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Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00233454
Recruitment Status : Completed
First Posted : October 5, 2005
Results First Posted : July 9, 2015
Last Update Posted : September 20, 2018
Sponsor:
Collaborators:
Novartis
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Jason Robert Gotlib, Stanford University

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Systemic Mastocytosis, Aggressive (ASM)
Leukemia, Mast Cell
Hematological Non-mast Cell Lineage Disease (AHNMD)
Intervention Drug: Midostaurin
Enrollment 26
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Midostaurin
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100 mg midostaurin twice daily as oral capsules

Midostaurin: 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

Period Title: Overall Study
Started 26
2 Months (for Response Rate) 26
Completed 20
Not Completed 6
Reason Not Completed
Death             6
Arm/Group Title Midostaurin
Hide Arm/Group Description

100 mg midostaurin twice daily as oral capsules

Midostaurin: 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

Overall Number of Baseline Participants 26
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants
<=18 years
0
   0.0%
Between 18 and 65 years
13
  50.0%
>=65 years
13
  50.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 26 participants
65
(24.8 to 79.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants
Female
11
  42.3%
Male
15
  57.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants
Hispanic or Latino
1
   3.8%
Not Hispanic or Latino
25
  96.2%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
25
  96.2%
More than one race
1
   3.8%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 26 participants
26
 100.0%
Disease Sub-type   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants
Aggressive systemic mastocytosis (ASM)
3
  11.5%
SM with associated hematologic neoplasm (SM-AHN)
17
  65.4%
Mast cell leukemia (MCL)
6
  23.1%
[1]
Measure Description: Systemic mastocytosis (SM) is comprised of 3 primary sub-types, aggressive SM (ASM); SM with an associated hematologic neoplasm (SM-AHN); and mast cell leukemia (MCL).
1.Primary Outcome
Title Subjects With Clinical Response [Partial Response (PR) + Complete Response (CR)]
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Midostaurin
Hide Arm/Group Description:

100 mg midostaurin twice daily as oral capsules

Midostaurin: 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

Overall Number of Participants Analyzed 26
Measure Type: Number
Unit of Measure: participants
25
2.Secondary Outcome
Title Overall Survival (OS)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Midostaurin
Hide Arm/Group Description:

100 mg midostaurin twice daily as oral capsules

Midostaurin: 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

Overall Number of Participants Analyzed 26
Measure Type: Number
Unit of Measure: participants
20
3.Secondary Outcome
Title Overall Survival (OS)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Midostaurin
Hide Arm/Group Description:

100 mg midostaurin twice daily as oral capsules

Midostaurin: 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

Overall Number of Participants Analyzed 26
Median (95% Confidence Interval)
Unit of Measure: months
40
(27.3 to 52.7)
Time Frame This study includes open-ended maintenance treatment. AEs are reported for the duration of treatment through follow-up to death or lost-to-follow-up.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Midostaurin
Hide Arm/Group Description

100 mg midostaurin twice daily as oral capsules

Midostaurin: 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

All-Cause Mortality
Midostaurin
Affected / at Risk (%)
Total   7/26 (26.92%)    
Show Serious Adverse Events Hide Serious Adverse Events
Midostaurin
Affected / at Risk (%) # Events
Total   12/26 (46.15%)    
Blood and lymphatic system disorders   
Blood and lymphatic system disorders - Other, hand swelling  1  1/26 (3.85%)  1
Febrile neutropenia  1  1/26 (3.85%)  1
Gastrointestinal disorders   
Diarrhea  1  3/26 (11.54%)  5
vomiting  1  1/26 (3.85%)  3
Rectal hemorrhage  1  1/26 (3.85%)  1
nausea  1  1/26 (3.85%)  3
Dehydration  1  1/26 (3.85%)  3
Small intestinal perforation  1  1/26 (3.85%)  1
General disorders   
Death NOS  1  1/26 (3.85%)  1
Death NOS-refactory sepsis  1  1/26 (3.85%)  1
Fatigue  1  1/26 (3.85%)  1
Fever  1  1/26 (3.85%)  1
General disorders - Other, increased fatigue with "cloudy thinkin  1  1/26 (3.85%)  3
Hepatobiliary disorders   
Hepatobiliary disorders - Other, Liver lesions-neuroendocrine tumor  1  1/26 (3.85%)  1
Infections and infestations   
Infections and infestations - Other, Urosepsis  1  1/26 (3.85%)  1
Lung infection  1  2/26 (7.69%)  3
Scrotal infection  1  1/26 (3.85%)  1
Injury, poisoning and procedural complications   
Fracture  1  1/26 (3.85%)  1
Investigations   
Lipase increased  1  1/26 (3.85%)  1
Platelet count decreased  1  1/26 (3.85%)  1
Blood bilirubin increased  1  1/26 (3.85%)  2
Metabolism and nutrition disorders   
Hypercalcemia  1  1/26 (3.85%)  3
Hyperkalemia  1  1/26 (3.85%)  1
Nervous system disorders   
Cognitive disturbance  1  1/26 (3.85%)  2
Nervous system disorders - Other, transient ischemic attack/ cerebrovascular accident  1  1/26 (3.85%)  1
Renal and urinary disorders   
Renal and urinary disorders - Other, Hematuria  1  1/26 (3.85%)  1
Reproductive system and breast disorders   
Scrotal pain  1  1/26 (3.85%)  1
Respiratory, thoracic and mediastinal disorders   
Dyspnea  1  1/26 (3.85%)  1
Pleural effusion  1  1/26 (3.85%)  2
Respiratory, thoracic and mediastinal disorders - Other, pneumonia  1  1/26 (3.85%)  2
Skin and subcutaneous tissue disorders   
Skin and subcutaneous tissue disorders - Other, blistery lesions on hands and lower arms  1  1/26 (3.85%)  1
1
Term from vocabulary, CTCAEv4
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Midostaurin
Affected / at Risk (%) # Events
Total   26/26 (100.00%)    
Blood and lymphatic system disorders   
Anemia  1  11/26 (42.31%)  12
Blood and lymphatic system disorders - Other, lymphadenopathy  1  1/26 (3.85%)  1
Febrile neutropenia  1  4/26 (15.38%)  5
Cardiac disorders   
Atrial fibrillation  1  1/26 (3.85%)  1
Atrioventricular block first degree  1  1/26 (3.85%)  1
Sinus bradycardia  1  1/26 (3.85%)  1
Eye disorders   
Blurred vision  1  3/26 (11.54%)  3
Cataract  1  3/26 (11.54%)  3
Gastrointestinal disorders   
Abdominal distension  1  7/26 (26.92%)  7
Abdominal pain  1  5/26 (19.23%)  6
Ascites  1  1/26 (3.85%)  1
Constipation  1  12/26 (46.15%)  12
Diarrhea  1  10/26 (38.46%)  10
Enterocolitis  1  2/26 (7.69%)  2
Gastrointestinal disorders - Other, increased saliva  1  1/26 (3.85%)  1
Gastrointestinal disorders - Other, bowel obstruction  1  1/26 (3.85%)  1
Nausea  1  24/26 (92.31%)  24
Rectal hemorrhage  1  2/26 (7.69%)  2
Vomiting  1  18/26 (69.23%)  18
General disorders   
Chills  1  2/26 (7.69%)  2
Edema limbs  1  9/26 (34.62%)  9
Fatigue  1  13/26 (50.00%)  14
Fever  1  6/26 (23.08%)  6
Flu like symptoms  1  4/26 (15.38%)  4
Gait disturbance  1  2/26 (7.69%)  2
General disorders and administration site conditions - Other, altitude sickness  1  1/26 (3.85%)  1
General disorders and administration site conditions - Other, failure to thrive  1  1/26 (3.85%)  1
General disorders and administration site conditions - Other, fluid retention  1  1/26 (3.85%)  1
General disorders and administration site conditions - Other, malnutrition  1  1/26 (3.85%)  1
General disorders and administration site conditions - Other, transfusion reaction  1  1/26 (3.85%)  1
General disorders and administration site conditions - Other, weakness  1  3/26 (11.54%)  3
General disorders and administration site conditions - Other, thrush  1  1/26 (3.85%)  1
General disorders and administration site conditions - Other animal or insect bite  1  3/26 (11.54%)  3
Localized edema  1  2/26 (7.69%)  2
Pain  1  3/26 (11.54%)  5
Hepatobiliary disorders   
Hepatobiliary disorders - Other, increased Hepatosplenomegaly  1  5/26 (19.23%)  5
Cholecystitis  1  1/26 (3.85%)  1
Infections and infestations   
Infections and infestations - Other, (tooth, peritoneal catheter)  1  2/26 (7.69%)  2
Infections and infestations - Other, herpes lesion(nasal/oral)  1  3/26 (11.54%)  3
Infections and infestations - Other, herpes zoster  1  1/26 (3.85%)  1
Infections and infestations - Other, Lyme's disease  1  1/26 (3.85%)  1
Infections and infestations - Other, peritonitis  1  1/26 (3.85%)  1
Infections and infestations - Other, skin (cellulitis)  1  2/26 (7.69%)  2
Infections and infestations - Other, staph infection  1  2/26 (7.69%)  2
Infections and infestations - Other, Urosepsis  1  1/26 (3.85%)  1
Infections and infestations - Other, viral  1  2/26 (7.69%)  2
Lung infection  1  1/26 (3.85%)  1
Sepsis  1  2/26 (7.69%)  2
Sinusitis  1  1/26 (3.85%)  1
Urinary tract infection  1  4/26 (15.38%)  4
Injury, poisoning and procedural complications   
Bruising  1  2/26 (7.69%)  2
Fracture  1  2/26 (7.69%)  2
Investigations   
Activated partial thromboplastin time prolonged  1  1/26 (3.85%)  1
Alanine aminotransferase increased  1  1/26 (3.85%)  1
Alkaline phosphatase increased  1  6/26 (23.08%)  6
Aspartate aminotransferase increased  1  2/26 (7.69%)  2
Blood bilirubin increased  1  1/26 (3.85%)  2
Creatinine increased  1  3/26 (11.54%)  3
Electrocardiogram QT corrected interval prolonged  1  2/26 (7.69%)  2
Investigations - Other, tryptase increased  1  1/26 (3.85%)  1
Lipase increased  1  6/26 (23.08%)  9
Platelet count decreased  1  8/26 (30.77%)  8
Weight gain  1  4/26 (15.38%)  5
Weight loss  1  1/26 (3.85%)  1
White blood cell decreased  1  2/26 (7.69%)  3
Serum Amylase Increased  1  1/26 (3.85%)  1
Metabolism and nutrition disorders   
Acidosis  1  1/26 (3.85%)  1
Dehydration  1  1/26 (3.85%)  1
Glucose intolerance  1  1/26 (3.85%)  1
Hypercalcemia  1  1/26 (3.85%)  1
Hyperglycemia  1  6/26 (23.08%)  7
Hyperuricemia  1  2/26 (7.69%)  2
Hypoalbuminemia  1  3/26 (11.54%)  3
Hypocalcemia  1  2/26 (7.69%)  2
Hypokalemia  1  4/26 (15.38%)  5
Hypomagnesemia  1  2/26 (7.69%)  2
Hyponatremia  1  2/26 (7.69%)  2
Hypophosphatemia  1  1/26 (3.85%)  1
Musculoskeletal and connective tissue disorders   
Arthralgia  1  3/26 (11.54%)  3
Back pain  1  2/26 (7.69%)  2
Bone pain  1  1/26 (3.85%)  1
Musculoskeletal and connective tissue disorder - Other, rotator cuff tear  1  2/26 (7.69%)  2
Myalgia  1  2/26 (7.69%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, basal cell CA  1  1/26 (3.85%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, squamous cell CA  1  3/26 (11.54%)  3
Treatment related secondary malignancy, lung CA, malignant neoplasm  1  2/26 (7.69%)  2
Nervous system disorders   
Cognitive disturbance  1  3/26 (11.54%)  3
Headache  1  8/26 (30.77%)  8
Nervous system disorders - Other, lightheadedness  1  6/26 (23.08%)  6
Nervous system disorders - Other, presyncope  1  1/26 (3.85%)  1
Nervous system disorders - Other, vertigo  1  1/26 (3.85%)  1
Peripheral sensory neuropathy  1  3/26 (11.54%)  3
Tremor  1  4/26 (15.38%)  4
Psychiatric disorders   
Confusion  1  4/26 (15.38%)  4
Depression  1  2/26 (7.69%)  2
Insomnia  1  3/26 (11.54%)  3
Psychosis  1  2/26 (7.69%)  2
Anxiety  1  1/26 (3.85%)  1
Renal and urinary disorders   
Acute kidney injury  1  1/26 (3.85%)  1
Hematuria  1  1/26 (3.85%)  1
Urinary frequency  1  1/26 (3.85%)  1
Respiratory, thoracic and mediastinal disorders   
Cough  1  3/26 (11.54%)  3
Dyspnea  1  7/26 (26.92%)  7
Epistaxis  1  2/26 (7.69%)  2
Hypoxia  1  1/26 (3.85%)  1
Laryngeal edema  1  1/26 (3.85%)  1
Pleural effusion  1  3/26 (11.54%)  3
Respiratory, thoracic and mediastinal disorders - Other, bronchitis  1  1/26 (3.85%)  1
Respiratory, thoracic and mediastinal disorders - Other, Upper Respiratory Infection  1  8/26 (30.77%)  8
Skin and subcutaneous tissue disorders   
Dry skin  1  1/26 (3.85%)  1
Hyperhidrosis  1  2/26 (7.69%)  2
Pruritus  1  5/26 (19.23%)  5
Rash maculo-papular  1  4/26 (15.38%)  4
Skin and subcutaneous tissue disorders - Other, dermatitis (blisters)  1  4/26 (15.38%)  4
Skin and subcutaneous tissue disorders - Other, injury (abrasion)  1  2/26 (7.69%)  2
Skin and subcutaneous tissue disorders - Other, rosacea  1  1/26 (3.85%)  1
Skin and subcutaneous tissue disorders - Other, not specified  1  2/26 (7.69%)  3
Skin and subcutaneous tissue disorders - Other, skin nodule  1  2/26 (7.69%)  3
Skin and subcutaneous tissue disorders - Other, sunburn  1  2/26 (7.69%)  2
Skin hyperpigmentation  1  1/26 (3.85%)  1
Skin hypopigmentation  1  1/26 (3.85%)  1
Vascular disorders   
Flushing  1  4/26 (15.38%)  4
Hematoma  1  3/26 (11.54%)  3
Hypotension  1  2/26 (7.69%)  2
Vascular disorders - Other, conjunctival hemorrhage  1  2/26 (7.69%)  2
1
Term from vocabulary, CTCAEv4
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jason R Gotlib, MD, Associate Professor of Medicine (Hematology)
Organization: Stanford University Medical Center
Phone: 650-867-2823
EMail: jason.gotlib@stanford.edu
Publications of Results:
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
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
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
Layout table for additonal information
Responsible Party: Jason Robert Gotlib, Stanford University
ClinicalTrials.gov Identifier: NCT00233454     History of Changes
Other Study ID Numbers: IRB-13704
95242 ( Other Identifier: Stanford University Secondary IRB Approval Number )
HEMMPD0003 ( Other Identifier: OnCore )
CPKC412D2201 ( Other Identifier: Novartis, Inc )
2213 ( Other Identifier: Novartis, Inc )
First Submitted: October 3, 2005
First Posted: October 5, 2005
Results First Submitted: June 16, 2015
Results First Posted: July 9, 2015
Last Update Posted: September 20, 2018