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

• ClinicalTrials.gov Identifier: NCT00782067
• Recruitment Status: Completed
• First Posted: October 29, 2008
• Results First Posted: June 6, 2017
• Last Update Posted: November 15, 2018
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Leukemia	Drug: Midostaurin (PKC412)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 116 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 13, 2008
• Actual Primary Completion Date: December 1, 2014
• Actual Study Completion Date: August 24, 2017

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Overall Response Rate (ORR) [ Time Frame: 6 months ]

   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.

Secondary Outcome Measures :

1. Median Time to Duration of Response (DoR) [ Time Frame: Up 5 years ]
   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.
2. Median Time to Response (TTR) [ Time Frame: Up 5 years ]
   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).
3. Median Time to Progression-Free Survival (PFS) [ Time Frame: Up 5 years ]
   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.
4. Median Time to Overall Survival (OS) [ Time Frame: Up 5 years ]
   The Overall Survival (OS) is defined as the time from start of treatment to the date of death due to any cause.
5. Long-term Safety and Tolerability of Midostaurin [ Time Frame: Up to 30 days after last dose of study treatment ]
   Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC)
6. Histopathologic Response [ Time Frame: Up 5 years ]
   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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

University of California at Los Angeles Dept. of Hematology Clinic

Los Angeles, California, United States, 90095

Stanford University Medical Center Stanford University 2

Stanford, California, United States, 94305-5750

United States, Georgia

Georgia Health Sciences University Dept.ofMedicalCollegeOfGeorgia

Augusta, Georgia, United States, 30912

United States, Massachusetts

Dana Farber Cancer Institute Hematology / Oncology

Boston, Massachusetts, United States, 02215

United States, Michigan

University of Michigan Comprehensive Cancer Center DeptofMichiganCancerCenter(3)

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

United States, New York

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

New York, New York, United States, 10021

United States, Oregon

Oregon Health and Science University Dept. Hematologic Malignancies

Portland, Oregon, United States, 97239

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Virginia

Virginia Commonwealth University SC

Richmond, Virginia, United States, 23284

Australia, New South Wales

Novartis Investigative Site

Camperdown, New South Wales, Australia, 2050

Australia, Victoria

Novartis Investigative Site

Prahran, Victoria, Australia, 3181

Austria

Novartis Investigative Site

Wien, Austria, 1090

Belgium

Novartis Investigative Site

Leuven, Belgium, 3000

Canada, Ontario

Novartis Investigative Site

London, Ontario, Canada, N6A 4G4

Novartis Investigative Site

Toronto, Ontario, Canada, M5G 2M9

France

Novartis Investigative Site

Amiens, France, 80054

Novartis Investigative Site

Paris cedex 15, France, 75015

Germany

Novartis Investigative Site

Mannheim, Baden-Württemberg, Germany, 68305

Novartis Investigative Site

Koeln, Nordrhein-Westfalen, Germany, 50937

Novartis Investigative Site

Berlin, Germany, 13353

Novartis Investigative Site

Hamburg, Germany, 20246

Novartis Investigative Site

Leipzig, Germany, 04103

Netherlands

Novartis Investigative Site

Groningen, Netherlands, 9713 GZ

Norway

Novartis Investigative Site

Oslo, Norway, NO-0310

Poland

Novartis Investigative Site

Gdansk, Poland, 80-952

Turkey

Novartis Investigative Site

Istanbul, Turkey, 34093

United Kingdom

Novartis Investigative Site

Glasgow - Scotland, United Kingdom, G12 OYN

Novartis Investigative Site

Liverpool, United Kingdom, L7 8XP

Novartis Investigative Site

London, United Kingdom, SE1 7EH

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00782067
• Other Study ID Numbers: CPKC412D2201; 2008-000280-42 ( EudraCT Number )
• First Posted: October 29, 2008
• Results First Posted: June 6, 2017
• Last Update Posted: November 15, 2018
• Last Verified: October 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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

Additional relevant MeSH terms:

Leukemia; Mastocytosis; Mastocytosis, Systemic; Leukemia, Mast-Cell; Aggression; Neoplasms by Histologic Type; Neoplasms; Behavioral Symptoms; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Skin Diseases; Immune Complex Diseases; Hypersensitivity; Immune System Diseases; Leukemia, Myeloid, Acute; Leukemia, Myeloid; Midostaurin; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action