Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

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)

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)

Study Overview

• Status: Completed
• Conditions: Systemic Mastocytosis, Aggressive (ASM); Leukemia, Mast Cell; Hematological Non-mast Cell Lineage Disease (AHNMD)
• Intervention / Treatment: Drug: Midostaurin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University-St. Louis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midostaurin; 100 mg midostaurin twice daily as oral capsules	Drug: Midostaurin; 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; Other Names: PKC412; CGP41251; CGP41231

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jason Robert Gotlib
• Collaborators: Novartis; Novartis Pharmaceuticals
• Investigators: Principal Investigator: Jason Robert Gotlib, Stanford University

Publications and helpful links

General Publications

• Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfield CD; Cancer and Leukemia Group B. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006 Aug 20;24(24):3904-11. doi: 10.1200/JCO.2006.06.9500.
• Gotlib JR, George TI, Linder A, et al. "Phase II Trial of the Tyrosine Kinase Inhibitor PKC412 in Advanced Systemic Mastocytosis: Preliminary Results." Blood. 16 November 2006;108(11)16:abs3609
• Gotlib JR, George TI, Corless C, et al. "The KIT Tyrosine Kinase Inhibitor Midostaurin (PKC412) Exhibits a High Response Rate in Aggressive Systemic Mastocytosis(ASM): Interim Results of a Phase 2 Trial." Blood. 16 November 2007;110(11):abs 3536
• Gotlib JR, DeAngelo DJ, George TI, et al. "KIT Inhibitor Midostaurin Exhibits a High Rate of Clinically Meaningful and Durable Responses in Advanced Systemic Mastocytosis: Report of a Fully Accrued Phase II Trial." Blood. 19 November 2010;116(21):abs316
• Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, Awan FT, Hexner E, Mauro MJ, Sternberg DW, Villeneuve M, Huntsman Labed A, Stanek EJ, Hartmann K, Horny HP, Valent P, Reiter A. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098.
• DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, Westervelt P, Merker JD, Berube C, Coutre S, Liedtke M, Medeiros B, Sternberg D, Dutreix C, Ruffie PA, Corless C, Graubert TJ, Gotlib J. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018 Feb;32(2):470-478. doi: 10.1038/leu.2017.234. Epub 2017 Jul 24.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2005
• Primary Completion (Actual): June 18, 2010
• Study Completion (Actual): April 16, 2011

Study Registration Dates

• First Submitted: October 3, 2005
• First Submitted That Met QC Criteria: October 3, 2005
• First Posted (Estimate): October 5, 2005

Study Record Updates

• Last Update Posted (Actual): September 20, 2018
• Last Update Submitted That Met QC Criteria: September 19, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Skin Diseases; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Hypersensitivity; Neoplasms, Connective Tissue; Immune Complex Diseases; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Aggression; Leukemia; Mastocytosis; Mastocytosis, Systemic; Leukemia, Mast-Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Midostaurin
• Other Study ID Numbers: IRB-13704; 95242 (Other Identifier: Stanford University Secondary IRB Approval Number); HEMMPD0003 (Other Identifier: OnCore); CPKC412D2201 (Novartis, Inc); 2213 (Novartis, Inc)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No