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

A Single Arm, Phase II, Open-Label Study to Determine the Efficacy of 100mg Twice Daily Oral Dosing of Midostaurin Administered to Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia +/- an Associated Hematological Clonal Non-Mast Cell Lineage Disease

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).

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: Midostaurin (PKC412)

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Novartis Investigative Site
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• Austria
  • Wien, Austria, 1090
    • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4G4
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• France
  • Amiens, France, 80054
    • Novartis Investigative Site
  • Paris cedex 15, France, 75015
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Baden-Württemberg
    • Mannheim, Baden-Württemberg, Germany, 68305
      • Novartis Investigative Site
  • Nordrhein-Westfalen
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • Novartis Investigative Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, NO-0310
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80-952
    • Novartis Investigative Site
• Turkey
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
• United Kingdom
  • Glasgow - Scotland, United Kingdom, G12 OYN
    • Novartis Investigative Site
  • Liverpool, United Kingdom, L7 8XP
    • Novartis Investigative Site
  • London, United Kingdom, SE1 7EH
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Dept. of Hematology Clinic
    • Stanford, California, United States, 94305-5750
      • Stanford University Medical Center Stanford University 2
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Health Sciences University Dept.ofMedicalCollegeOfGeorgia
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute Hematology / Oncology
  • Michigan
    • Ann Arbor, Michigan, United States, +1 48109 0944
      • University of Michigan Comprehensive Cancer Center DeptofMichiganCancerCenter(3)
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center Dept. of MSKCC (2)
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University Dept. Hematologic Malignancies
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Virginia
    • Richmond, Virginia, United States, 23284
      • Virginia Commonwealth University SC

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

Key inclusion criteria:

• 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.

Key exclusion criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Midostaurin (PKC412); 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); Midostaurin was provided as 25 mg soft gelatin capsules for oral administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Time to Duration of Response (DoR)	The Duration of response (DoR) was defined as the time from first onset of confirmed response (MR or PR) to the date of first documented and confirmed progression or death due to ASM/MCL.	Up 5 years
Median Time to Response (TTR)	The Time to response (TTR) was defined as the time from start of treatment until the date of onset of confirmed response (MR or PR).	Up 5 years
Median Time to Progression-Free Survival (PFS)	The Progression-free survival (PFS) is defined as the time from start of treatment to the date of the first documented and confirmed progression or death due to any cause.	Up 5 years
Median Time to Overall Survival (OS)	The Overall Survival (OS) is defined as the time from start of treatment to the date of death due to any cause.	Up 5 years
Long-term Safety and Tolerability of Midostaurin	Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC)	Up to 30 days after last dose of study treatment
Histopathologic Response	Histopathologic response was summarized to demonstrate the change from baseline in percentage of mast cell infiltrations in the Bone Marrow (BM) and related serum tryptase levels.	Up 5 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 13, 2008
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): August 24, 2017

Study Registration Dates

• First Submitted: October 28, 2008
• First Submitted That Met QC Criteria: October 28, 2008
• First Posted (ESTIMATE): October 29, 2008

Study Record Updates

• Last Update Posted (ACTUAL): November 15, 2018
• Last Update Submitted That Met QC Criteria: October 16, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: tyrosine kinase inhibitor; Systemic; mast cell leukemia; Aggressive; Aggressive systemic mastocytosis; C-Findings; KIT mutation; AHNMD
• 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: CPKC412D2201 (Novartis, Inc); 2008-000280-42 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No