Safety Evaluation of Dasatinib in Subjects With Scleroderma Pulmonary Fibrosis

• ClinicalTrials.gov Identifier: NCT00764309
• Recruitment Status: Completed
• First Posted: October 2, 2008
• Results First Posted: February 29, 2012
• Last Update Posted: February 29, 2012
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

Brief Summary:

The purpose of this study was to evaluate the safety of Dasatininb in the treatment of scleroderma pulmonary interstitial fibrosis.

Condition or disease	Intervention/treatment	Phase
Scleroderma	Drug: dasatinib	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Study to Evaluate the Safety of Dasatinib in the Treatment of Scleroderma Pulmonary Interstitial Fibrosis
• Study Start Date: January 2009
• Actual Primary Completion Date: June 2010
• Actual Study Completion Date: April 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: A1	Drug: dasatinib; Tablets, Oral, 100 mg, once daily, 6 months; Other Names: Sprycel; BMS 354825

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) [ Time Frame: From start of study drug therapy up to 30 days after the last dose. The duration of dasatinib dosing in this study was up to 2 years ]
   AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded.
2. Reasons for Discontinuation of Study Treatment [ Time Frame: From start of study drug therapy up to 30 days after the last dose. The duration of dasatinib dosing in this study was up to 2 years ]

   Participants who discontinued the study due to any AEs were recorded.

   Significant drug-related discontinuations were those SAEs recorded on the SAE case report forms with relationship to study drug of related or missing and action taken regarding study drug of discontinued or missing.

3. Laboratory Test Results Summary of Toxicity: Hematology [ Time Frame: From start of study drug therapy up to 30 days after the last dose. The duration of dasatinib dosing in this study was up to 2 years ]
   Toxicity was graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0. (Grade (GR)0=normal, GR1=mild, GR2=moderate, GR3=severe, GR4=life threatening). Granulocyte count (x 10^9 /L), GR1: ≥1.0 - <1.5, GR2: ≥0.5 - <1.0; Hemoglobin (g/dL), GR0: 13-17, GR1: <13 - 10.0 , GR2: 8.0 - <10.0, GR3: 6.5 - <8.0; Platelet count (x 10^9 /L) GR0: 150-400, GR2: ≥50.0 - <75.0; Leukocyte count (x 10^9 /L ), GR0: 3.5-11.1, GR2: 2.0 - <3.0.
4. Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) [ Time Frame: From start of study drug therapy up to 30 days after the last dose. The duration of dasatinib dosing in this study was up to 2 years ]
   GR0=normal,1=mild,2=moderate,3=severe,4=life-threatening. ALP(U/L) GR0:40-135,GR1:>135-337; ALT(U/L) GR0:0-47,GR1:>47-117; AST(U/L) GR0:0-37,GR1:>37-93; High(↑) Calcium(mg/dL) GR0:8.4-10.2,GR1:>10.2-11.5; Low(↓) Calcium(mg/dL) GR0:8.4-10.2,GR1:<8.4-8.0,GR2:7.0-<8.0; CK(U/L) GR0:24-195,GR1:>195-488, GR2:>488-975; Creatinine(mg/dL) GR0:0.6-1.4,GR1:>1.4-2.1,GR2:>2.1-4.2; ↑Potassium(mEq/L) GR0:3.6-5.2,GR1:>5.2-5.5,GR2:>5.5-6.0; ↑Sodium(mEq/L) GR0:134-146; ↓Sodium(mEq/L) GR0:134-146,GR1:<134-130; Inorganic Phosphorus(mg/dL) GR0:2.4-4.9,GR2:≥2.0-<2.5; Total Bilirubin(mg/dL) GR0:0-1.1,GR1:>1.1-2.75.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Target Population

• meet American College of Rheumatology (ACR) criteria for scleroderma
• have clinical evidence of active skin disease with a skin score of ≥15
• have had the onset of their first non-Raynaud phenomenon feature of SSc no more than 3 years prior to screening
• have evidence of fibrosing alveolitis (active pulmonary fibrosis) manifested by a forced vital capacity (FVC) between 45% and 80% of predicted normal and/or diffusing capacity (DLCO) between 30% and 70% of predicted normal values
• have an abnormal high resolution Computed tomography (CT) scan of the chest/lungs demonstrating typical ground glass changes of alveolitis with background fibrosis
• have adequate renal function- no evidence of renal crisis in the 2 months prior to enrollment and serum creatinine < 3 mg/dL
• for both sexes, must use an acceptable form of birth control
• age ≥ 18

Exclusion Criteria:

• Clinically significant pleural or pericardial effusion in the previous 12 months: Grade 3 or 4. Patients with recent Grade I or II effusions or peripheral edema will be permitted to enter the study
• Clinically significant cardiac disease (New York Heart Association Class III or IV) including preexisting arrhythmia, (such as ventricular tachycardia, ventricular fibrillation, or "Torsade de Pointes"), myocardial infarction, uncontrolled angina within 6 months, congestive heart failure, cardiomyopathy, or pericardial disease
• Clinically-significant coagulation or platelet function disorder (eg, known von Willebrand's disease)
• Abnormal QTcF interval prolonged (> 450 msec) after electrolytes have been corrected on baseline electrocardiogram

Laboratory Test Findings

• Hgb < 10 g/dL; platelet count < 100,000/dL; WBC < 3,000/dL; PMN < 1,000/dL; OR lymphocytes < 350/dL
• The presence of any of the following laboratory findings at screening: positive for antibodies to hepatitis C virus; positive for antibodies to hepatitis B surface antigen (HBsAg); serum bilirubin 2 times normal, Alanine Aminotransferase (ALT), or Aspartate Aminotransferase (AST)> 2.5 times upper limit of normal

Prohibited Treatments and/or Therapies

• use of other immunosuppressive therapies must be discontinued at enrollment, eg methotrexate, azathioprine, cyclophosphamide, mycophenolic acid, mycophenolate mofetil, cyclosporine
• treatment with any other experimental or investigational drug(s) concurrently or less than 12 weeks prior to study enrollment
• use of anti-fibrotic agents must be discontinued at enrollment, eg colchicine, D-penicillamine, minocycline or Type 1 oral collagen

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Arizona

Scottsdale, Arizona, United States, 85259

United States, California

Ucla Division Of Rheumatology

Los Angeles, California, United States, 90095

United States, Connecticut

University Of Connecticut Health Center

Farmington, Connecticut, United States, 06030

United States, District of Columbia

Georgetown University Hospital

Washington, District of Columbia, United States, 20007

United States, Illinois

Northwestern University Feinberg School Of Medicine

Chicago, Illinois, United States, 60611

United States, Massachusetts

Boston University School Of Medicine

Boston, Massachusetts, United States, 02118

United States, Michigan

University Of Michigan

Ann Arbor, Michigan, United States, 48106

West Michigan Rheumatology

Grand Rapids, Michigan, United States, 49546

United States, New Jersey

Umdnj Clinical Research Center

New Brunswick, New Jersey, United States, 08903

United States, New York

Hospital For Special Surgery

New York, New York, United States, 10021

United States, Pennsylvania

University Of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15261

United States, Rhode Island

Rhode Island Hospital

Providence, Rhode Island, United States, 02905

United States, South Carolina

Medical University Of South Carolina

Charleston, South Carolina, United States, 29425

Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Martyanov V, Kim GJ, Hayes W, Du S, Ganguly BJ, Sy O, Lee SK, Bogatkevich GS, Schieven GL, Schiopu E, Marangoni RG, Goldin J, Whitfield ML, Varga J. Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease. PLoS One. 2017 Nov 9;12(11):e0187580. doi: 10.1371/journal.pone.0187580. eCollection 2017.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00764309
• Other Study ID Numbers: CA180-267
• First Posted: October 2, 2008
• Results First Posted: February 29, 2012
• Last Update Posted: February 29, 2012
• Last Verified: January 2012

Additional relevant MeSH terms:

Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized; Connective Tissue Diseases; Skin Diseases; Dasatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action