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 Patients with AML.

Activating mutations in FLT3 (fms-like tyrosine kinase), either an ITD (repeat of 3–33 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients, are associated with poor prognosis, and represent an attractive therapeutic target. PKC412 is a multi-targeted kinase inhibitor which has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) AML, but rarely produces remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We combined DA induction (daunorubicin 60 mg/m2 d 1–3 and cytarabine 100 mg/m2/d by IVCI x 7d) and post-remission therapy (cytarabine 3 gm/m2/3h q 12h, d1,3,5 for 3 cycles) plus PKC412 in previously untreated AML patients less than or equal to age 60 in a phase Ib trial. Results with the original dose schedules of PKC 412: 100 mg po bid from day 8 continuously (arm 1) or day 1 continuously (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). We now report results with a new amendment in which pts receive the same chemo regimen plus PKC412 at a reduced dose of 50 mg po bid (previously has been shown that PKC at 50 mg bid produces plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2).

None of the 19 pts treated to date have had drug-related death; the most common drug related toxicities during induction and consolidation cycles were nausea (53%), vomiting (47%), ALT increase (32%), AST increase (26%), diarrhea (26%) and rash (21%); all were transient and/or reversible. No Grade 3 or 4 nausea and vomiting were recorded. As of this report, 4 pts have completed the study, and 7 pts are still on study receiving consolidation after achieving CR. Causes of discontinuation include resistant disease (5), transplant after achieving CR (2), and non-drug related toxicity of sepsis and neutropenia (1). All 19 patients are evaluable for response: 9/12 (75%) achieved CR in Arm 1 and 5/7 (71%) achieved CR in Arm 2. Six out of six (100%) FLT3mut patients and 8/13 (62%) FLT3WT patients achieved CR. When a comparison of CR rate is made across all 49 patients in this study overall, there was a significant difference between the FLT3WT CR = 17/32 (53%), and FLT3mut CR=10/11 (91%) (p=0.033 by Fischers exact test). Median follow-up is short, 5 months (1–15). All ten FLT3mut patients that entered CR are alive with only one known relapse (at 15 months post-CR). Conclusions: PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed ≤ 60 years old AML patients in combination with DA and high dose cytarabine. These combinations merit further study especially in patients with mutant FLT3 AML.