Abstract C24: Phase I trial of dasatinib and ixabepilone in patients with solid tumors.

Abstract

Abstract Background: Ixabepilone is an epothilone B analog that stabilizes tubulin, disrupts homeostasis and induces apoptosis. Dasatinib is a potent oral tyrosine kinase inhibitor (TKI), which inhibits multiple targets including SRC. Synergistic activity has been reported when combining dasatinib with chemotherapy agents. This phase I study was conducted to determine the dose-limiting toxicities (DLTs), maximum tolerated doses (MTDs), pharmacokinetics (PK) and preliminary antitumor activity for ixabepilone and dasatinib when used in combination. Methods: Patients with metastatic or unresectable solid tumors who progressed on standard therapy received ixabepilone and dasatinib at escalating doses. An expansion cohort was formed after the MTD was reached. PK studies were performed. Results: Nineteen patients were enrolled. No DLTs were seen at dose level (DL) 1 (ixabepilone 30 mg/m2 IV Q 3 weeks, dasatinib 100 mg PO QD). At DL 2 (ixabepilone 40 mg/m2 IV Q 3 weeks, dasatinib 100 mg PO QD), the second patient had 3 DLTs (grade 3 diarrhea, grade 4 neutropenia and grade 3 febrile neutropenia), thus DL 2 was expanded to include 6 patients. No additional DLTs were seen at DL 2. At DL 3 (ixabepilone 40 mg/m2 IV Q 3 weeks, dasatinib 150 mg PO QD), the first patient developed grade 3 diarrhea during cycle 2 and the second patient had a DLT (grade 3 diarrhea) and grade 3 mucositis during cycle 2. Accrual to DL 3 was halted due to these toxicities and MTDs were designated to be ixabepilone 40 mg/m2 IV every 3 weeks and dasatinib 100 mg PO daily (DL 2). Additional 8 patients were then enrolled to DL 2. Three of these patients experienced DLTs (grade 4 neutropenia, grade 3 hyperkalemia and grade 3 fatigue). The best responses included one (5%) partial response (PR) in a lung cancer patient. Twelve (63%) patients had stable disease (SD) for at least 2 cycles. Altogether 13 (68%) patients came off study due to toxicities. Conclusion: The combination of ixabepilone and dasatinib showed modest clinical activity with doses 40 mg/m2 IV every 3 weeks and100 mg PO QD, respectively. Treatment related toxicities were seen frequently. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C24.