Scleroderma
Conditions
Brief summary
The purpose of this study was to evaluate the safety of Dasatininb in the treatment of scleroderma pulmonary interstitial fibrosis.
Interventions
DRUGdasatinib
Tablets, Oral, 100 mg, once daily, 6 months
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) | 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. |
| Reasons for Discontinuation of Study Treatment | 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. |
| Laboratory Test Results Summary of Toxicity: Hematology | 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. |
| Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | 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. |
Countries
United States
Participant flow
Pre-assignment details
Of the 47 participants enrolled, 31 were treated. Reasons for not entering treatment period were: withdrew consent-1, lost to follow up-2, no longer met study criteria-12, other reasons-1.
Participants by arm
| Arm | Count |
|---|---|
| 100 mg Dasatinib, Oral Administration Participants received 100 mg dasatinib once daily orally for up to 2 years (6 months of dosing to evaluate the primary endpoint + 18 months of dosing to assess longer-term safety and efficacy) | 31 |
| Total | 31 |
Baseline characteristics
| Characteristic | 100 mg Dasatinib, Oral Administration |
|---|---|
| Age Continuous | 50.8 years STANDARD_DEVIATION 12.44 |
| Age, Customized <65 years | 26 Years |
| Age, Customized >=65 years | 5 Years |
| Baseline Pulmonary Function FEV1, n=30 | 2.614 Liters STANDARD_DEVIATION 1.3495 |
| Baseline Pulmonary Function FVC, n=30 | 2.955 Liters STANDARD_DEVIATION 0.7978 |
| Baseline Pulmonary Function TLC, n=26 | 4.292 Liters STANDARD_DEVIATION 1.1784 |
| Baseline Pulmonary Function: Diffusion capacity | 14.223 mL/min/mmHg STANDARD_DEVIATION 4.8012 |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 participants |
| Race/Ethnicity, Customized Black / African American | 3 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 3 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 28 participants |
| Race/Ethnicity, Customized Other | 3 participants |
| Race/Ethnicity, Customized White | 24 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 10 Participants |
| Time from Initial Scleroderma Diagnosis to Start of Study 12 - 23 months | 8 Participants |
| Time from Initial Scleroderma Diagnosis to Start of Study < 12 months | 12 Participants |
| Time from Initial Scleroderma Diagnosis to Start of Study 24 - 36 months | 7 Participants |
| Time from Initial Scleroderma Diagnosis to Start of Study > 36 months | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 31 |
| serious Total, serious adverse events | 7 / 31 |
Outcome results
Primary
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.
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
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Alkaline Phosphatase (ALP), GR0 | 30 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | ALP, GR1 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Alanine Aminotransferase (ALT), GR0 | 24 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | ALT, GR1 | 7 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Aspartate Aminotransferase (AST), GR0 | 21 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | AST, GR1 | 10 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | High Calcium, GR0 | 23 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | High Calcium, GR1 | 8 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Low Calcium, GR0 | 28 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Low Calcium, GR1 | 2 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Low Calcium, GR2 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Creatine Kinase (CK), GR0 | 16 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | CK, GR1 | 11 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | CK, GR2 | 2 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | CK, GR not reported | 2 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Creatinine, GR 0 | 26 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Creatinine, GR1 | 3 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Creatinine, GR2 | 2 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | High Potassium, GR0 | 28 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | High Potassium, GR1 | 2 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | High Potassium, GR2 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Low Potassium, GR 0 | 27 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Low Potassium, GR 1 | 4 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | High Sodium, GR0 | 31 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Low Sodium, GR0 | 28 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Low Sodium, GR1 | 3 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Inorganic Phosphorus, GR 0 | 30 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Inorganic Phosphorus, GR 2 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Total Bilirubin, GR0 | 30 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Blood Chemistry Per (NCI-CTCAE) Version 3.0 Grade (GR) | Total Bilirubin, GR1 | 1 participants |
Primary
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.
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
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Granulocyte count, GR0 | 28 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Granulocyte count, GR1 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Granulocyte count, GR2 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Granulocyte count, GR not reported | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Hemoglobin, GR0 | 4 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Hemoglobin, GR1 | 17 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Hemoglobin, GR2 | 8 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Hemoglobin, GR3 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Hemoglobin, GR not reported | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Platelet count, GR0 | 29 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Platelet count, GR2 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Platelet count, GR not reported | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Leukocyte count, GR0 | 29 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Leukocyte count, GR2 | 1 participants |
| 100 mg Dasatinib, Oral Administration | Laboratory Test Results Summary of Toxicity: Hematology | Leukocyte count, GR not reported | 1 participants |
Primary
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.
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
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 100 mg Dasatinib, Oral Administration | Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) | Deaths | 0 Participants |
| 100 mg Dasatinib, Oral Administration | Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) | AEs | 31 Participants |
| 100 mg Dasatinib, Oral Administration | Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) | SAEs | 7 Participants |
| 100 mg Dasatinib, Oral Administration | Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) | Drug-Related Death | 0 Participants |
| 100 mg Dasatinib, Oral Administration | Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) | Drug-Related AEs | 24 Participants |
| 100 mg Dasatinib, Oral Administration | Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), or Adverse Events (AEs) | Drug-Related SAEs | 5 Participants |
Primary
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.
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
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | AEs | 13 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | SAEs | 4 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Drug-Related AEs | 8 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Drug-Related SAEs | 3 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Significant Drug-Related Pericardial Effusion | 0 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Significant Drug-Related Pleural Effusion | 2 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Significant Drug-Related Bone Marrow Suppression | 0 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Significant Worsening of Underlying Scleroderma | 0 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Unforeseen toxicity of dasatinib | 0 Participants |
| 100 mg Dasatinib, Oral Administration | Reasons for Discontinuation of Study Treatment | Significant Drug-Related Peripheral Edema | 0 Participants |