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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00782067
• Other study ID #: CPKC412D2201
• Secondary ID: 2008-000280-42
• Status: Completed
• Phase: Phase 2
• Start date: October 13, 2008
• Est. completion date: August 24, 2017

Study information

• Verified date: October 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 116
• Est. completion date: August 24, 2017
• Est. primary completion date: December 1, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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-a, or 2 chlorodeoxyadenosine within 30 days prior to start of midostaurin treatment.

• Patients who had ASM with eosinophilia and known positivity for the FIP1L1- PDGFRa 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.

Related Conditions & MeSH terms

• Aggression
• Leukemia
• Leukemia, Mast-Cell
• Mastocytosis

Intervention

Drug:
• Midostaurin (PKC412)
Midostaurin was provided as 25 mg soft gelatin capsules for oral administration.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Camperdown	New South Wales
Australia	Novartis Investigative Site	Prahran	Victoria
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
France	Novartis Investigative Site	Amiens
France	Novartis Investigative Site	Paris cedex 15
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mannheim	Baden-Württemberg
Netherlands	Novartis Investigative Site	Groningen
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Gdansk
Turkey	Novartis Investigative Site	Istanbul
United Kingdom	Novartis Investigative Site	Glasgow - Scotland
United Kingdom	Novartis Investigative Site	Liverpool
United Kingdom	Novartis Investigative Site	London
United States	University of Michigan Comprehensive Cancer Center DeptofMichiganCancerCenter(3)	Ann Arbor	Michigan
United States	Georgia Health Sciences University Dept.ofMedicalCollegeOfGeorgia	Augusta	Georgia
United States	Dana Farber Cancer Institute Hematology / Oncology	Boston	Massachusetts
United States	University of California at Los Angeles Dept. of Hematology Clinic	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center Dept. of MSKCC (2)	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Oregon Health and Science University Dept. Hematologic Malignancies	Portland	Oregon
United States	Virginia Commonwealth University SC	Richmond	Virginia
United States	Stanford University Medical Center Stanford University 2	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Netherlands,  Norway,  Poland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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