Dasatinib (SPRYCEL®) in Children and Adolescents with Relapsed or Refractory Leukemia: Preliminary Results of the CA180018 Phase I/II Study.

Leukemia is the most common type of cancer in pediatric patients (pts). Treatment options for Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) include: risk-adapted chemotherapy, imatinib (im) and stem cell transplant (SCT). Relapsed leukemia has few therapeutic options. Dasatinib (SPRYCEL^®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, KIT, and SRC kinases that was recently granted approval for adults with CML, and Ph+ ALL with resistance or intolerance to prior therapy. CA180018 is the first trial evaluating dasatinib in pediatric patients pts and Ph+ and in Ph- leukemias. CA180018 is a phase I/II dose-finding study of dasatinib in pts aged 1–20 with CML or relapsed Ph+ ALL resistant or intolerant to im, or Ph- ALL or AML in ≥2^nd relapse performed in collaboration with 12 centers (6 countries) from the ITCC Consortium. Preliminary data are available on the first 15 pts treated from March-July 2006 (2 chronic phase (CP) CML, 7 Ph+ ALL, 1 accelerated phase (AP) CML, 3 Ph- ALL, and 2 Ph- AML) at a starting dose of 60 mg/m² daily (course = 3 weeks). Intra-patient dose escalation was allowed for lack of initial response, and a 3+3 design for maximum tolerated dose (MTD) determination. Hematologic, cytogenetic, and molecular responses, as well as plasma and cerebrospinal fluid (CSF) pharmacokinetic (PK) analysis and BCR-ABL mutational analysis are ongoing. Median age was 11 yrs (range 4–17), median time from diagnosis of leukemia was 19.5 months (range 1.4–89.9). Prior therapy included chemotherapy, im, and stem cell transplant. Median duration on study is 0.69 month (range 0.03–3.45). Intra-patient dose escalation to 80 or 100 mg/m² occurred in 7 pts. Six pts remain on study. There have been 7 responders: 4 complete hematologic responses (CHR): 1 CP CML, 1 AP CML, 2 Ph+ ALL; 5 cytogenetic responses (CyR): 2 Ph+ ALL complete CyR (CCyR), 1 AP CML CCyR, 1 CP CML partial CyR (PCyR), 1 Ph+ ALL minor CyR who never achieved a CHR, and then progressed; and 2 Ph+ ALL pts with CNS disease who cleared the CSF of leukemic blasts with single agent dasatinib. Preliminary PK in 7 pts showed rapid absorption with a median T_max of 1.0 h, and mean terminal phase half-life (SD) of 2.7 (1.1) h. There is one dose-limiting toxicity (DLT): grade 4 anaphylactic shock which occurred 5 hours after the first dose. Dasatinib has otherwise been well tolerated up to 100 mg/m² with toxicities including grade 3/4 thrombocytopenia, and sepsis. Nine pts are off study: 8 for progressive disease (2 Ph+ ALL pts with a resistant T315I BCR-ABL mutation), and 1 DLT. These preliminary results provide evidence supporting the safety and efficacy of dasatinib in pediatric pts with relapsed or refractory leukemia. An updated analysis including further enrollment, safety data, PK, cytogenetic and molecular responses, and mutational analyses will be presented.