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| ID | Type | Description | Link |
|---|---|---|---|
| BMS CA180089 |
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| Name | Class |
|---|---|
| Bristol-Myers Squibb | INDUSTRY |
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The purpose of this study is to find out if dasatinib will safely reduce the size or spread of your tumor.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dasatinib | Experimental | 50- 100 mg PO BID |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dasatinib | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 16 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kimberly Blackwell, MD | Duke University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Palm Beach Cancer Center Institute | West Palm Beach | Florida | 33401 | United States | ||
| Presbyterian Health Care |
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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Dasatinib | 50-100 mg PO BID |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Dasatinib | 50-100mg by mouth twice a day |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Number | 95% Confidence Interval | percentage of participants | 16 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dasatinib | 50-100mg po bid |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain | General disorders | CTCAE (3.0) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| anorexia | General disorders | CTCAE (3.0) | Non-systematic Assessment | grade 1 19% grade 2 13% grade 3 10% |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kimberly Blackwell, MD | Duke University Health System | 919-668-1478 | kimberly.blackwell@duke.edu |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D000069439 | Dasatinib |
| ID | Term |
|---|---|
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
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|
| 16 weeks |
| 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) | 4 weeks |
| Correlate SRC Dysregulation Results With Response to Dasatinib Therapy | Since all patients progressed there is no comparison to between responders and non-responders. | 16 weeks |
| 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 | Baseline Src measure to first progression |
| To Explore the Association Between Dasatinib and Osteoclastic Bone Resorption | Not assessed secondary to limited number of subjects. | not assessed |
| Charlotte |
| North Carolina |
| 28204 |
| United States |
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
50mg-100mg po BID |
|
|
| 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 | Proportion with Best Response of Stable Disease | Posted | Number | percentage of participants | 16 weeks |
|
|
|
| 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) | Twenty patients with evaluable biopsies at baseline and 4 week follow-up | Posted | Median | Inter-Quartile Range | percentage of change in p-SRC | 4 weeks |
|
|
|
|
| Secondary | Correlate SRC Dysregulation Results With Response to Dasatinib Therapy | Since all patients progressed there is no comparison to between responders and non-responders. | 20 patients with baseline and 4 week Src measures. 11 patients came off due to screen failure, toxicity or progression before 4 week biopsy. | Posted | Mean | 95% Confidence Interval | percentage change in p-SRC | 16 weeks |
|
|
|
|
| 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 | 11 patients had both change in Src level and progression time intervals | Posted | Number | correlation coefficient | Baseline Src measure to first progression |
|
|
|
| Secondary | To Explore the Association Between Dasatinib and Osteoclastic Bone Resorption | Not assessed secondary to limited number of subjects. | Posted | not assessed |
|
|
| 10 |
| 31 |
| 30 |
| 31 |
| Pain, back | General disorders |
|
| Pain, extrimity limb | General disorders | CTCAE (3.0) |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) |
|
| Anorexia | Metabolism and nutrition disorders | CTCAE (3.0) |
|
| Syncope | General disorders | CTCAE (3.0) |
|
| Edema, limb | Blood and lymphatic system disorders | CTCAE (3.0) |
|
| AST | Hepatobiliary disorders | CTCAE (3.0) |
|
| Pleural Effusion | Respiratory, thoracic and mediastinal disorders |
|
| Pain, chest/thorax | General disorders |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) |
|
| Thrombosis | Blood and lymphatic system disorders |
|
| hyponatremia | General disorders | CTCAE (3.0) |
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| infection | Infections and infestations |
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| diarrhea | Gastrointestinal disorders |
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| fever | General disorders |
|
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| fatigue | General disorders | CTCAE (3.0) | number of subject effected: Grade 1=7 grade 2=8 grade 3=1 |
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| fever: non-neutropenic | Gastrointestinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=3 grade 2=2 grade 3=0 |
|
| Flushing | General disorders | CTCAE (3.0) | number of subjects effected: Grade 1=5 grade 2=2 grade 3=0 |
|
| insomnia | General disorders | CTCAE (3.0) | number of subjects effected: Grade 1=6 grade 2=2 grade 3=0 |
|
| diarrhea | Gastrointestinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=10 grade 2=5 grade 3=0 |
|
| constipation | Gastrointestinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=8 grade 2=3 grade 3=0 |
|
| nausea | Gastrointestinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=10 grade 2=8 grade 3=1 |
|
| vomiting | Gastrointestinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=10 grade 2=3 grade 3=0 |
|
| cough | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=6 grade 2=0 grade 3=0 |
|
| dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=4 grade 2=5 grade 3=3 |
|
| pneumonitis | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=0 grade 2=1 grade 3=2 |
|
| paricardial effusion | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=2 grade 2=0 grade 3=0 |
|
| pain: abdomen | Gastrointestinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=6 grade 2=0 grade 3=0 |
|
| pain: bone | Musculoskeletal and connective tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=5 grade 2=0 grade 3=1 |
|
| pain: chestwall | Skin and subcutaneous tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=2 grade 2=2 grade 3=0 |
|
| pain:extremity | Musculoskeletal and connective tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=3 grade 2=2 grade 3=1 |
|
| pain: headache | Nervous system disorders | CTCAE (3.0) | number of subjects effected: Grade 1=9 grade 2=2 grade 3=0 |
|
| pain:joint | Musculoskeletal and connective tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=4 grade 2=3 grade 3=2 |
|
| pain: muscle | Musculoskeletal and connective tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=1 grade 2=3 grade 3=0 |
|
| elevated ALT | Hepatobiliary disorders | CTCAE (3.0) | number of subjects effected: Grade 1=4 grade 2=1 grade 3=0 |
|
| elevated AST | Hepatobiliary disorders | CTCAE (3.0) | number of subjects effected: Grade 1=2 grade 2=0 grade 3=0 |
|
| hyponatremia | Investigations | CTCAE (3.0) | number of subjects effected: Grade 1=1 grade 2=0 grade 3=1 |
|
| thrombocytopenia | Investigations | CTCAE (3.0) | number of subjects effected: Grade 1=0 grade 2=1 grade 3=1 |
|
| DVT | Vascular disorders | CTCAE (3.0) | number of subjects effected: Grade 1=0 grade 2=0 grade 3=2 |
|
| edema:facial | General disorders | CTCAE (3.0) | number of subjects effected: Grade 1=4 grade 2=1 grade 3=0 |
|
| edema: extremity | General disorders | CTCAE (3.0) | number of subjects effected: Grade 1=5 grade 2=1 grade 3=0 |
|
| cellulitis | Skin and subcutaneous tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=0 grade 2=0 grade 3=1 |
|
| rash | Skin and subcutaneous tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=14 grade 2=2 grade 3=0 |
|
| mucositis | Skin and subcutaneous tissue disorders | CTCAE (3.0) | number of subjects effected: Grade 1=4 grade 2=0 grade 3=0 |
|
| rhinitis | General disorders | CTCAE (3.0) | number of subjects effected: Grade 1=5 grade 2=0 grade 3=0 |
|
| neuropathy sensory | Nervous system disorders | CTCAE (3.0) | number of subjects effected: Grade 1=7 grade 2=2 grade 3=0 |
|
| plueral effusion | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | number of subjects effected: Grade 1=5 grade 2=8 grade 3=3 |
|
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| D017437 |
| Skin and Connective Tissue Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011743 | Pyrimidines |