A Phase II Study of Dasatinib in Patients with Accelerated Phase Chronic Myeloid Leukemia (CML) Who Are Resistant or Intolerant to Imatinib: First Results of the CA180005 ‘START-A’ Study.

Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that targets BCR-ABL and SRC kinases. Results from a phase I trial showed dasatinib to be well-tolerated and to induce hematologic (HR) and cytogenetic responses (CyR) in pts with imatinib (IM)-resistant (IM-R)/intolerant (IM-I) CML at all stages of disease. Phase II evaluation of dasatinib in this group of pts is currently ongoing - this is an open-label study of dasatinib in accelerated phase (AP)-CML carried out in 39 centers worldwide. was originally designed to accrue 60 AP-CML pts, but was subsequently expanded to further assess safety and efficacy. Between December 2004 and May 2005, a total of 107 pts were treated (56 males; median age 49, range 24-74). We report our preliminary experience on the first 35 pts enrolled. Dasatinib was given orally at 70 mg twice daily (BID), based on phase I data, including complete inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 100 mg BID or reduction to 50 mg and 40 mg BID were allowed for poor initial response or persistent toxicity, respectively. Blood counts were performed weekly and bone marrow, including cytogenetic, evaluation monthly. A total of 35 pts (33 IM-R, 2 IM-I) are summarized. Mean age was 55 years (range 23–79), 86% of pts were Caucasian and 49% were male. Median time from diagnosis of CML was 91.4 months (range 30.8–176.6); 69% of pts had prior interferon and 14% had prior stem cell transplant. Most pts were extensively pretreated with IM, at doses >600 mg/day in 19 (54%) pts, and duration of IM treatment was >3 years in 25 (71%) pts; 30 pts (86%) had achieved a complete HR (CHR) on prior IM and 9 (26%) had a major CyR. At study entry, 13 (37%) pts had baseline WBC ≥20,000/ml and 13 (37%) pts had platelets <100,000/ml. 14 (40%) pts had ≥15% bone marrow blasts. Assessment of mutation in the ABL kinase domain was performed in all pts; 6/10 pts currently evaluable had mutations; none were of the T315I type. The median duration on study was 2 months. Dose interruptions occurred in 20 pts, dose reduction in 6 pts and dose escalation in 6 pts. 23 (66%) pts achieved a major hematologic response (7 CHR and 16 no evidence of leukemia [CHR without complete recovery of neutrophils or platelets]). CyR were documented in 13/24 pts (54%) including 4 complete CyR (0% Ph+) and 2 partial CyR (1–35% Ph+). Responses were seen in pts who never responded to IM (2 major HR and 1 minor CyR). Molecular responses are not yet available. Myelosuppression was profound, with PMN <500/ml in 17 pts and platelets <25,000 /ml in 20 pts. Non-hematologic toxicity consisted mainly of diarrhea (10 pts), nausea (5 pts), headache (5 pts), peripheral edema (3 pts) and pleural effusion (2 pts); all grade 1 or 2. In conclusion, despite a relatively short follow-up, dasatinib demonstrated substantial hematologic and cytogenetic activity in this heavily pretreated population of accelerated phase CML pts. Data will be updated at the time of the meeting on all 107 pts, with a minimum of 6 months’ follow-up.