Supplementary Tables S1-S6, Figures S1-S2. Table S1. Criteria for defining dose-limiting toxicities Table S2. Summary of primary plasma PK parameters for BKM120 by treatment Table S3. Summary of primary plasma PK parameters for GSK1120212 by treatment Table S4. All causality AEs occurring in >10% of patients (all Grades and Grades 3-4; overall and by dose level - escalation and expansion) Table S5. SAEs suspected to be related to treatment (all Grades and Grades 3-4; overall and by dose level) Table S6. Summary statistics of exposure of study drug in the first four cycles and overall by treatment Full analysis set Figure S1A. Percentage change from baseline on p-S6 (H-score) in fresh tumour as per central review by primary site of cancer and treatment - phosphoserine 240-S6 ribosomal protein Figure S1B. Percentage change from baseline on p-S6 (H-score) in fresh tumour as per central review by primary site of cancer and treatment - phosphorylated ribosomal protein S6 235 Figure S1C. Percentage change from baseline on p-ERK (H-score) in fresh tumour as per central review by primary site of cancer and treatment Figure S2. Exposure plot (patients treated at MTD and RP2D, all cycles) Full analysis set Figure S3. Exposure plot (patients treated at MTD and RP2D, first 9 cycles) Full analysis set
ARTICLE ABSTRACTPurpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non–small cell lung, ovarian, or pancreatic cancer.Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR.