Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia

NCT00782067 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: CPKC412D22012008-000280-42
• Study Type: interventional
• Target: 116
• Locations: 11 countries
• Sites: 28

Brief Summary

The purpose of this study was to determine the efficacy and safety of twice daily (bid) oral midostaurin in patients with Aggressive Systemic Mastocytosis (ASM) or Mast Cell Leukemia (MCL) with or without an Associated Hematological clonal Non-Mast cell lineage Disease (AHNMD).

Conditions

Leukemia

Keywords

Aggressive systemic mastocytosis; mast cell leukemia; C-Findings; tyrosine kinase inhibitor; KIT mutation; AHNMD; Systemic; Aggressive

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Overall Response Rate (ORR)

  Overall Response Rate (ORR) was defined as the percentage of participants who classified as confirmed responders (Major Response (MR) or Partial Response (PR)) by the adjudication of the SSC and based on a Modified Valent Criteria. A major responder had complete resolution of at least one C-Finding and no progression in other C-Findings. A partial responder showed a measurable improvement in one or more C-Finding(s) without confirmed progression in other C-Findings. A C-Finding was a Clinical Finding, which was considered by the investigator and corroborated by the Study Steering Committee (SSC) Chairperson or designee, attributable to the mast cell disease component and not the associated hematological clonal non-mast cell lineage disease (AHNMD) component or any other cause.

  6 months

Secondary Outcomes (6)

• Median Time to Duration of Response (DoR)

  Up 5 years

• Median Time to Response (TTR)

  Up 5 years

• Median Time to Progression-Free Survival (PFS)

  Up 5 years

• Median Time to Overall Survival (OS)

  Up 5 years

• Long-term Safety and Tolerability of Midostaurin

  Up to 30 days after last dose of study treatment

Study Arms (1)

Midostaurin (PKC412)

EXPERIMENTAL

Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.

Drug: Midostaurin (PKC412)

Interventions

Midostaurin (PKC412) DRUG

Midostaurin was provided as 25 mg soft gelatin capsules for oral administration.

Midostaurin (PKC412)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients ≥ 18 years of age who provided written informed consent, Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 and a life expectancy of \>12 weeks, electrocardiogram with a QTcF of ≤ 450 ms, with a diagnosis of SM and sub-variants based on WHO criteria.
• Patients with ASM or MCL were to have one or more measurable clinical findings (termed "C-findings") and defined as those attributable to the mast cell disease component and not to AHNMD or any other cause.
• Patients with MCL were to have BM aspirate smears with ≥ 20% immature MCs. Patients with AHNMD were eligible if it was not life-threatening or in an acute stage.

You may not qualify if:

• Patients with cardiovascular disease including congestive heart failure class III or IV according to the New York Heart Association classification, left ventricular ejection fraction (LVEF) of \<50%, myocardial infarction within the previous 6 months, or poorly controlled hypertension.
• Patients with a heart block of any degree at screening (for Canada only).
• Patients with an AHNMD who required immediate cytoreductive therapy or targeted therapy (other than midostaurin).
• Patients who had demonstrated relapse after 3 or more prior regimens of SM treatment regardless of treatment regimen for supportive care (e.g., symptom-limiting therapies).
• Patients who had received any investigational agent, targeted therapy, chemotherapy, interferon-α, or 2 chlorodeoxyadenosine within 30 days prior to start of midostaurin treatment.
• Patients who had ASM with eosinophilia and known positivity for the FIP1L1- PDGFRα fusion unless they had demonstrated relapse or disease progression on prior imatinib therapy.
• Patients who had received any treatment with midostaurin prior to study entry.
• Patients who had received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment.
• Patients who had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1 of midostaurin treatment.
• Patients with any pulmonary infiltrate, including those suspected to be of infectious origin. In particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray were not eligible until the pulmonary infiltrates had completely resolved. Exception: patients with ASM/MCL ± AHNMD-related pleural effusion as judged by the Investigator and approved by the SSC Chairperson or designee were permitted to enter the study.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (29)

University of California at Los Angeles Dept. of Hematology Clinic

Los Angeles, California, 90095, United States

Location

Stanford University Medical Center Stanford University 2

Stanford, California, 94305-5750, United States

Location

Georgia Health Sciences University Dept.ofMedicalCollegeOfGeorgia

Augusta, Georgia, 30912, United States

Location

Dana Farber Cancer Institute Hematology / Oncology

Boston, Massachusetts, 02215, United States

Location

University of Michigan Comprehensive Cancer Center DeptofMichiganCancerCenter(3)

Ann Arbor, Michigan, +1 48109 0944, United States

Location

Memorial Sloan Kettering Cancer Center Dept. of MSKCC (2)

New York, New York, 10021, United States

Location

Oregon Health and Science University Dept. Hematologic Malignancies

Portland, Oregon, 97239, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Virginia Commonwealth University SC

Richmond, Virginia, 23284, United States

Location

Novartis Investigative Site

Camperdown, New South Wales, 2050, Australia

Location

Novartis Investigative Site

Prahran, Victoria, 3181, Australia

Location

Novartis Investigative Site

Vienna, 1090, Austria

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

London, Ontario, N6A 4G4, Canada

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Amiens, 80054, France

Location

Novartis Investigative Site

Paris, 75015, France

Location

Novartis Investigative Site

Mannheim, Baden-Wurttemberg, 68305, Germany

Location

Novartis Investigative Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Hamburg, 20246, Germany

Location

Novartis Investigative Site

Leipzig, 04103, Germany

Location

Novartis Investigative Site

Groningen, 9713 GZ, Netherlands

Location

Novartis Investigative Site

Oslo, NO-0310, Norway

Location

Novartis Investigative Site

Gdansk, 80-952, Poland

Location

Novartis Investigative Site

Istanbul, 34093, Turkey (Türkiye)

Location

Novartis Investigative Site

Glasgow - Scotland, G12 OYN, United Kingdom

Location

Novartis Investigative Site

Liverpool, L7 8XP, United Kingdom

Location

Novartis Investigative Site

London, SE1 7EH, United Kingdom

Location

Related Publications (3)

• Medawar G, Sakalabaktula K, Magri J, Rinker E, Baratam P. KIT V560D-Mutated Systemic Mastocytosis Associated With High-Risk Myelodysplastic Syndrome: A Unique Case of Systemic Mastocytosis-Associated Hematologic Neoplasm. Case Rep Hematol. 2024 Nov 30;2024:4360304. doi: 10.1155/crh/4360304. eCollection 2024.

  PMID: 39649724 DERIVED

• Hartmann K, Gotlib J, Akin C, Hermine O, Awan FT, Hexner E, Mauro MJ, Menssen HD, Redhu S, Knoll S, Sotlar K, George TI, Horny HP, Valent P, Reiter A, Kluin-Nelemans HC. Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis. J Allergy Clin Immunol. 2020 Aug;146(2):356-366.e4. doi: 10.1016/j.jaci.2020.03.044. Epub 2020 May 11.

  PMID: 32437738 DERIVED

• 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.

  PMID: 27355533 DERIVED

MeSH Terms

Conditions

Leukemia; Mastocytosis, Systemic; Leukemia, Mast-Cell; Aggression

Interventions

midostaurin

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Mastocytosis; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Mast Cell Activation Disorders; Immune System Diseases; Leukemia, Myeloid, Acute; Leukemia, Myeloid; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior; Social Behavior

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2008
• First Posted: October 29, 2008
• Study Start: October 13, 2008
• Primary Completion: December 1, 2014
• Study Completion: August 24, 2017
• Last Updated: November 15, 2018
• Results First Posted: June 6, 2017

Record last verified: 2018-10

Locations

AU (2); CA (2); DE (5); NL (1); NO (1); US (9); TU (1); FR (2); PL (1); GB (3); BE (1)