STAR Cape+BKM120 MBC With Brain Met

This is a Phase 2, multicenter, single-arm study to determine the safety and efficacy of BKM120 plus capecitabine in breast cancer patients with brain metastases. 40 patients will be included, who have either ER+/HER2-, HER2+ or triple negative breast cancer.. The Graded Prognostic Assessment (GPA) is a recently developed, validated prognostic score for patients with brain metastases. The Graded Prognostic Assessment will be utilized to evaluate efficacy in this clinical study. Capecitabine is a prodrug which is enzymatically converted to 5-fluorouracil in its tumor target where it inhibits DNA synthesis and slows tumor growth. It is currently FDA approved for both colorectal and breast cancer. BMK120 is a pan phosphatidylinositol-3-kinase inhibitor being developed under IND# 102,823 by Novartis Corporation. As of September 2012 over 600 patients had been enrolled in fourteen separate Novartis sponsored monotherapy or combination therapy clinical studies of BMK120. Phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions including cell proliferation, survival, translational regulation of protein synthesis, glucose metabolism, cell migration, and angiogenesis. PI3K signaling also serves a central role in the pathogenesis of numerous cancers. Constitutive activation of PI3K signaling is known to be a critical step in mediating the transforming potential of oncogenes and tumor suppressors in many tumor types. Resistance to a variety of therapeutic interventions, including hormonal therapy, anti-HER2 therapies and chemotherapy can also be linked to constitutive activation of the PI3K pathway. Preliminary data suggest that activation of the PI3K pathway is a predictor of a poor prognostic outcome in many cancer types. Thus, as a pan-PI3K inhibitor, BMK120 may provide a therapeutic benefit to patients with MBC. Both capecitabine and BMK120 have previously shown activity in patients with MBC. Like capecitabine, BMK120 is also effective in crossing the blood brain barrier making it a preferred candidate for its evaluation in patients with MBC. Trastuzumab is a monoclonal antibody that targets the HER2 receptor which is overexpressed or amplified in approximately 20-25% of breast cancers. The clinical benefit of trastuzumab in women with metastatic breast cancer has been demonstrated in two pivotal studies. Current clinical experience with BMK120 has shown that its most frequent adverse events (AEs) include fatigue, decreased appetite, diarrhea, hyperglycemia, nausea, rash and mood alteration disorders. Therefore patients will be closely monitored for fasting plasma glucose (FPG) HbA1c, and insulin C-peptide. Patients will also be frequently and routinely evaluated for mood disorders and disturbances. The remaining most frequent AEs will be detected by regular, frequent monitoring with symptomatic treatment to be provided as required.