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

Outcome for children with relapsed/refractory leukemia is unsatisfactory. Dasatinib is a novel oral kinase inhibitor of BCR-ABL, KIT, and SRC family kinases. Recently, approval was granted for adult CML and Ph+ ALL with resistance to prior therapy. CA180018, the 1st trial evaluating dasatinib in children (age 1–20 yrs) and conducted in 12 centres from the ITCC Consortium, is a phase I/II dose-finding study in patients (pts) with either imatinib resistant/intolerant CML, relapsed/refractory Ph+ or Ph− ALL, or AML in 2nd or greater relapse. The starting dose was 60 mg/m² QD; intra-pt dose escalation for lack of initial response and dose-(de)escalations were safety and efficacy guided and aimed at establishing a safe and effective dose for each leukemia sub-type. These data reflect the first 34 pts (median age 12.6 y, range 1.6–20) treated from Mar 06 to Aug 07: 6 chronic phase [CP] CML, 2 advanced phase [AP] CML, 8 Ph+ ALL, 6 Ph− ALL, and 12 Ph− AML. Prior therapy included chemotherapy, imatinib, and stem cell transplant. Intra-pt dose escalation to 80 or 100 mg/m² occurred in 21 pts. 7 pts remain on study. Safety: 51 SAEs in 22 patients were noted, and included febrile neutropenia/infections (n=27), GI toxicity (n=8), rash (n=4), and grade 3/4 thrombocytopenia (n=3). One dose-limiting toxicity (DLT) was observed: a grade 4 anaphylactic reaction 5 h after the first dose in a pt with a history of hypensensitivity reactions. One pt had a pleural effusion that also contained leukemic cells. Responses: 5/6 CP CML pts are evaluable for response: 3 pts went into complete hematologic remission; 2 had a complete and 1 had a partial cytogenetic response (CygR). One pt was enrolled with molecular disease only, and PCR values became undetectable after 3 months. One pt never achieved a hematological or CygR, yet no resistance mutations were detected. The pt with myeloid AP CML had a major CygR for ∼3 months; the pt with lymphoid BP CML had a complete CygR (14% BCR-ABL+ cells using FISH), but experienced clonal evolution with ∼28% blasts in the marrow at the same time. Of the 8 pts with Ph+ ALL, 3 showed complete morphologic and cytogenetic remission, lasting for 6 weeks, 1 month, and >2 months for one pt still on study. One other pt with isolated CSF relapse cleared the CSF for ∼7 months with dasatinib only, has subsequently received additional intrathecal chemotherapy, and remains on study 17 months later. Four pts did not respond, 2 of who harbored the T315I mutation. Of the 6 Ph− ALL pts, 4 were evaluable, and none achieved a CR. In 1/4 pts there was a significant drop in WBC for approximately 2 months. Among the 12 Ph− AML pts, one had a drop in BM blasts from 60 to 2% (without full PB regeneration), and one pt from 60 to 15% blasts. None of the AMLs appeared to be KIT-mutated. These data show that dasatinib was well tolerated up to 100 mg/m²; the encouraging early signs of response in Ph+ disease support its further exploration in relapsed/refractory pediatric leukemia pts. Higher dose levels are currently being explored and updated clinical and PK data will be presented.