Phase II PKC412 in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Jason Robert Gotlib, Stanford University Identifier:
First received: October 3, 2005
Last updated: January 27, 2015
Last verified: January 2015

To evaluate the efficacy of twice-daily oral doses of PKC412 when administered to patients with ASM/MCL and AHNMD (associated hematological clonal non-mast cell lineage disease) by measuring response rate.

Condition Intervention Phase
Mastocytosis, Systemic
Leukemia, Mast-Cell
Drug: PKC 412
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Single Arm, Phase II, Open-Label Study to Determine the Efficacy of Twice Daily Oral Dosing of PKC412 Administered to Patients With Aggressive Systemic Mastocytosis (ASM) and Mast Cell Leukemia (MCL)

Resource links provided by NLM:

Further study details as provided by Stanford University:

Primary Outcome Measures:
  • To evaluate the efficacy of twice-daily oral doses of PKC412 when administered to patients with ASM/MCL + AHNMD (associated hematological clonal non-mast cell lineage disease) by measuring response rate. [ Time Frame: Unknown ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To investigate ASM/MCL-specific DNA mutations and compare gene expression changes in blood and bone marrow cells and in plasma for biomarker development before and during twice-daily oral dosing of PKC412 when administered to patients with ASM/MCL. [ Time Frame: Unknown ] [ Designated as safety issue: No ]
  • To investigate the effects of genetic variation in drug metabolism genes, disease related genes and drug target genes on patient response to twice-daily oral dosing of PKC412 when administered to patients with ASM/MCL. [ Time Frame: Unknown ] [ Designated as safety issue: No ]
  • To evaluate the safety and pharmacokinetics of twice-daily oral doses of PKC412 after a long term of treatment when administered to patients with ASM/MCL + AHNMD. [ Time Frame: Unknown ] [ Designated as safety issue: No ]
  • To evaluate the effect of PKC412 on survival after one year of treatment in ASM/MCL + AHNMD patients treated with PKC412. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 25
Study Start Date: March 2005
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PKC412 Drug: PKC 412
100 mg, oral
Other Name: Midostaurin

Detailed Description:

To evaluate the activity and safety profile of a novel investigational drug, PKC412, in patients with ASM/MCL. Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by excessive bone marrow production of mast cells which can release harmful substances, and can infiltrate tissues, resulting in organ damage. These diseases have very limited treatment options and poor prognosis. Existing treatments such as interferon-alpha +/-, corticosteroids, and cladribine exhibit low response rates in advanced mast cell disease and are usually partial in nature.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically documented aggressive systemic mastocytosis or mast cell leukemia + AHNMD, regardless of the presence of absence of the D816V c-kit mutation, or the FIP1L1-PDGFR alpha fusion.
  • Tissue for evaluation of KIT mutation status of the tumor cells must be collected and availability confirmed by PI within 6 months prior to entry into study (e.g. wild-type, D816V, or other KIT mutation). Patients who have systemic mastocytosis with eosinophilia and known positivity for the FIP1L1-PDGFR alpha fusion are also eligible only if they have demonstrated relapse or disease progression on prior imatinib therapy.
  • Karnofsky performance status of >30%.
  • Liver enzyme values within normal limits unless the sole cause of liver elevation is due to ASM/MCL. Else, patients must have the following laboratory values: AST and ALT <= 4X ULN, and/or bilirubin <= 4X ULN if elevation of liver enzymes is considered solely due to ASM/MCL.
  • Serum creatinine <2.0 mg/dL
  • For patients with grade >2 blood values, the screening bone marrow exam (e.g. presence of mast cell infiltrate as defined in Appendix B) and/or the presence of disease-related hypersplenism should establish that the likely causes of these cytopenia(s) is related to ASM/MCL.
  • No clinical or radiographic (by PA and lateral chest x-ray) evidence of active pulmonary disease which is considered by the investigator to be unrelated to mastocytosis.
  • Patient must give written informed consent.

Exclusion Criteria:

  • Female patients who are pregnant or breast-feeding, or any adult, male or female, of reproductive potential not agreeing to employ barrier contraceptives throughout the study.
  • Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study drug, are required to use barrier contraception for the duration of the study and for 3 months post study because of the long half life of the metabolite, CGP52421, and must avoid breast-feeding.
  • Any other known disease, concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months, any Grade 3/4 cardiac problems as defined by the New York Heart Association Criteria and poorly controlled hypertension, chronic renal disease, active uncontrolled infection) which could compromise participation in the study.
  • Known confirmed diagnosis of HIV infection or active viral hepatitis.
  • Patients who have received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA) within 30 days prior to Day 1 of PKC412 treatment.
  • Patients who have received interferon-alpha within 30 days prior to Day 1 of PKC412 treatment.
  • Patients who have received hematopoietic growth factor support within 14 days of Day 1 of PKC412 treatment.
  • Glucocorticoids should be tapered off within 14 days of Day 1 of PKC412 treatment if it is anticipated that patients can be tapered off these drugs. Otherwise, for glucocorticoid-requiring patients, investigators should attempt to taper to the minimal dose possible at the time of PKC412 start on day 1.
  • Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1 of PKC412 treatment.
  • Patients unwilling or unable to comply with the protocol.
  • Patients with known malignant disease involving the central nervous system.
  • Patient with any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in the previous 4 weeks. However, if a patient has a pleural effusion which is considered related to systemic mastocytosis (e.g. secondary to ascites) and not causing symptomatic respiratory complaints, the patient may be eligible after discussion with the sponsor.
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Please refer to this study by its identifier: NCT00233454

United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University-St. Louis
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Jason Robert Gotlib
Principal Investigator: Jason Robert Gotlib Stanford University
  More Information

Responsible Party: Jason Robert Gotlib, Associate Professor of Medicine, Stanford University Identifier: NCT00233454     History of Changes
Other Study ID Numbers: HEMMPD0003, 95242, Novartis 2213, 13704
Study First Received: October 3, 2005
Last Updated: January 27, 2015
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Mast-Cell
Mastocytosis, Systemic
Urticaria Pigmentosa
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Mastocytosis, Cutaneous
Neoplasms by Histologic Type
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Pigmentation Disorders
Skin Diseases
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses processed this record on July 05, 2015