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

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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:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 116 participants
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


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.




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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00782067


  Show 29 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00782067     History of Changes
Other Study ID Numbers: CPKC412D2201
2008-000280-42 ( EudraCT Number )
First Posted: October 29, 2008    Key Record Dates
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:
Mastocytosis
Mastocytosis, Systemic
Leukemia
Aggression
Leukemia, Mast-Cell
Neoplasms by Histologic Type
Neoplasms
Behavioral Symptoms
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Skin Diseases
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Midostaurin
Staurosporine
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action