Safety Evaluation of Dasatinib in Subjects With Scleroderma Pulmonary Fibrosis

An Open Label Study to Evaluate the Safety of Dasatinib in the Treatment of Scleroderma Pulmonary Interstitial Fibrosis

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

Study Overview

• Status: Completed
• Conditions: Scleroderma
• Intervention / Treatment: Drug: dasatinib

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Arizona
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Division of Rheumatology
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • University of Michigan
    • Grand Rapids, Michigan, United States, 49546
      • West Michigan Rheumatology
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • UMDNJ Clinical Research Center
  • New York
    • New York, New York, United States, 10021
      • Hospital For Special Surgery
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs)	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.	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
Reasons for Discontinuation of Study Treatment	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.	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
Laboratory Test Results Summary of Toxicity: Hematology	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.	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
Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR)	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.	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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: October 1, 2008
• First Submitted That Met QC Criteria: October 1, 2008
• First Posted (Estimate): October 2, 2008

Study Record Updates

• Last Update Posted (Estimate): February 29, 2012
• Last Update Submitted That Met QC Criteria: January 30, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Connective Tissue Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dasatinib
• Other Study ID Numbers: CA180-267