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

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

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: Dasatinib

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • West Palm Beach, Florida, United States, 33401
      • Palm Beach Cancer Center Institute
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Presbyterian Health Care
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dasatinib; 50- 100 mg PO BID	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.; Other Names: BMS-354825; Sprycel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Kimberly Blackwell, MD, Duke University

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: October 16, 2007
• First Submitted That Met QC Criteria: October 16, 2007
• First Posted (Estimate): October 18, 2007

Study Record Updates

• Last Update Posted (Estimate): July 17, 2013
• Last Update Submitted That Met QC Criteria: July 15, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Advanced Breast Cancer; Breast cancer; Metastatic Breast Cancer; Dasatinib; Inoperable Stage III Breast Cancer; Stage IV Breast Cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dasatinib
• Other Study ID Numbers: Pro00007578; BMS CA180089