Phase II Trial of the Tyrosine Kinase Inhibitor PKC412 in Advanced Systemic Mastocytosis: Preliminary Results.
Authors: Gotlib Jason , George Tracy I. , Linder Andrea , Ruddell Alisa , Quesada Sylvia , Akin Cem , DeAngelo Daniel J. , Cohen Pamela , Graubert Timothy 
Published: October 2019

Abstract
Background: Advanced forms of systemic mastocytosis (aggressive systemic mastocytosis [ASM] and mast cell leukemia [MCL]) are myeloproliferative disorders with few treatment options and a poor prognosis. In the majority of patients (pts), the pathogenesis of ASM/MCL is related to constitutive activation of the receptor tyrosine kinase (TK) KIT, due to an aspartate to valine mutation within protein codon 816 (D816V). D816V KIT is imatinib resistant both in vitro and in vivo. We demonstrated that PKC412 (N-benzoyl-staurosporine), a structurally different KIT TK inhibitor, can block the growth of D816V KIT-transformed cells at a low 50% inhibitory concentration of 30-40 nM (vs. imatinib > 1 uM). In addition, we treated a MCL pt with PKC412 on a compassionate basis, resulting in a good partial response (Gotlib et al, Blood. 2005; 106:2865-70). Therefore, we initiated a phase II study designed to assess PKC412 efficacy and safety in ASM/MCL pts.
Methods: PKC412 100 mg bid was administered in 28-day cycles. Pts without a major response (MR) or partial response (PR) by Valent criteria after 2 cycles were discontinued.
Results: To date, 11 ASM pts (n=6 male) have been enrolled, 7 with an associated CMML or mixed MDS/MPD. Median age at entry was 62 yrs (range 30–72); the median # of prior therapies was 1 (range 0–3).
Efficacy: Currently, 9 pts are evaluable for efficacy. Responses were observed in 6/9 (67%) pts, including 2 pts with a MR (both incomplete remission), and 4 pts with a PR (3 good PR, 1 minor response). Three pts were discontinued after 2 cycles (2 progressive disease, 1 stable disease). The 2 MRs consisted of resolution of hypoalbuminemia and correction of the platelet count to >100,000/mm3 in one pt, and normalization of splenomegaly with a 69% decrease in serum tryptase in the second pt. The 3 good PRs includedalmost complete resolution of large-volume ascites,> 50% reduction in palpable hepatosplenomegaly, and>50% reduction in direct hyperbilirubinemia.Serum tryptase decreased by 60–70% in 2 of these pts. All MRs and good PRs were accompanied by a marked improvement in performance status. Median duration of treatment in responders is 4.5 cycles (2+ - 11+). Bone marrow (BM) mast cell (MC) burden was stable to slightly decreased in responders; in 1 PR pt, the BM MC burden decreased from 50% to 20% with loss of expression of the neoplastic mast cell surface marker CD25.
Safety: PKC412 was generally well tolerated. Non-hematologic AEs included grade 1–2 nausea and/or vomiting (N/V), and less commonly diarrhea, fatigue, and headache (HA). Worsening of pre-existing anemia developed in 2 pts (grade 2 and 3, n=1 each). Dose reduction to 50 mg bid was undertaken in 3 pts for grade 3 thrombocytopenia, grade 2 N/V, and grade 2 HA. Two pts discontinued therapy after 4 cycles (1 for grade 3 fatigue and 1 for grade 2 N/V).
Conclusion: PKC412 demonstrates a high rate of MRs and PRs in this initial cohort of advanced SM pts, supporting further accrual in this Simon two-stage trial. Ongoing biologic investigations include pharmacokinetics, KIT mutation and phosphorylation status, serum KIT/KIT ligand levels, and ex vivo effects of PKC412 with BM MC.