Phase II Dasatinib Study in Advanced Breast Cancer

Advanced Breast Cancer Clinical Trial

Official title:

A Phase II Trial of Dasatinib to Treat Women With Stage IV or Inoperable Stage III Advanced Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00546104
• Other study ID #: Pro00007578
• Secondary ID: BMS CA180089
• Status: Completed
• Phase: Phase 2
• First received: October 16, 2007
• Last updated: July 15, 2013
• Start date: October 2007
• Est. completion date: May 2011

Study information

• Verified date: July 2013
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to find out if dasatinib will safely reduce the size or spread of your tumor.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Advanced Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Dasatinib
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.

Locations

Country	Name	City	State
United States	Presbyterian Health Care	Charlotte	North Carolina
United States	Duke University Medical Center	Durham	North Carolina
United States	Palm Beach Cancer Center Institute	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	16 weeks	No
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	16 weeks	No
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)	4 weeks	No
Secondary	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	No
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	Baseline Src measure to first progression	No
Secondary	To Explore the Association Between Dasatinib and Osteoclastic Bone Resorption	Not assessed secondary to limited number of subjects.	not assessed	No