-78); sex male/females: 11/7; most frequent histologies: colorectal (CRC)/ pancreas/ prostate: 10/2/2; median PS: 1; median of prior tx: 3. No DLTs were observed in cohorts 1A, 2A, 1B and 2B. Two pts have experienced DLTs in cohort 3A: Grade (gr) 3 DVT/gr 4 hematological adverse events (AEs), and cohort 3B: gr 4 mucositis/gr 3 dehydration. Other gr 3/4 AEs (not DLTs): neutropenia (6), anemia (5), fatigue (5), lymphopenia (3), thrombocytopenia (2) and neuropathy (2). Best responses: 2 PR, 5 SD and 7 PD. The PRs and most cases of SD were observed in heavily pretreated CRC pts. Conclusions: So far, the combination of Ix and S appears to have acceptable toxicity and shows promising activity. Enrollment in dose-level 3A and 3B is ongoing. PK and ABM analysis are underway. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Pfizer Pfizer Bristol-Myers Squibb, Pfizer