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Safety Evaluation of Dasatinib in Subjects With Scleroderma Pulmonary Fibrosis

Primary Purpose

Scleroderma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
dasatinib
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Scleroderma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Mayo Clinic Arizona
  • Ucla Division Of Rheumatology
  • University Of Connecticut Health Center
  • Georgetown University Hospital
  • Northwestern University Feinberg School Of Medicine
  • Boston University School Of Medicine
  • University Of Michigan
  • West Michigan Rheumatology
  • Umdnj Clinical Research Center
  • Hospital For Special Surgery
  • University Of Pittsburgh
  • Rhode Island Hospital
  • Medical University Of South Carolina

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

A1

Arm Description

Outcomes

Primary Outcome Measures

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.
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.
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.
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.

Secondary Outcome Measures

Full Information

First Posted
October 1, 2008
Last Updated
January 30, 2012
Sponsor
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT00764309
Brief Title
Safety Evaluation of Dasatinib in Subjects With Scleroderma Pulmonary Fibrosis
Official Title
An Open Label Study to Evaluate the Safety of Dasatinib in the Treatment of Scleroderma Pulmonary Interstitial Fibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
January 2012
Overall Recruitment Status
Completed
Study Start Date
January 2009 (undefined)
Primary Completion Date
June 2010 (Actual)
Study Completion Date
April 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Scleroderma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A1
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
dasatinib
Other Intervention Name(s)
Sprycel, BMS 354825
Intervention Description
Tablets, Oral, 100 mg, once daily, 6 months
Primary Outcome Measure Information:
Title
Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs)
Description
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.
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
Title
Reasons for Discontinuation of Study Treatment
Description
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.
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
Title
Laboratory Test Results Summary of Toxicity: Hematology
Description
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.
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
Title
Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR)
Description
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.
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
Ucla Division Of Rheumatology
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University Of Connecticut Health Center
City
Farmington
State/Province
Connecticut
ZIP/Postal Code
06030
Country
United States
Facility Name
Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
Northwestern University Feinberg School Of Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Boston University School Of Medicine
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
University Of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48106
Country
United States
Facility Name
West Michigan Rheumatology
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49546
Country
United States
Facility Name
Umdnj Clinical Research Center
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08903
Country
United States
Facility Name
Hospital For Special Surgery
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
University Of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15261
Country
United States
Facility Name
Rhode Island Hospital
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02905
Country
United States
Facility Name
Medical University Of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
29121645
Citation
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.
Results Reference
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Safety Evaluation of Dasatinib in Subjects With Scleroderma Pulmonary Fibrosis

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