A Study of Dasatinib (BMS-354825) in Patients With Advanced 'Triple-negative' Breast Cancer

Study Overview
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Brief Summary
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This study will determine whether the investigational drug dasatinib is effective in treatment of women with progressive advanced triple-negative breast cancer.

Official Title
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Phase II Study of Dasatinib (BMS-354825) for Advanced 'Triple-negative' Breast Cancer

Conditions
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Breast Cancer, Metastasis

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: females, 18 or older recurrent or progressive locally advanced, or 'triple negative' metastatic breast cancer paraffin-embedded tissue block must be available measurable disease prior chemotherapy with an anthracycline, a taxane, or both (neoadjuvant, adjuvant, or metastatic setting) 0, 1 or 2 chemotherapies in the metastatic setting adequate organ function Exclusion Criteria: Metastatic disease confined to bone only Symptomatic CNS metastasis Concurrent medical condition which may increase the risk of toxicity Unable to take oral medication

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Dasatinib<br>* Tablets, Oral, 100 mg, twice daily as long as the patient benefits (avg <6 months)<br>* Other names: BMS-354825;|
| Experimental: 2<br> | Drug: Dasatinib<br>* Tablets, Oral, 70 mg, twice daily as long as the patient benefits (avg <6 months)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR) or Partial Response (PR) | Tumor response was defined as the number of participants whose best response was CR or PR, per the Response Evaluation Criteria in Solid Tumor (RECIST): CR: disappearance of all target/non-target lesions; PR: >= 30% decrease in the sum of the LDs of target lesions relative to the baseline sum LD. | Baseline to end of study drug therapy (up to 65 weeks). | 
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) | The percentage of participants whose best response was CR or PR, per the RECIST: CR: disappearance of all target/non-target lesions; PR: >= 30% decrease in the sum of the LDs of target lesions relative to the baseline sum LD. | Baseline to end of study drug therapy (up to 65 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) at or After 16 Weeks on Study | The number of participants whose best response was CR, PR or SD (per the RECIST) at or after 16 weeks on study: CR: disappearance of all target/non-target lesions; PR: >=30% decrease in the sum of the LDs of target lesions relative to baseline sum LD; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD: appearance of new lesion/s, or >=20% increase in the sum of the LD of target lesions, relative to the smallest sum LD recorded since treatment start, or unequivocal progression of existing non-target lesions. | Baseline to 16 weeks. | 
| Percentage of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) at or After 16 Weeks on Study | The percentage of participants whose best response was CR, PR or SD (per the RECIST) at or after 16 weeks on study: CR: disappearance of all target/non-target lesions; PR: >=30% decrease in the sum of the LDs of target lesions relative to baseline sum LD; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD: appearance of new lesion/s, or >=20% increase in the sum of the LD of target lesions, relative to the smallest sum LD recorded since treatment start, or unequivocal progression of existing non-target lesions. | Baseline to 16 weeks | 
| Proportion of Participants With Progression-Free Survival (PFS) at Weeks 9, 17, and 25 | PFS:time from first dose until the date that progressive disease (PD) or clinical PD (cPD) observed,per RECIST criteria.PD:appearance of new lesion/s,or >=20% increase in the sum of the LD of target lesions,relative to smallest sum LD recorded since treatment start,or unequivocal progression of existing non-target lesions;cPD:deterioration related to disease requiring treatment discontinuation,but without radiographic PD.Participants who died without PD were considered to have PD on the date of death.For participants who neither progressed nor died,date of the last tumor assessment was used. | Weeks 9, 17, and 25 | 
| Mean Number of Weeks of Complete Response (CR) or Partial Response (PR) | Mean number of weeks of CR/PR (time from first date of CR/PR until first date PD observed. Tumor response defined per RECIST: CR: disappearance of all target/non-target lesions; PR: >=30% decrease in sum of LDs of target lesions relative to baseline sum LD; PD: appearance of new lesion or >=20% increase in sum of LD of target lesions relative to smallest sum LD or unequivocal progression of existing non-target lesions. Participants who died without reported PD were considered to have PD on date of death. For participants who neither progressed nor died, date of last tumor assessment used. | Baseline to end of study drug therapy (up to 53.86 weeks) | 
| Mean Plasma Concentration at Week 3 | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose and 1, 3, 6 and 12 hours after each dose administration | 
| Mean Plasma Concentration at Week 7 | Mean plasma concentration was obtained directly from the concentration-time data. | At pre-dose and 1, 3, 6 and 12 hours after each dose administration | 
| Mean Change in Concentration of Collagen Type IV From Baseline | Collagen Type IV is a measure of anti-angiogenic activity. Plasma samples for assessment of change in concentration of Collagen Type IV were obtained and analyzed by enzyme-linked immunosorbent assay. | Baseline, Week 3 and Week 5 | 
| Mean Change in Concentration of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) From Baseline | VEGFR2 is a measure of anti-angiogenic activity. Plasma samples for assessment of change in concentration of VEGFR2 were obtained and analyzed by enzyme-linked immunosorbent assay. | Baseline, Week 3 and Week 5 | 
| Percentage Change in Tumor Biomarkers | Tumor markers are indicators of tumor activity which may be used to predict clinical benefit and circulating biomarkers may reveal key mechanisms of action. Tissue staining was performed for caveolin, phospho-caveolin, EphA2 and insulin-like growth factor binding protein 2 (IGFBP2) markers using immunohistochemistry assays. | Baseline | 
| Profiling of Messenger-ribonucleic Acid (mRNA) Expression: mRNA Signal Intensity | Pharmacogenomic analysis included the assessment of the relationship between clinical benefit and mRNA expression levels and between clinical benefit and protein phosphorylation. Tumor mRNA expression was analyzed in all available tissues. mRNA was extracted from 96 formalin-fixed paraffin-embedded tissue (FFPET) samples, amplified, and fluorescently labeled. Gene expression profiling was conducted using Affymetrix Human Genome U133A 2.0 DNA microarrays. mRNA expression is reported as quantile normalized RMA values. | Baseline | 
| Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs) or Adverse Events (AEs) | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). An SAE was defined as an AE that resulted in death, was life-threatening, required hospitalization (or prolongation of existing hospitalization), or was an important medical event. | From start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants Who Experienced Drug-related SAEs, Drug-related AEs, Drug-related Grade 3 AEs and Discontinuations Due to Drug-related AEs | AE=any new untoward medical occurrence/worsening of pre-existing medical condition.SAE=AE that resulted in death, was life-threatening, required hospitalization (or prolongation of existing hospitalization), or was an important medical event. Drug-related SAEs or AEs are those events with relationship to study therapy of certain, probable or possible.AEs were graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), v3: Grade 1=mild, 2=moderate, 3=severe, 4=life threatening, 5=death.Participants who discontinued the study due to any drug-related AEs were also recorded. | From start of study drug therapy up to 30 days after the last dose. | 
| Most Frequent Drug-related Adverse Events (AEs) | Most frequent drug-related AEs are those AEs with frequency >=25% in either group. Drug-related AEs are those events with relationship to study therapy of certain, probable or possible. | From start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Grade 3 or 4 Abnormalities in Hematology Measurements | Abnormalities were graded according to the NCI CTC, version 3.0: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening. Grades 3 and 4 criteria are defined as follows: Granulocytes: Grade 3 <1.0 - 0.5 x 10^9/L; Grade 4, <0.5 x 10^9/L. Hemoglobin: Grade 3, <8.0 - 6.5 g/dL; Grade 4, <6.5 g/dL. Platelets: Grade 3, <50.0 - 25.0 x 10^9/L; Grade 4, <25.0 x 10^9/L. Leukocytes: Grade 3, <2.0 - 1.0 x 10^9/L; Grade 4, <1.0 x 10^9/L. | Throughout study, from start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Abnormalities (Grade 1 or 2) in Prothrombin Time (PT) | PT is a measure of the clotting ability of the blood. Abnormalities were graded according to the NCI CTC, version 3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening and 5=death. | Throughout study, from start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Abnormalities (Grade 1 or 2) in Partial Thromboplastin Time (PTT) | PTT is a measure of the clotting ability of the blood. Abnormalities were graded according to the NCI CTC, version 3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening and 5=death. | Throughout study, from start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Grade 3 or 4 Serum Chemistry Abnormalities in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase | Abnormalities were graded according to the NCI CTC, version 3.0: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening. Grade 3 and 4 criteria are defined as follows: ALT, AST and alkaline phosphatase: Grade 3: >5-20 x upper limit of normal (ULN), Grade 4: >20 x ULN. | Throughout study, from start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Grade 3 or 4 Serum Chemistry Abnormalities in Calcium, Potassium, Magnesium and Sodium | Abnormalities were graded according to the NCI CTC, version 3.0: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening. Grade 3 and 4 criteria are defined as follows: Calcium: Grade 3-4 : <6.0 - <7.0 or >12.5 - >13.5 mg/dL, Potassium: Grade 3-4 : <2.5 - <3.0 or >6.0 - >7.0 mEq/L, Magnesium: Grade 3-4 : <0.6 - <0.8 or >2.46 - >6.6 mEq/L, Sodium:< 120- 130 or >155 - >160 mEq/L. | Throughout study, from start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Grade 3 or 4 Serum Chemistry Abnormalities in Creatinine, Bicarbonate, Inorganic Phosphorous and Bilirubin (Total). | Abnormalities were graded according to the NCI CTC, version 3.0: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening. Grade 3 and 4 criteria are defined as follows: Creatinine: Grade 3-4 : > 3.0 -6.0 ULN (upper limit of normal),Bicarbonate: Grade 3-4: <16 -<22 mEq/L, Phosphorous: Grade 3-4 : <1.0 - <2.0 mg/dL, Bilirubin, total: Grade 3-4: >3.0 - >10.0 ULN. | Throughout study, from start of study drug therapy up to 30 days after the last dose. | 
| Number of Participants With Identified Electrocardiogram (ECG) Abnormalities | ECGs were performed and all recordings were evaluated by the investigator. Abnormalities, if present at any study time point, were listed. The following ECG variables were collected: heart rate, PR interval, QRS width, and QT interval. Abnormalities in ECGs were defined by reference to institutional reports. | Baseline, Weeks 3, 9, 17 and 25, then every 8 weeks until the end of study treatment (up to 17 weeks). | 
| Number of Participants With Abnormal Vital Signs Measurements | Vital signs included systolic and diastolic blood pressure and heart rate. The investigator used his or her judgement to decide whether or not the values were abnormal. | At each study visit (Week 3, 5, 7, 9, 13, 17 and 25) and end of treatment (up to 17 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent, locally-advanced, or 'triple negative' metastatic breast cancer