Oral PKC 412 has activity in patients (pts) with mutant FLT3 acute myeloid leukemia (AML): A phase II trial

Category: Leukemia, Adult

Authors: R. M. Stone, V. Klimek, D. Deangelo, I. Galinsky, E. Fox, S. Nimer, E. Estey, A. Yap, D. G. Gilliland, J. Griffin; Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; MD Anderson Cancer Center, Houston, TX; Novartis, Basel, Switzerland

Abstract: The pathophysiology in 30% of AML pts may be due to activation of the FLT3 transmembrane tyrosine kinase (TK) due an acquired mutation, either a 6-33 amino acid repeat in the juxtamembrane region (internal tandem duplication, ITD) or a point mutation in the D835 codon. Both types of mutations confer growth factor independence in leukemic cell lines and cause a fatal myeloproliferative syndrome (MPS) in mice. PKC 412 (N-benzoylstaurosporine) inhibits FLT3 TK activity (IC50=10 nM), specifically kills cell lines transfected with activated FLT3 and prolongs survival in mice with activated FLT3-induced MPS. Based on this preclinical activity and on phase I trials in solid tumor pts, we performed a phase II study of continuous treatment with PKC 412 at 75 mg po tid in adults with poor prognosis untreated or refractory and/or relapsed mutant FLT3 AML not on hydroxyurea 7d prior or during the study. We have treated 14 pts (12 male) with median age 56 (range 38-78). The median number of prior regimens was 3 (range 0-5); 11 had normal cytogenetics. 13 had an ITD and one a D835Y. Grade I-II nausea occurred in 12 pts. One pt each stopped drug on: d15 (pulmonary toxicity, died on d22), d15 (high bilirubin with sepsis), d22 (death of unknown cause), d28 (elevated SGOT), and on d50 (severe infection). Progressions occurred on d22 and after initial responses on d29(2), 63, 72, and 85. 2 pts remain on drug at d54 and 74; one pt stopped drug on d99 to undergo BMT. 12/14 pts had a > 50% reduction in peripheral blasts compared with baseline (BL), including two who cleared blasts by d29 despite BL blast counts of 16K-110K/ul. 5 pts marrow blasts decreased by >50% compared with BL, including a pt with <5% blasts and a normal CBC on d96. PK studies revealed a steady state level of 10 uM on d2 (>99% of the drug is protein bound). A decrease in FLT3 autophosphorylation on tyrosine relative to total FLT3 protein occurred in 3/4 pts blast samples obtained 24h after the start of PKC 412 therapy compared with BL. This study reveals a hematological response rate with PKC412 in advanced AML pts comparable to that observed with imatinib in CML in blast crisis and argues for continued development of this agent in AML.