Study of Dasatinib (BMS-354825) in Patients With Advanced Estrogen/Progesterone Receptor-positive (ER+/PR+) or Her2/Neu-positive (Her2/Neu+)Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This study will determine whether the investigational drug dasatinib is effective in treatment of women with progressive advanced ER+/PR+ or Her2/neu+ breast cancer

Official Title
-----------------
Phase II Study of Dasatinib (BMS-354825) for Advanced Estrogen/Progesterone Receptor-Positive or Her2/Neu-Positive Breast Cancer

Conditions
-----------------
Breast Cancer, Metastasis

Intervention / Treatment
-----------------
* Drug: Dasatinib
* Drug: Dasatinib 100 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: females, 18 or older recurrent, locally advanced, or metastatic breast cancer with expression of ER/PR receptor and/or overexpression of Her2/neu paraffin-embedded tissue block must be available measurable disease prior chemotherapy with an anthracycline and/or a taxane (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 central nervous system (CNS) metastasis Concurrent medical condition which may increase the risk of toxicity Unable to take oral medication

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: Dasatinib<br>Participants with either a Human epidermal growth factor (Her2/neu)-amplified tumor type or ER and/or PgR positive tumor types received oral dasatinib twice daily (BID). | Drug: Dasatinib<br>* Tablets, Oral, 70 mg, twice daily, as long as the participant benefits (average <6 months)<br>* Other names: BMS-354825;Drug: Dasatinib 100 mg<br>* Tablets, Oral, 100mg, twice daily, as long as the participant benefits (average <6 months)<br>* Other names: BMS-354825;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Response | Tumor response was assessed according RECIST criteria: PR=at least 30% reduction in the sum of the LD of all target lesions in reference to the baseline sum LD, CR=Disappearance of all non-target lesions. Objective tumor response was defined as a PR or CR. | From day of first treatment through Week 25 or at time of discontinuation from study treatment. | 
| Percentage of Participants With Objective Response | Tumor response was assessed according RECIST criteria: PR=at least 30% reduction in the sum of the LD of all target lesions in reference to the baseline sum LD, CR=Disappearance of all non-target lesions. Percentage of participants with objective tumor response was determined by the number of participants with PR or CR divided by the total number of response-evaluable participants. | From day of first treatment through Week 25 or at time of discontinuation from study treatment | 
| Best Overall Response | Response assessed using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR)=disappearance of all target and non-target lesions; Partial Response (PR)=≥30% decrease in sum of longest diameter (LD) of target lesions; SD=small changes not meeting above criteria; Progressive Disease (PD)=appearance of new lesion(s), ≥ 20% increase in the sum of the LD of target lesions, or progression of existing non-target lesions; Clinical Progression (cPD)=deterioration related to disease requiring treatment without radiographic PD. | From day of first treatment through Week 25 or at time of discontinuation from study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Response-evaluable Participants With Disease Control (DCR) | Disease control was defined in response-evaluable participants as having a best response of CR or PR (or uPR), or SD at/after 16 Weeks. | From day of first treatment through Week 25 or at time of discontinuation from study treatment. | 
| Percentage of Response-evaluable Participants With Disease Control (DCR) | Disease control was defined in response-evaluable participants as having a best response of objective response (CR or PR) or SD at/after 16 Weeks. | From day of first treatment through Week 25 or at time of discontinuation from study treatment. | 
| Number of Participants Who Progressed | PFS was defined as time from first dosing date until the first date that Progressive Disease (PD) was observed. | From Baseline (Week 0) to time of PD or discontinuation of last participant from study treatment (Week 45) | 
| Median Progression Free Survival (PFS) | PFS was defined as time from first dosing date until the first date that PD was observed. The distribution of PFS was estimated using the Kaplan-Meier product limit method. A two-sided 95% confidence interval (Brookmeyer and Crowley method) for the median PFS was computed. | From Baseline (Week 0) to time of PD or discontinuation of last participant from study treatment (Week 45) | 
| Percentage of Participants With Progression-free Survival (PFS) at Weeks 9, 17, and 25 | PFS was defined as time from first dosing date until the first date that progressive disease (PD) was observed. | At Weeks 9, 17, and 25 | 
| Duration Of Objective Response | Duration of objective response was defined as the time (in weeks) between the first date that criteria for CR or PR were met and the first date that progressive disease (PD) or clinical progressive disease (cPD) was observed. Date of death was used as PD date for participants who died before reporting PD. Participants who neither progressed nor died were censored at the date of their last tumor assessment. | the time (in weeks) between the first date that criteria for PR were met and the first date that PD or cPD was observed | 
| Number of Participants With Death, Adverse Events (AEs), and AEs Leading to Discontinuation | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. AEs graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. | Continuous assessment beginning at initiation of study drug until 30 days after the last dose of study drug | 
| Number of Participants With On-study CTCAE Version 3.0 Grade 3-4 Laboratory Abnormalities | Normal ranges for laboratory abnormalities: granulocytes=1.5x10^3-8x10^3 mm^3 (range may have varied by institution); hemoglobin=12-16 g/dL; platelets=150-440x10^9c/L; partial thromboplastin time=27-37.1 seconds; alkaline phosphatase=38-126 U/L; alanine aminotransferase=15-48 U/L; aspartate aminotransferase=14-38 U/L; creatine=0.7-1.1 mg/dL; hypokalemia (potassium [K])=3.5-5mEq/L; hyponatremia (sodium [Na])=135-145 mEq/L; phosphorous=2.4-4.5 mg/dL; bilirubin=0-1.2. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening/disabling, Gr 5=Death. | Continuous assessment beginning at initiation of study drug until 30 days after the last dose of study drug | 
| Number of Participants With Serious AEs (SAEs), Drug-related AEs, Drug-related SAEs, and Drug-Related Grade 3 AEs | AEs and SAEs considered possibly, probably, or certainly related to study treatment, graded according to CTCAE Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. | Continuous assessment beginning at initiation of study drug until 30 days after the last dose of study drug | 
| Number Of Participants With Notable Drug-related AEs | Notable drug-related AEs for dasatinib include gastrointestinal symptoms (diarrhea, nausea, vomiting and abdominal pain), fatigue, lethargy, headache, rash, fever, pleural effusion, and dyspnea. | Continuous assessment beginning at initiation of study drug until 30 days after the last dose of study drug | 
| Pharmacokinetics (PK): Plasma Concentration of Dasatinib at Week 3 | Blood samples (3 mL) were used for measurement of dasatinib plasma concentration and metabolites. | PK assessment was performed at Week 3 visit (Day 15 ±4 days). Blood samples were obtained at Time = 0 hours, and at 1, 3 and 6 hours after each dose, and a trough sample was obtained immediately prior to any dose ( 12 hours). | 
| PK: Plasma Concentration of Dasatinib at Week 7 or Week 9 | Blood samples (3 mL) were used for measurement of dasatinib plasma concentration and metabolites. | PK assessment was performed at Week 7 or 9 visit. Blood samples were obtained at Time = 0 hours, and at 1, 3 and 6 hours after each dose, and a trough sample was obtained immediately prior to any dose ( 12 hours). | 
| Pharmacodynamics: Percent Change From Baseline In Plasma Level of Collagen Type IV at Week 3 in Participants With and Without DCR | Collagen Type IV is a circulating marker related to the modulation of the vascular endothelial growth factor (VEGF)-pathway. An assay of Collagen Type IV in plasma was performed by ELISA. | At Baseline and Week 3 of treatment (Day 15 ±4 days) | 
| Pharmacodynamics: Percent Change From Baseline In Plasma Level of Collagen Type IV at Week 5 in Participants With and Without DCR | Collagen Type IV is a circulating marker related to the modulation of the vascular endothelial growth factor (VEGF)-pathway. An assay of Collagen Type IV in plasma was performed by ELISA. | Week 5 | 
| Pharmacodynamics: Percent Change From Baseline In Plasma Level of VEGFR2 at Week 3 in Participants With and Without DCR | VEGF-stimulated disruption of the cadherin-catenin complex leads to tumor cell invasion and metastasis. VEGFR2 plasma levels were assayed by ELISA as a marker of VEGF pathway modulation. | At Baseline and Week 3 of treatment (Day 15 ±4 days) | 
| Pharmacodynamics: Percent Change From Baseline In Plasma Level of VEGFR2 at Week 5 in Participants With and Without DCR | VEGF-stimulated disruption of the cadherin-catenin complex leads to tumor cell invasion and metastasis. VEGFR2 plasma levels were assayed by ELISA as a marker of VEGF pathway modulation. | At Baseline and Week 5 of treatment | 

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