A phase I trial of dasatinib, a Src-family kinase Inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.

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A phase I trial of dasatinib, a Src-family kinase Inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.

Clin Cancer Res. 2012 Jul 26;

Authors: Alvarez Secord A, Teoh DK, Barry WT, Yu M, Broadwater G, Havrilesky LJ, Lee PS, Berchuck A, Lancaster JM, Wenham RM

Abstract
PURPOSE: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer. EXPERIMENTAL DESIGN: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Using a "3+3" design, cohorts of 3-6 patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. RESULTS: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 years (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 patients in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3-4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 40% (3 complete responses, (15%); 5 partial responses, (25%)),10 (50%) had stable disease, and 2 were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. CONCLUSIONS: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.

PMID: 22837181 [PubMed - as supplied by publisher]

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