Phase II Dasatinib Study in Advanced Breast Cancer
A Phase II Trial of Dasatinib to Treat Women With Stage IV or Inoperable Stage III Advanced Breast Cancer
Descripción general del estudio
Estado
Estado
Condiciones
Condiciones
Intervención / Tratamiento
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Tipo de estudio
Inscripción (Actual)
Inscripción
Fase
Fase
- Fase 2
Contactos y Ubicaciones
Ubicaciones de estudio
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Florida
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West Palm Beach, Florida, Estados Unidos, 33401
- Palm Beach Cancer Center Institute
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North Carolina
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Charlotte, North Carolina, Estados Unidos, 28204
- Presbyterian Health Care
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Durham, North Carolina, Estados Unidos, 27710
- Duke University Medical Center
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-
Criterios de participación
Criterio de elegibilidad
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
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
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: No aleatorizado
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Número de brazos
Armas e Intervenciones
Grupo de participantes/brazoGrupo de participantes/brazo |
Intervención / TratamientoIntervención / Tratamiento |
|---|---|
|
Experimental: Dasatinib
50- 100 mg PO BID
|
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.
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Estimation of the Proportion of Progression-free Patients at 16 Wks.
Periodo de tiempo: 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. |
16 weeks
|
Medidas de resultado secundarias
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
To Measure Response to Protocol Therapy Per RECIST Criteria
Periodo de tiempo: 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 |
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)
Periodo de tiempo: 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)
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4 weeks
|
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Correlate SRC Dysregulation Results With Response to Dasatinib Therapy
Periodo de tiempo: 16 weeks
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Since all patients progressed there is no comparison to between responders and non-responders.
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16 weeks
|
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To Explore the Association Between Each Patient's SRC Signature and Their Time to Progression.
Periodo de tiempo: Baseline Src measure to first progression
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Spearman's correlation between the change in SRC signature from baseline to 4 weeks and time to progression
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Baseline Src measure to first progression
|
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To Explore the Association Between Dasatinib and Osteoclastic Bone Resorption
Periodo de tiempo: not assessed
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Not assessed secondary to limited number of subjects.
|
not assessed
|
Colaboradores e Investigadores
Patrocinador
Patrocinador
Colaboradores
Colaboradores
Investigadores
Investigadores
- Investigador principal: Kimberly Blackwell, MD, Duke University
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Inicio del estudio
Finalización primaria (Actual)
Finalización primaria
Finalización del estudio (Actual)
Finalización del estudio
Fechas de registro del estudio
Enviado por primera vez
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Publicado por primera vez
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
Última actualización publicada
Última actualización enviada que cumplió con los criterios de control de calidad
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
Otros números de identificación del estudio
- Pro00007578
- BMS CA180089
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