Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

NCT00233454 | Completed Phase 2 Results DMC

• 5 other identifiers: IRB-1370495242HEMMPD0003CPKC412D22012213
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 3

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)

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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.

  2 months

Secondary Outcomes (2)

• Overall Survival (OS)

  11 months

• Overall Survival (OS)

  40 months

Study Arms (1)

Midostaurin

EXPERIMENTAL

100 mg midostaurin twice daily as oral capsules

Drug: Midostaurin

Interventions

Midostaurin DRUG

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

Also known as: PKC412, CGP41251, CGP41231

Midostaurin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Jason Robert Gotlib: lead
• Novartis: collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (3)

Stanford University School of Medicine

Stanford, California, 94305, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Washington University-St. Louis

St Louis, Missouri, 63110, United States

Location

Related Publications (6)

• 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.

  PMID: 16921041 BACKGROUND

• 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

  RESULT

• 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

  RESULT

• 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

  RESULT

• 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.

  PMID: 27355533 RESULT

• 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.

  PMID: 28744009 RESULT

MeSH Terms

Conditions

Mastocytosis, Systemic; Aggression; Leukemia, Mast-Cell

Interventions

midostaurin

Condition Hierarchy (Ancestors)

Mastocytosis; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Mast Cell Activation Disorders; Immune System Diseases; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior; Social Behavior; Leukemia; Leukemia, Myeloid, Acute; Leukemia, Myeloid; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Jason R Gotlib, MD, Associate Professor of Medicine (Hematology)
• Organization: Stanford University Medical Center

jason.gotlib@stanford.edu

650-867-2823

Study Officials

• Jason Robert Gotlib

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: October 3, 2005
• First Posted: October 5, 2005
• Study Start: March 1, 2005
• Primary Completion: June 18, 2010
• Study Completion: April 16, 2011
• Last Updated: September 20, 2018
• Results First Posted: July 9, 2015

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)