Phase IB Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Simultaneous Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine Consolidation in Newly Diagnosed Adult Patients (pts) with Acute Myeloid Leukemia (AML) under Age 61.

FLT3 (fms-like tyrosine kinase) activating mutations, either an ITD (repeat of 3->100 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients (pts). ITD mutations are associated with a relatively poor prognosis. PKC412 is a multi-targeted kinase inhibitor that has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) FLT3 AML, but rarely produces complete remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We conducted a phase Ib trial with DA (daunorubicin 60 mg/m² d 1–3 and cytarabine 100 mg/m²/d by IVCI x 7d) induction and post-remission therapy (cytarabine 3 gm/m²/3h q 12h, d1,3, and 5 for 3 cycles) plus PKC412 at 100 mg bid po continuously beginning on day 8 (arm 1) or day 1 (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) in previously untreated adult AML pts ≤ age 60. Results demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). The study was then amended to include the same chemotherapy, but with 50 mg PKC412 po bid (previously shown to lead to plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2); tolerability improved to acceptable levels with no patients withdrawing due to nausea, vomiting, or diarrhea (Stone at al, ASH 2005). The study has completed accrual (40 pts enrolled after the PKC412 50 mg po bid amendment) with 38 pts (26 with wild type FLT3 (FLT3^wt) blasts and 12 with mutated FLT3 (FLT3^mut) blasts) evaluable for efficacy and 37 pts for safety. Complete response (CR) occurred in 27/38 (71%). The CR rate in FLT3^wt pts was 18/26 (69%); 9/13 (69%) pts achieved CR in each of the arms. CR occurred in 11/12 (92%) FLT3^mut pts. CR rate in FLT3^mut pts was 7/7 (100%) in Arm 1 and, 4/5 (80%) in arm 2. 4/11 CR pts relapsed after 7, 7, 10 and 15 months; 7 pts remain in first CR for 3–15 months. No drug-related deaths were reported. One patient withdrew due to Grade 4 increase in alkaline phosphatase. The most common serious Grade 3–4 side effects reported to date include thrombocytopenia 6/19 (31.5%), anemia 5/19 (26%) and neutropenia 5/19 (26%) in pts on arm 1; thrombocytopenia 2/18 (11%), anemia 1/18 (5.5%) and neutropenia 2/18 (11%) in pts on arm 2. All Grade 3–4 events were transient and/or reversible. No Grade 3 or 4 nausea and vomiting occurred in either arm. In conclusion, PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed adult AML pts ≤ 60 years old in combination with DA and high dose cytarabine. The CR rate and preliminary DFS in FLT3^mut pts is encouraging. A phase III study of chemotherapy +/− PKC 412 at 50 mg po bid on d8–21 per cycle in newly diagnosed pts ages 18–60 with mutant FLT3 AML is planned.