Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia: Interim Results of the CA180-018 Phase I Study from the ITCC Consortium.

Relapsed/refractory leukemia in childhood carries a grave prognosis. Dasatinib (SPRYCEL®) is a potent oral kinase inhibitor of BCR-ABL, KIT, and SRC kinases. Dasatinib is approved for adults with Philadelphia chromosome-positive (Ph(+) CML and ALL, resistant or intolerant to prior imatinib therapy. An investigational phase I dose- finding study of dasatinib treatment of patients aged 1–21 years with various leukemia subtypes is currently being conducted in 12 European centers. The aim of the study is to establish a safe and effective dose for each of the leukemia sub-types. Patients were stratified into three treatment groups - Stratum 1: CML in chronic phase, resistant or intolerant to imatinib; Stratum 2/3: advanced-phase CML resistant or intolerant to imatinib, Ph(+) ALL, relapsed/ refractory after imatinib, or Ph(+) AML, ≥ 2nd relapse; Stratum 4: Ph(−) ALL, or Ph(−) AML in second/subsequent relapse. The starting dose was 60mg/m² once daily for all strata. Intra-patient dose escalation was allowed for lack of initial response and dose reductions for toxicity. Current data reflect the first 41 patients (median age 11 years, range 1–21) treated from March 2006 through May 2008, including eight in Stratum 1, twelve in Stratum 2/3, and twenty-one in Stratum 4. The patients were heavily pretreated and prior therapy included chemotherapy (n=35), imatinib (n=20), and stem cell transplant (n=24). Dasatinib was well tolerated up to the current 120mg/m² dose. Treatment-related toxicities were mostly mild to moderate in severity with nausea (34% grade 1/2; 2% grade 3/4) and diarrhea (15% grade 1/2; 0% grade 3/4) occurring most frequently. In Stratum 4, two dose-limiting toxicities were seen: anaphylaxis 5 hours after the first dose (60mg/m²) and upper-GI bleed on Day 6 of dasatinib dosing (120mg/ m²). Only one of the 41 patients experienced a malignant/hemorrhagic pleural effusion at 100mg/m² dose. A maximum tolerated dose has not been established. PK studies were performed on samples from 32 patients after 60 mg/m², 80 mg/m² and 100 mg/m² dosing. Absorption occurred rapidly (median T_max 0.75 – 1.0 hour). The area under the curve (AUC) and maximum concentration (Cmax) proportionately increased with higher dose levels, but the difference was much greater between 60 and 80 mg/m² than between 80 and 100 mg/m². Complete Hematological Response (CHR) occurred in 75% of patients with CML-CP. Major Hematological Response (MaHR) was achieved in 25% of patients with advanced CML/Ph(+) and Ph(+) ALL/ AML. Major Cytogenetic Response occurred in 88% of CML-CP patients and 50% of patients with advanced Ph(+) CML and Ph(+) ALL/ AML. Stratum 4 observations included a temporary decrease in peripheral blood (PB) blast count in one Ph(−) ALL patient and in PB and bone marrow (BM) blast counts in two Ph(−) AML patients (one with AML7 and one with Down’s syndrome). Additionally, three Ph(+) ALL patients had a CSF response. These interim data demonstrate a favorable safety profile for dasatinib. Clear efficacy was seen in patients with CML-CP, and other Ph(+) leukemias. Further exploration is needed in the Ph(−) leukemias in the pediatric population. Updated data will be presented.