Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).

Abstract

7003 Background: FLT3 Internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations are seen in 30% of AML patients (pts) and are associated with poor survival. Secondary FLT3-TKD mutations are associated with treatment failure with tyrosine kinase inhibitors. ASP2215 is a potent inhibitor of FLT3 and Axl with activity against FLT3-ITD and FLT3-TKD. Methods: A phase I/II trial was conducted to investigate safety and efficacy in pts with R/R AML. The dose escalation followed a 3+3 design and evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in dose escalation. Results: 166 pts have enrolled between October 2013, and December 2014, 25 in the dose escalation and 141 in the dose expansion cohorts. At the 450 mg dose, 2 pts had a DLT (grade 3 diarrhea and ALT/AST elevation), and the maximum tolerated dose was determined to be 300 mg. Common possibly or probably drug related treatment emergent adverse events of any grade include fatigue (13%), constipation (10%), anemia (8%), nausea (8%), diarrhea (7%), thrombocytopenia (6%), decreased platelet count (6%), vomiting (6%), dizziness (6%), peripheral edema (5%), increased transaminases (5%) and hypomagnesemia (5%). 120 pts are evaluable for response. Overall response rate (ORR) was 57% in 82 pts with FLT3 mutations, and 63% in 68 pts in the 80 mg and higher dose levels. A plasma inhibitory activity assay confirmed effective, sustained in vivo FLT3 inhibition consistently in pts receiving doses of 80 mg and above. Conclusions: ASP2215, a potent inhibitor of FLT3/Axl, is well tolerated in patients with R/R AML and results in a high degree of clinical activity. Randomized phase III trials of ASP 2215 at 200 mg per day in newly diagnosed and R/R AML are planned. Clinical trial information: NCT02014558. Response FLT3 mutated FLT3 wild type n (%) (38 pts) 20-300 mg n (%) (82 pts) ≥ 80 mg n (%) (65 pts) Complete Remission (CR) 4 (5%) 3 (5%) 0 CR, incomplete platelet recovery (CRp) 4 (5%) 4 (6%) 0 CR, incomplete hematologic recovery (CRi) 27 (33%) 25 (38%) 3 (8%) Partial Remission (PR) 12 (15%) 10 (15%) 1 (3%) Composite CR (CR+CRp+CRi) 35 (43%) 32 (49%) 3 (8%) ORR (CRc+PR) 47 (57%) 42 (65%) 4 (11%)