Abstract P2-16-13: Phase I dose escalation clinical trial of the PI3K inhibitor BKM120 and capecitabine (C) in metastatic breast cancer (MBC)

Abstract

Abstract Background: PIK3CA is one of the most frequently mutated genes in human breast cancer, and the high expression of a PIK3CA-pathway signature is associated with the poor prognosis Luminal B and Basal-like expression subtypes. BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which has shown activity in preclinical and early clinical testing, and synergy with both endocrine and chemotherapy. In this trial we sought to evaluate the safety and estimate the maximum tolerated dose (MTD) of the combination of BKM120 and C in patients (pts) with MBC. Methods: In a 3+3 dose escalation design, we evaluated four cohorts of BKM 120 daily plus C BID x 14 days in 21 day cycles. Standard definitions for DLT and MTD were used and evaluated on the first cycle. Toxicity was graded by CTCAE version 4. Response was evaluated after 2 cycles by RECIST criteria. Pts with MBC appropriate for treatment with C who had <4 prior chemotherapy regimens and normal organ, bone marrow and cardiac parameters were eligible. Results: 21 pts (11 hormone receptor (HR)+, 3 HER2+, 9 HR/HER2-negative) were enrolled and treated. All were evaluable for toxicity and 14 for response to date. Median age was 54 (range 35-65). Median prior chemotherapy regimens for MBC was 2 (range 1-4). The following dose levels (DL) were evaluated: BKM120 50 mg/d + C 1000 mg/m2/BID x 14(DL 1-4 pts), BKM120 80 mg/d + C 1000 mg/m2/BID x 14 (DL2-3 pts), BKM120 100 mg/d + C 1000 mg/m2/BID x 14 (DL3-9 pts), BKM120 100 mg/d + C 1250 mg/m2/BID x 14 (DL4-5 pts). Most frequent adverse events (all grades) included: Nausea (12), mood disorders (11), PPE (9), diarrhea (8), fatigue (7), vomiting (5) mucositis (4), rash (4), photosensitivity (3), hyperglycemia (3). Grade 3 or higher AEs in any cycle were transaminitis (3) diarrhea (2) mood disorder (2), hyperglycemia, fatigue, photosensitivity, PPE (1 pt each). DLTs: grade 3 hyperglycemia (1/6 pts at DL3), and grade 3 mood disorder in 1/5 pts DL 4. Additionally 4 of 5 patients at DL 4 required dose reduction or delay prior to C3D1. Thus DL 4 exceeded the MTD and DL 3 was expanded for further safety evaluation. Antitumor activity was seen with best responses of 1 CR (at DL 3), 3 PR (DL1 and 4) and 7 SD. PK analysis, assessment of tumor PIK3CA mutation status and intrinsic subtype by PAM50 is ongoing. Conclusions: The combination of BKM120 100 mg po q day and C 1000 mg/m2 / BID x 14 d in 21 day cycles is tolerable and appears active. PK and biomarker analysis are ongoing. A phase II trial is planned. Acknowledgements: This study was funded by Novartis Pharmaceuticals and by a grant from Susan G. Komen for the Cure (SAC 110044). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-13.