Clinical trial NCT00546104: Phase II Dasatinib Study in Advanced Breast Cancer
Official title: A Phase II Trial of Dasatinib to Treat Women With Stage IV or Inoperable Stage III Advanced Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced Breast Cancer
Keywords: Advanced Breast Cancer
Breast cancer
Dasatinib
Inoperable Stage III Breast Cancer
Metastatic Breast Cancer
Stage IV Breast Cancer
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2007-10-18
Enrollment: 31
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Estimation of the Proportion of Progression-free Patients at 16 Wks.
timeFrame: 16 weeks
Secondary outcomes:
measure: To Measure Response to Protocol Therapy Per RECIST Criteria
timeFrame: 16 weeks
measure: 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)
timeFrame: 4 weeks
measure: Correlate SRC Dysregulation Results With Response to Dasatinib Therapy
timeFrame: 16 weeks
measure: To Explore the Association Between Each Patient's SRC Signature and Their Time to Progression.
timeFrame: Baseline Src measure to first progression
measure: To Explore the Association Between Dasatinib and Osteoclastic Bone Resorption
timeFrame: not assessed
Other outcomes:
Locations:
city: West Palm Beach
country: United States
facility: Palm Beach Cancer Center Institute
state: Florida
city: Charlotte
country: United States
facility: Presbyterian Health Care
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University
name: Kimberly Blackwell, MD
role: PRINCIPAL_INVESTIGATOR
References: