Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

316 Background: The pathogenetic and high frequency D816V KIT mutation in aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) exhibits in vitro and clinical resistance to imatinib. Midostaurin (PKC412) is an inhibitor of the KIT tyrosine kinase and can block D816V KIT-transformed cell growth at an IC50 of 30–40nM. Herein we report updated results of our fully accrued investigator-initiated, multicenter, phase II study of oral PKC412 in World Health Organization-defined ASM/MCL patients (pts). Method: PKC412 100 mg bid was administered as continuous 28-day cycles until progression/ intolerable toxicity. Lack of a major response (MR) or partial response (PR) per Valent criteria by the end of 2 cycles resulted in discontinuation from the protocol. Result: Efficacy and safety data for all 26 pts (15 male: 11 female) are presented. The distribution of SM pts with one or more “C” findings included ASM (n=4), SM-CMML (n=14), SM-MDS (n=3), SM-MDS/MPN-U (n=1), and MCL (n=4, two with associated MDS). The median age of pts was 62 years (range 24–79 years), and the median # of prior therapies was 1.5 (range 0–4). Responses have been observed in 18/26 pts (69%), consisting of 10 pts (38%) with a MR (6 incomplete remissions and 4 pure clinical responses), 5 pts (19%) with a good partial response (GPR), and 3 pts with a minor PR . Four pts had stable disease, and 4 pts exhibited progressive disease (PD). In subjects with higher quality responses, responses have been durable, with PKC412 administered for a median of 19.5 cycles (1.5 years) for MR pts and 15 cycles (1.2 years) for MR+PR pts (range 4+ - 58+ cycles). Major responses have included normalization of hypoalbuminemia, improvement of hemoglobin and platelet counts, and resolution of liver function abnormalities. High quality responses have also included near complete resolution of pleural effusion and ascites (with reduction of paracentesis), and substantial reversion or normalization of weight loss (including one pt discontinuing TPN). Clinically meaningful responses have been accompanied by reduction of palpable and/or 3-D volumetric CT measurement of hepato/splenomegaly, a >50% decrease in the serum tryptase level and/or marrow mast cell (MC) burden, and improvement in mediator symptoms and ECOG performance status. Cutaneous mast cell lesions faded in 2 pts. One patient with MCL has achieved a near complete remission with RBC transfusion independence, normalization of albumin, disappearance of 18 cm palpable splenomegaly (70% volume reduction by imaging), decrease of serum tryptase from 763 to < 20 ng/mL, and decrease of marrow MC burden from 60–70% to 5%. Of particular interest, in 3 pts with SM-CMML (all D816V KIT+), associated marked eosinophilia normalized (e.g. decreased from 50% to 1% in one pt).The most common grade 1–2 non-hematologic toxicities were nausea and/or vomiting, and less frequently diarrhea and fatigue. Asymptomatic and reversible hyperlipasemia occurred in 5 pts (grade 3, n=1). Hematologic toxicity with a suspected relationship to PKC412 has included ≥ grade 3 worsening of pre-existing anemia, and in one pt, recurrent grade 3 thrombocytopenia despite dose reduction to 50 mg bid. Dose reduction was undertaken in 4 additional pts (N/V, n=2; HA, n=1; transient increase in pre-existing pleural effusion, n=1). Dose re-escalation to 100 mg bid was feasible in 3 of these 4 pts. As of August 5, 2010, 8 pts continue PKC412, and treatment has been discontinued in 18 pts. Among the latter, 2 pts had PKC412 discontinued after 4 cycles (grade 3 fatigue, grade 2 N/V, n=1 each), and 7 initial responders have terminated therapy for PD after 8–39 cycles (1 for progression of CMML). Allele-specific PCR detected D816V KIT in 18/26 (69%) pts, and a novel, activating two–amino acid insertion in MPL was identified in a D816V KIT-negative pt. A statistically significant association was observed between positivity for D816V KIT and achieving a MR versus any other type of response (p=0.0095, Fisher's exact test). Pharmacokinetic data and histopathologic correlates of response (e.g. marrow MC burden and serum tryptase levels) will be presented. Conclusion: PKC412 is well tolerated and exhibits clinically relevant and durable responses which compare very favorably to literature reports of interferon-alpha or cladribine in advanced SM. An ongoing international trial aims to further evaluate the efficacy and safety of PKC412 in this pt population. Disclosures: Gotlib: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. George:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dutreix:Novartis: Employment. Gross:Novartis: Employment. Nikolova:Novartis: Employment. Graubert:Novartis: Research Funding.

Background: Constitutively activated receptor tyrosine kinase (TK) D816V KIT contributes to the pathogenesis of most ASM cases and exhibits resistance to imatinib. Midostaurine (MST, PKC412) is an inhibitor of the KIT TK and can block D816V KIT-transformed cell growth at an IC50 of 30–40nM. We report updated results of our ongoing phase II study of oral MST in ASM patients (pts). Methods: MS 100 mg bid was administered as continuous 28-day cycles until progression/intolerable toxicity. Lack of a major response (MR) or partial response (PR) per Valent criteria after 2 cycles resulted in pt discontinuation. To date, 15 pts have been enrolled, 9 with an associated MDS/MPD. Median age was 62 yrs (range 24–76), median # prior therapies was 1 (0–3). All 15 pts are evaluable for efficacy and safety. Responses were observed in 11/15 pts (73%). Best responses included 5 pts with a MR (all incomplete remissions), and 6 pts with a PR (5 good, 1 minor). Four pts were stopped after 2 cycles (2 stable disease, 2 progressive disease (PD)). The 5 MRs included resolution of hypoalbuminemia (n=3), increase in hemoglobin to >10 g/dL (n=1), and normalization of mild splenomegaly by CT (n=1). Additional MR findings in these pts included improvement in platelets to >100,000/mm3, and normalization of LFTs. Good PRs included reduction of ascites (n=2), >50% reduction in palpable hepatosplenomegaly (n=1), and >50% reduction in direct hyperbilirubinemia (n=2). In MR/PR pts, other findings included marked reduction in pleural effusion (n=2), reversion of weight loss, and improvement in cutaneous mastocytosis (MC) lesions. Among responders, the median duration of treatment was 10 cycles (4–18+). In 4 pts, the marrow MC burden decreased from the 50–60% to 10–15% range (stable in other responders). There was inconsistent reduction in the serum tryptase level among MR/PR pts. Safety: Nausea and/or vomiting (N/V) was the most frequent non-hematologic toxicity. Grade 1 tremor, grade 1–2 diarrhea, fatigue, and headache (HA) were less common. Possibly related hematologic toxicity consisted of worsening anemia in 2 pts (grade 3), and recurrent grade 3 thrombocytopenia despite dose reduction to 50 mg bid. Dose reduction occurred in 4 additional pts (N/V, n=2; HA, n=1; recurrent pleural effusion, n=1). Dose re-escalation to 100 mg bid was feasible in 3 of these 4 pts. Two pts had MST discontinued after 4 cycles (grade 3 fatigue, grade 2 N/V, n=1 each), and after cycles 8 and 15 for PD (n=2). Real-time allele-specific PCR has preliminarily detected D816V KIT in 9/15 (60%) pts. Further accrual is required to render any correlation between KIT mutation status and response. Preliminary pharmacokinetic analysis reveals that plasma concentrations of MST reached a maximal level of ∼3462 ng/mL on day 3, gradually decreased with time, and reached a stable level of ∼1368 ng/mL after cycle 1. This time dependent pattern is consistent with previous findings in AML pts. In conclusion, Midostaurine has sustained partial remitting activity in a high proportion of ASM pts.

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.

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