Phase II study of dasatinib in children and adolescents with newly diagnosed chronic phase chronic myelogenous leukemia (CP-CML) or Philadelphia-positive (Ph+) leukemias resistant or intolerant to imatinib.

Abstract

TPS281 Background: Dasatinib, a highly potent BCR-ABL inhibitor, is safe and effective in adults with Ph+ leukemias. In response to an unmet need for novel agents in childhood diseases with poor outcomes, a comprehensive pediatric drug development program for dasatinib has been initiated. Pediatric studies include one completed phase I study (Aplenc et al. ASCO 2008; 26;3591) in patients (pts) with refractory solid tumors and Ph+ leukemia, and three ongoing studies (one phase I [Zwaan et al. Blood 2008;112:3241] and two phase II) in pts with Ph+ leukemias (1st-line or refractory setting). Although no efficacy was observed in solid tumors, preliminary data show dasatinib is active and tolerable in pts with Ph+ leukemia. In a phase I study in relapsed/refractory Ph+ leukemias resistant/intolerant to imatinib, among 41 evaluable pts, a complete hematologic response (CHR) of 75% was seen in CP-CML, and a major cytogenetic response rate (MCyR) of 88% in CP-CML and 50% in Ph+ CML and ALL/AML2. A phase II study is ongoing to determine the feasibility and toxicity of an intensified chemotherapy backbone + dasatinib in newly diagnosed pts with Ph+ ALL. Methods: A phase II nonrandomized, global study evaluates dasatinib in three cohorts: 1) Ph+ CP-CML ≥ 2nd-line (n=25), 2) Ph+ ALL, AP-CML, or BP-CML ≥ 2nd-line (n=34), and 3) newly diagnosed, treatment-naïve Ph+ CML (n=50). A minimum of 109 pts will be enrolled. Pts (age birth to ≤18 yr) are treated daily with dasatinib 60 mg/m2 (Cohorts 1 and 3) or 80 mg/m2 (Cohort 2) for at least 24 mos. Primary endpoints are MCyR in children with CP-CML resistant/intolerant to imatinib, CHR in Ph+ ALL, AP-CML, and BP-CML resistant/intolerant to or relapsed following imatinib and complete CyR in CP- CML. Secondary endpoints include safety and tolerability; best cytogenetic and hematologic RR; time to and duration of response; disease-free, progression-free, and overall survival; and rates of complete and major molecular response. BCR-ABL mutations will be evaluated at baseline, progression, or end of treatment, and for their potential as predictors of response. The study is actively enrolling pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb