Phase 1/2 Study of Tandutinib (MLN518) Plus Standard Induction Chemotherapy in Newly Diagnosed Acute Myelogenous Leukemia (AML).

Background: Tandutinib is an orally bioavailable small molecule inhibitor of FLT3, c-KIT, and PDGFR with a single-agent MTD of 525 mg b.i.d. Tandutinib demonstrated single agent anti-leukemic activity in patients with relapsed/refractory AML with FLT3 ITD mutations, with ≥50% decreases in bone marrow and peripheral blast counts in 12/25 patients and 1 CR without platelet normalization. Since tandutinib is synergistic with cytarabine and daunorubicin in vitro, we sought to determine the MTD of tandutinib in combination with standard induction chemotherapy in patients with newly diagnosed AML, with or without FLT3 ITD mutations.

Methods: A starting dose of Tandutinib 200 mg b.i.d was administered during induction and consolidation therapy, and for an additional 6 months. Induction therapy consists of cytarabine 200mg/m²/day IVCI, days 1–7, plus daunorubicin 60mg/m²/day, days 1–3. Consolidation therapy is given as 2–4 cycles of standard (3000mg/m² IV every 12h, days 1, 3, 5) or in older patients modified (2000mg/m²/day IV, days 1–5) high-dose cytarabine. DLT is defined as failure to recover marrow function (ANC ≥500/μL; platelets ≥20,000/μL), or grade 3/4 non-hematologic toxicity not resolved to grade 2 (except anorexia, alopecia, fatigue) by day 42 of induction therapy, or any unexpected grade 3/4 non-hematologic toxicities.

Results: 29 patients have been enrolled: median age 60y (range 26–83); 13M, 16F; 23 de novo, 6 secondary AML; 9 with unfavorable cytogenetics; 5 with FLT3 ITD mutations. Cohort 1 consisted of 7 patients treated with continuous daily dosing of tandutinib 200 mg b.i.d. Due to GI intolerance, the protocol was amended so that tandutinib was administered only on days 1–14 of induction therapy and each cycle of consolidation. Under the amended schedule 8 patients were treated with tandutinib 200 mg b.i.d. (Cohort 2) and 14 patients have been treated with tandutinib 500 mg b.i.d. (Cohort 3). Full safety and efficacy data are available for the 15 patients in cohorts 1 and 2. Diarrhea, nausea and vomiting have been the most common drug-related AEs, and were more frequent with continuous daily dosing of tandutinib. GI tolerance in Cohort 2 has been acceptable, with no patients requiring termination or reduction in tandutinib for GI toxicity. Although continuous dosing was not feasible, no DLTs were seen in Cohorts 1 or 2; one DLT consisting of obtundation not clearly related to tandutinib during induction occurred in Cohort 3, One patient in Cohort 3 experienced non-dose limiting generalized muscle weakness, which reversed within 24 hours after discontinuation of tandutinib. Tandutinib was restarted at a reduced dose in this patient without recurrence. 5/7 patients in Cohort 1 and 6/8 patients in Cohort 2 achieved a CR. PK data have been collected for all 15 patients in Cohorts 1 and 2; median steady state tandutinib concentration was 195 ng/mL (range: 52–486).

Conclusions: Tandutinib 200 and 500 mg b.i.d. in combination with standard therapy for newly diagnosed AML appears well tolerated using the amended dosing schedule (days 1–14). Updated results from Cohort 3 (tandutinib 500 mg b.i.d) will be presented.