Advanced Breast Cancer
Conditions
Keywords
Advanced Breast Cancer, Breast cancer, Dasatinib, Inoperable Stage III Breast Cancer, Metastatic Breast Cancer, Stage IV Breast Cancer
Brief summary
The purpose of this study is to find out if dasatinib will safely reduce the size or spread of your tumor.
Detailed description
The introduction of biologics with specific molecular targets has initiated a trend toward improved survival in women with metastatic breast cancer. The tyrosine kinase SRC (pp60src) is a member of a family of proteins that contribute to cellular signal transduction activities such as cell growth, differentiation, survival, adhesion and migration. Abnormal signaling has been linked to cancer metastases; thus, identification of molecular regulators or inhibitors of SRC present therapeutic opportunity for cancer patients. Src kinases consist of eight non-receptor tyrosine kinases (Src, Fyn, Yes, Lck, Lyn, Hck, Fgr and Blk) that interact with the intracellular domains of growth factor/cytokine receptors, (G-protein-coupled receptor)GPCRs and integrins. Inhibition of SRC has also been associated with reversal of chemoresistance and restored sensitivity to drug-resistant ovarian cancer cells, suggesting potential as second- line treatment for previously treated populations. Dasatinib is a potent, broad spectrum inhibitor of 5 critical oncogenic tyrosine kinases, including SRC. Patients will receive dasatinib, a Src inhibitor, at an initial dose of 50 mg PO BID, with real-time PharmacoDynamic dose adjustment following 4 weeks of therapy based on inhibition of phosphorylation of SRC, focal adhesion kinase (FAK) and paxillin, until progression. The primary objective is to assess tolerability and estimate the proportion of patients who are progression-free at 16 weeks from the date of study enrollment. A minimum of 2 (maximum of 3) tumor biopsies will be analyzed and compared for SRC signature: one at baseline (study enrollment, all patients); the second after 4 weeks of dasatinib therapy (all patients); and the third at progression (only patients who progress after a documented response). Patients will receive continuous daily administration until documented disease progression, and will be followed until death. The results of this study may be useful in designing future studies using dasatinib alone or in combination with chemotherapy, thus having the potential to alter the current standard of care in this incurable population. Additional correlative studies will be conducted. Tumor biopsies will be analyzed and compared for SRC, pSRC, Ki67, and related genomic signatures.
Interventions
DRUGDasatinib
An initial dose of 50 mg PO BID; following 4 weeks of treatment, dose adjustment will be based on inhibition of phosphorylation of FAK and paxillin per biopsy assessment, as well as toxicity assessment.
Sponsors
Bristol-Myers Squibb
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Measurable Stage IV or inoperable Stage III advanced breast cancer. * There is no limit on the number of prior therapies. * At least 3 weeks since prior chemotherapy, biological or hormonal therapy. * At least 2 weeks since surgical biopsy. * At least 3 weeks since major (open thoracic/abdominal/cardiac) surgery. * No central nervous system (CNS) metastases except solitary brain metastasis * No cardiac dysfunction * left ventricular ejection fraction (LVEF) ≥ 50% as determined by multiple gated acquisition scan (MUGA)/echocardiogram * Adequate blood counts * Normal liver and kidney function * Negative serum pregnancy test. * Able to provide informed consent
Exclusion criteria
* Pregnant or breast feeding. * Prior treatment with dasatinib. * Bone as the only site of disease. * Significant gastrointestinal bleeding * Septicemia, infection, acute hepatitis, hypokalemia, or hypomagnesemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimation of the Proportion of Progression-free Patients at 16 Wks. | 16 weeks | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as appropriate. Proportion progression-free at 16 weeks.From first day of study related treatment with Dasatinib until the date of first documented progression or date of death from any cause, whichever came first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Measure Response to Protocol Therapy Per RECIST Criteria | 16 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression At least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as a reference the smallest sum longest diameter recorded since treatment started, or the appearance of one or more new lesions. RECIST 1.0 Overall response: Complete Response (CR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) CR= CR+CR and No new lesions PR= CR+SD; PR+SD and no new lesions SD= SD+SD and no new lesions PD= PD+any new lesions |
| Characterization and Comparison of SRC (A Protein Tyrosine Kinase)Dysregulation at Baseline (All Patients), After 4 Weeks of Dasatinib Treatment (All Patients), and at Progression (Only Patients Who Progress After Documented Response) | 4 weeks | For the 20 patients with evaluable biopsies at baseline and week 4, the median relative change from baseline in tissue biomarker levels of phospho-Src (p-Src) |
| Correlate SRC Dysregulation Results With Response to Dasatinib Therapy | 16 weeks | Since all patients progressed there is no comparison to between responders and non-responders. |
| To Explore the Association Between Each Patient's SRC Signature and Their Time to Progression. | Baseline Src measure to first progression | Spearman's correlation between the change in SRC signature from baseline to 4 weeks and time to progression |
| To Explore the Association Between Dasatinib and Osteoclastic Bone Resorption | not assessed | Not assessed secondary to limited number of subjects. |
Countries
United States
Participant flow
Recruitment details
Subjects will be identified in cancer center outpatient clinics multi-site. The study will be introduced by a physician or caregiver known to the patient. We will need to review protected health information in order to identify subjects, and information resulting from this activity will be used only to assess eligibility of a subject.
Pre-assignment details
Meds which inhibit platelet function/coagulation,potent inhibitors of cytochrome CYP3A, or meds that prolong the QT interval during study require a 7 day wash-out.IV bisphosphonates must be held for 2 wks before/6 wks after trial tx. Subjects must be 3 wks since prior to therapy, 2 wks since surgical bx and 3 wks since major surgery.
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib 50-100mg by mouth twice a day | 31 |
| Total | 31 |
Baseline characteristics
| Characteristic | Dasatinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 54.4 years STANDARD_DEVIATION 13.4 |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 31 |
| serious Total, serious adverse events | 10 / 31 |
Outcome results
Primary
Estimation of the Proportion of Progression-free Patients at 16 Wks.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as appropriate. Proportion progression-free at 16 weeks.From first day of study related treatment with Dasatinib until the date of first documented progression or date of death from any cause, whichever came first.
Time frame: 16 weeks
Population: 31 patients on this trial, 1 patient was found to have disease progression at 16-weeks, 16 patients had disease progression prior to 16 weeks, 8 patients were taken off-treatment due to toxicity, and 6 patients voluntarily withdrew from treatment. These latter two groups of patients were censored in the analysis of Progression Free Survival.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib | Estimation of the Proportion of Progression-free Patients at 16 Wks. | 0 percentage of participants |
Secondary
Characterization and Comparison of SRC (A Protein Tyrosine Kinase)Dysregulation at Baseline (All Patients), After 4 Weeks of Dasatinib Treatment (All Patients), and at Progression (Only Patients Who Progress After Documented Response)
For the 20 patients with evaluable biopsies at baseline and week 4, the median relative change from baseline in tissue biomarker levels of phospho-Src (p-Src)
Time frame: 4 weeks
Population: Twenty patients with evaluable biopsies at baseline and 4 week follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib | Characterization and Comparison of SRC (A Protein Tyrosine Kinase)Dysregulation at Baseline (All Patients), After 4 Weeks of Dasatinib Treatment (All Patients), and at Progression (Only Patients Who Progress After Documented Response) | -0.125 percentage of change in p-SRC |
Comparison: The median change in SRC from baseline to 4 weeks was estimated.p-value: 0.395% CI: [-30, 9]t-test, 2 sided
Secondary
Correlate SRC Dysregulation Results With Response to Dasatinib Therapy
Since all patients progressed there is no comparison to between responders and non-responders.
Time frame: 16 weeks
Population: 20 patients with baseline and 4 week Src measures. 11 patients came off due to screen failure, toxicity or progression before 4 week biopsy.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dasatinib | Correlate SRC Dysregulation Results With Response to Dasatinib Therapy | -.10 percentage change in p-SRC |
p-value: 0.395% CI: [-0.3, 0.1]t-test, 1 sided
Secondary
To Explore the Association Between Dasatinib and Osteoclastic Bone Resorption
Not assessed secondary to limited number of subjects.
Time frame: not assessed
Secondary
To Explore the Association Between Each Patient's SRC Signature and Their Time to Progression.
Spearman's correlation between the change in SRC signature from baseline to 4 weeks and time to progression
Time frame: Baseline Src measure to first progression
Population: 11 patients had both change in Src level and progression time intervals
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib | To Explore the Association Between Each Patient's SRC Signature and Their Time to Progression. | 0.27 correlation coefficient |
Secondary
To Measure Response to Protocol Therapy Per RECIST Criteria
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression At least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as a reference the smallest sum longest diameter recorded since treatment started, or the appearance of one or more new lesions. RECIST 1.0 Overall response: Complete Response (CR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) CR= CR+CR and No new lesions PR= CR+SD; PR+SD and no new lesions SD= SD+SD and no new lesions PD= PD+any new lesions
Time frame: 16 weeks
Population: Proportion with Best Response of Stable Disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib | To Measure Response to Protocol Therapy Per RECIST Criteria | 16.7 percentage of participants |