Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

Study Overview
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Brief Summary
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The safety and efficacy of midostaurin (PKC412), a novel investigational drug, will be evaluated on the basis of response rate, when administered to patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL)

Detailed Description
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This study assesses the activity and safety profile of twice-daily oral doses of midostaurin in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) with or without associated clonal hematological non-mast cell lineage disease (AHNMD). Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by excessive bone marrow production of mast cells which can can infiltrate tissues and release harmful substances, resulting in organ damage. These diseases have very limited treatment options and poor prognosis. Existing treatments for in advanced mast cell disease, eg, interferon-alpha; corticosteroids; and/or cladribine, exhibit low response rates that are usually partial in nature.

Official Title
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A Single Arm, Phase 2, Open-Label Study to Determine the Efficacy of Twice Daily Oral Dosing of PKC412 <Midostaurin> Administered to Patients With Aggressive Systemic Mastocytosis (ASM) and Mast Cell Leukemia (MCL)

Conditions
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Systemic Mastocytosis, Aggressive (ASM), Leukemia, Mast Cell, Hematological Non-mast Cell Lineage Disease (AHNMD)

Intervention / Treatment
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* Drug: Midostaurin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria At least 18 years of age. Karnofsky performance status (KPS) of > 30% (equivalent to ECOG 0 to 3) Mast cell disease, histologically confirmed and documented to be Aggressive systemic mastocytosis (ASM) OR Mast cell leukemia (MCL) meeting the following criteria Meets criteria for systemic mastocytosis Biopsy indicates diffuse infiltration by atypical, immature mast cells Bone marrow aspirate smears show at least 20% mast cells Confirmed availability of tissue sample within 6 months prior to entry into study, for evaluation of KIT mutation status of the tumor cells. Subjects who have systemic mastocytosis PLUS eosinophilia AND known positivity for FIP1L1-PDGFR-alpha fusion are eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy Blood levels of liver enzymes within normal limits (EXCEPTION: If the sole cause of elevated blood levels of liver enzymes is ASM/MCL, then AST and ALT ≤ 4X upper limit of normal (ULN), and/or bilirubin ≤ 4X ULN) Serum creatinine < 2.0 mg/dL If ANC < 1500/mm3; Hb < 10 g/dL; platelets < 75,000/mm3; AND/OR other blood values are > grade 2, then the relationship of these cytopenia(s) should be established as related to ASM or MCL on the basis of presence of mast cell infiltrate in the screening bone marrow exam and/or the presence of disease-related hypersplenism Prior use of glucocorticoids must be tapered off within 14 days of Day 1 of midostaurin treatment (EXCEPTION: If in the opinion of the investigator, the subject can be tapered off glucocorticoids, then dosage should be tapered to the minimal dose possible before first treatment with midostaurin) Negative serum pregnancy test for women of childbearing potential within 48 hours prior to administration of study drug Written informed consent. Anyone of reproductive potential must agree to use barrier contraceptives for the duration of the study Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study drug, and must agree to: Use barrier contraception for the duration of the study Use barrier contraception for 3 months post-study Not breast-feed Exclusion criteria Active pulmonary disease based on physical assessment or lateral chest X-ray, considered by the investigator to be unrelated to mastocytosis Any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks (EXCEPTION: pleural effusion related to systemic mastocytosis, eg, secondary to ascites, AND not causing symptomatic respiratory complaints, may be eligible) Cardiovascular disease, including congestive heart failure Myocardial infarction within 6 months Poorly-controlled hypertension with any Grade 3/4 cardiac problems (per New York Heart Association Criteria) Uncontrolled diabetes Chronic renal disease Active uncontrolled infection Known malignant disease involving the central nervous system (CNS) Known confirmed diagnosis of HIV infection or active viral hepatitis. Any other known disease, or concurrent severe and/or uncontrolled medical condition which could compromise participation in the study, including but not limited to: Received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA) within 30 days prior to Day 1 of PKC412 treatment. Received interferon-alpha within 30 days prior to Day 1 of midostaurin treatment. Received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment. Any surgical procedure, excluding central venous catheter placement or other minor procedures (eg, skin biopsy) within 14 days of Day 1 of midostaurin treatment Pregnant or breast-feeding Unwilling or unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midostaurin<br>100 mg midostaurin twice daily as oral capsules | Drug: Midostaurin<br>* Midostaurin is a broad-spectrum protein kinase inhibitor, acting on conventional PKC isoforms (α, β, γ); PDFRβ; VEGFR2; Syk; PKCη; Flk-1; Flt3; Cdk1/B; PKA; c-Kit; c-Fgr; c-Src; VEGFR1; and EGFR<br>* Other names: CGP41231;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects With Clinical Response [Partial Response (PR) + Complete Response (CR)] | Clinical Response [PR + CR] will be assessed after 2 cycles of treatment, with each cycle being 28 days (4 weeks) in length. Except as otherwise noted, the minimum criteria for PR is improvement by at least 50% from the baseline value towards the indicated value for one or more of the criteria below: BONE MARROW & BLOOD ANC <1000/uL Hb <10 g/dL Platelets >100,000/uL LIVER If hepatomegaly with ascites, decrease in frequency of paracenteses by 50% Elevated enzyme levels > upper limit of normal (ULN) Hypoalbuminemia < ULN Portal hypertension > ULN SPLEEN If palpable splenomegaly with hypersplenism/thrombocytopenia, hypersplenism markers improved GI TRACT If malabsorption with hypoalbuminemia and/or weight loss, albumin improved BONES If huge osteolyses or/and severe osteoporosis with pathologic fractures, partial resolution of osteolyses Subjects with PR or greater continue, those without response discontinue. | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival will be assessed after 12 cycles of treatment, with each cycle being 28 days (4 weeks) in length. 12 cycles of treatment is considered to be about 11 months. | 11 months | 
| Overall Survival (OS) | Overall survival was assessed as the median duration of survival at the time of data cut-off, and reported with 95% confidence interval. | 40 months |