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Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

Primary Purpose

Systemic Mastocytosis, Aggressive (ASM), Leukemia, Mast Cell, Hematological Non-mast Cell Lineage Disease (AHNMD)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Midostaurin
Sponsored by
Jason Robert Gotlib
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Systemic Mastocytosis, Aggressive (ASM)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria At least 18 years of age. Karnofsky performance status (KPS) of > 30% (equivalent to ECOG 0 to 3) Mast cell disease, histologically confirmed and documented to be Aggressive systemic mastocytosis (ASM) OR Mast cell leukemia (MCL) meeting the following criteria Meets criteria for systemic mastocytosis Biopsy indicates diffuse infiltration by atypical, immature mast cells Bone marrow aspirate smears show at least 20% mast cells Confirmed availability of tissue sample within 6 months prior to entry into study, for evaluation of KIT mutation status of the tumor cells. Subjects who have systemic mastocytosis PLUS eosinophilia AND known positivity for FIP1L1-PDGFR-alpha fusion are eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy Blood levels of liver enzymes within normal limits (EXCEPTION: If the sole cause of elevated blood levels of liver enzymes is ASM/MCL, then AST and ALT ≤ 4X upper limit of normal (ULN), and/or bilirubin ≤ 4X ULN) Serum creatinine < 2.0 mg/dL If ANC < 1500/mm3; Hb < 10 g/dL; platelets < 75,000/mm3; AND/OR other blood values are > grade 2, then the relationship of these cytopenia(s) should be established as related to ASM or MCL on the basis of presence of mast cell infiltrate in the screening bone marrow exam and/or the presence of disease-related hypersplenism Prior use of glucocorticoids must be tapered off within 14 days of Day 1 of midostaurin treatment (EXCEPTION: If in the opinion of the investigator, the subject can be tapered off glucocorticoids, then dosage should be tapered to the minimal dose possible before first treatment with midostaurin) Negative serum pregnancy test for women of childbearing potential within 48 hours prior to administration of study drug Written informed consent. Anyone of reproductive potential must agree to use barrier contraceptives for the duration of the study Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study drug, and must agree to: Use barrier contraception for the duration of the study Use barrier contraception for 3 months post-study Not breast-feed Exclusion criteria Active pulmonary disease based on physical assessment or lateral chest X-ray, considered by the investigator to be unrelated to mastocytosis Any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks (EXCEPTION: pleural effusion related to systemic mastocytosis, eg, secondary to ascites, AND not causing symptomatic respiratory complaints, may be eligible) Cardiovascular disease, including congestive heart failure Myocardial infarction within 6 months Poorly-controlled hypertension with any Grade 3/4 cardiac problems (per New York Heart Association Criteria) Uncontrolled diabetes Chronic renal disease Active uncontrolled infection Known malignant disease involving the central nervous system (CNS) Known confirmed diagnosis of HIV infection or active viral hepatitis. Any other known disease, or concurrent severe and/or uncontrolled medical condition which could compromise participation in the study, including but not limited to: Received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA) within 30 days prior to Day 1 of PKC412 treatment. Received interferon-alpha within 30 days prior to Day 1 of midostaurin treatment. Received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment. Any surgical procedure, excluding central venous catheter placement or other minor procedures (eg, skin biopsy) within 14 days of Day 1 of midostaurin treatment Pregnant or breast-feeding Unwilling or unable to comply with the protocol

Sites / Locations

  • Stanford University School of Medicine
  • Dana Farber Cancer Institute
  • Washington University-St. Louis

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Midostaurin

Arm Description

100 mg midostaurin twice daily as oral capsules

Outcomes

Primary Outcome Measures

Subjects With Clinical Response [Partial Response (PR) + Complete Response (CR)]
Clinical Response [PR + CR] will be assessed after 2 cycles of treatment, with each cycle being 28 days (4 weeks) in length. Except as otherwise noted, the minimum criteria for PR is improvement by at least 50% from the baseline value towards the indicated value for one or more of the criteria below: BONE MARROW & BLOOD ANC <1000/uL Hb <10 g/dL Platelets >100,000/uL LIVER If hepatomegaly with ascites, decrease in frequency of paracenteses by 50% Elevated enzyme levels > upper limit of normal (ULN) Hypoalbuminemia < ULN Portal hypertension > ULN SPLEEN If palpable splenomegaly with hypersplenism/thrombocytopenia, hypersplenism markers improved GI TRACT If malabsorption with hypoalbuminemia and/or weight loss, albumin improved BONES If huge osteolyses or/and severe osteoporosis with pathologic fractures, partial resolution of osteolyses Subjects with PR or greater continue, those without response discontinue.

Secondary Outcome Measures

Overall Survival (OS)
Overall survival will be assessed after 12 cycles of treatment, with each cycle being 28 days (4 weeks) in length. 12 cycles of treatment is considered to be about 11 months.
Overall Survival (OS)
Overall survival was assessed as the median duration of survival at the time of data cut-off, and reported with 95% confidence interval.

Full Information

First Posted
October 3, 2005
Last Updated
September 19, 2018
Sponsor
Jason Robert Gotlib
Collaborators
Novartis, Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00233454
Brief Title
Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia
Official Title
A Single Arm, Phase 2, Open-Label Study to Determine the Efficacy of Twice Daily Oral Dosing of PKC412 <Midostaurin> Administered to Patients With Aggressive Systemic Mastocytosis (ASM) and Mast Cell Leukemia (MCL)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
March 2005 (Actual)
Primary Completion Date
June 18, 2010 (Actual)
Study Completion Date
April 16, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jason Robert Gotlib
Collaborators
Novartis, Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The safety and efficacy of midostaurin (PKC412), a novel investigational drug, will be evaluated on the basis of response rate, when administered to patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL)
Detailed Description
This study assesses the activity and safety profile of twice-daily oral doses of midostaurin in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) with or without associated clonal hematological non-mast cell lineage disease (AHNMD). Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by excessive bone marrow production of mast cells which can can infiltrate tissues and release harmful substances, resulting in organ damage. These diseases have very limited treatment options and poor prognosis. Existing treatments for in advanced mast cell disease, eg, interferon-alpha; corticosteroids; and/or cladribine, exhibit low response rates that are usually partial in nature.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Systemic Mastocytosis, Aggressive (ASM), Leukemia, Mast Cell, Hematological Non-mast Cell Lineage Disease (AHNMD)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Midostaurin
Arm Type
Experimental
Arm Description
100 mg midostaurin twice daily as oral capsules
Intervention Type
Drug
Intervention Name(s)
Midostaurin
Other Intervention Name(s)
PKC412, CGP41251, CGP41231
Intervention Description
Midostaurin is a broad-spectrum protein kinase inhibitor, acting on conventional PKC isoforms (α, β, γ); PDFRβ; VEGFR2; Syk; PKCη; Flk-1; Flt3; Cdk1/B; PKA; c-Kit; c-Fgr; c-Src; VEGFR1; and EGFR
Primary Outcome Measure Information:
Title
Subjects With Clinical Response [Partial Response (PR) + Complete Response (CR)]
Description
Clinical Response [PR + CR] will be assessed after 2 cycles of treatment, with each cycle being 28 days (4 weeks) in length. Except as otherwise noted, the minimum criteria for PR is improvement by at least 50% from the baseline value towards the indicated value for one or more of the criteria below: BONE MARROW & BLOOD ANC <1000/uL Hb <10 g/dL Platelets >100,000/uL LIVER If hepatomegaly with ascites, decrease in frequency of paracenteses by 50% Elevated enzyme levels > upper limit of normal (ULN) Hypoalbuminemia < ULN Portal hypertension > ULN SPLEEN If palpable splenomegaly with hypersplenism/thrombocytopenia, hypersplenism markers improved GI TRACT If malabsorption with hypoalbuminemia and/or weight loss, albumin improved BONES If huge osteolyses or/and severe osteoporosis with pathologic fractures, partial resolution of osteolyses Subjects with PR or greater continue, those without response discontinue.
Time Frame
2 months
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
Overall survival will be assessed after 12 cycles of treatment, with each cycle being 28 days (4 weeks) in length. 12 cycles of treatment is considered to be about 11 months.
Time Frame
11 months
Title
Overall Survival (OS)
Description
Overall survival was assessed as the median duration of survival at the time of data cut-off, and reported with 95% confidence interval.
Time Frame
40 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria At least 18 years of age. Karnofsky performance status (KPS) of > 30% (equivalent to ECOG 0 to 3) Mast cell disease, histologically confirmed and documented to be Aggressive systemic mastocytosis (ASM) OR Mast cell leukemia (MCL) meeting the following criteria Meets criteria for systemic mastocytosis Biopsy indicates diffuse infiltration by atypical, immature mast cells Bone marrow aspirate smears show at least 20% mast cells Confirmed availability of tissue sample within 6 months prior to entry into study, for evaluation of KIT mutation status of the tumor cells. Subjects who have systemic mastocytosis PLUS eosinophilia AND known positivity for FIP1L1-PDGFR-alpha fusion are eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy Blood levels of liver enzymes within normal limits (EXCEPTION: If the sole cause of elevated blood levels of liver enzymes is ASM/MCL, then AST and ALT ≤ 4X upper limit of normal (ULN), and/or bilirubin ≤ 4X ULN) Serum creatinine < 2.0 mg/dL If ANC < 1500/mm3; Hb < 10 g/dL; platelets < 75,000/mm3; AND/OR other blood values are > grade 2, then the relationship of these cytopenia(s) should be established as related to ASM or MCL on the basis of presence of mast cell infiltrate in the screening bone marrow exam and/or the presence of disease-related hypersplenism Prior use of glucocorticoids must be tapered off within 14 days of Day 1 of midostaurin treatment (EXCEPTION: If in the opinion of the investigator, the subject can be tapered off glucocorticoids, then dosage should be tapered to the minimal dose possible before first treatment with midostaurin) Negative serum pregnancy test for women of childbearing potential within 48 hours prior to administration of study drug Written informed consent. Anyone of reproductive potential must agree to use barrier contraceptives for the duration of the study Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study drug, and must agree to: Use barrier contraception for the duration of the study Use barrier contraception for 3 months post-study Not breast-feed Exclusion criteria Active pulmonary disease based on physical assessment or lateral chest X-ray, considered by the investigator to be unrelated to mastocytosis Any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks (EXCEPTION: pleural effusion related to systemic mastocytosis, eg, secondary to ascites, AND not causing symptomatic respiratory complaints, may be eligible) Cardiovascular disease, including congestive heart failure Myocardial infarction within 6 months Poorly-controlled hypertension with any Grade 3/4 cardiac problems (per New York Heart Association Criteria) Uncontrolled diabetes Chronic renal disease Active uncontrolled infection Known malignant disease involving the central nervous system (CNS) Known confirmed diagnosis of HIV infection or active viral hepatitis. Any other known disease, or concurrent severe and/or uncontrolled medical condition which could compromise participation in the study, including but not limited to: Received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA) within 30 days prior to Day 1 of PKC412 treatment. Received interferon-alpha within 30 days prior to Day 1 of midostaurin treatment. Received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment. Any surgical procedure, excluding central venous catheter placement or other minor procedures (eg, skin biopsy) within 14 days of Day 1 of midostaurin treatment Pregnant or breast-feeding Unwilling or unable to comply with the protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason Robert Gotlib
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University-St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
16921041
Citation
Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfield CD; Cancer and Leukemia Group B. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006 Aug 20;24(24):3904-11. doi: 10.1200/JCO.2006.06.9500.
Results Reference
background
Citation
Gotlib JR, George TI, Linder A, et al. "Phase II Trial of the Tyrosine Kinase Inhibitor PKC412 in Advanced Systemic Mastocytosis: Preliminary Results." Blood. 16 November 2006;108(11)16:abs3609
Results Reference
result
Citation
Gotlib JR, George TI, Corless C, et al. "The KIT Tyrosine Kinase Inhibitor Midostaurin (PKC412) Exhibits a High Response Rate in Aggressive Systemic Mastocytosis(ASM): Interim Results of a Phase 2 Trial." Blood. 16 November 2007;110(11):abs 3536
Results Reference
result
Citation
Gotlib JR, DeAngelo DJ, George TI, et al. "KIT Inhibitor Midostaurin Exhibits a High Rate of Clinically Meaningful and Durable Responses in Advanced Systemic Mastocytosis: Report of a Fully Accrued Phase II Trial." Blood. 19 November 2010;116(21):abs316
Results Reference
result
PubMed Identifier
27355533
Citation
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.
Results Reference
result
PubMed Identifier
28744009
Citation
DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, Westervelt P, Merker JD, Berube C, Coutre S, Liedtke M, Medeiros B, Sternberg D, Dutreix C, Ruffie PA, Corless C, Graubert TJ, Gotlib J. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018 Feb;32(2):470-478. doi: 10.1038/leu.2017.234. Epub 2017 Jul 24.
Results Reference
result

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Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

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