452P - A Phase 1B Study to Evaluate the Safety and Pharmacology of the Dual PI3K-MTOR Inhibitor GDC-0980 in Combination with a Fluoropyrimidine, Oxaliplatin, and Bevacizumab (BEV) in Patients with Advanced Solid Tumors

Abstract

ABSTRACT Background PI3K signaling is altered in many cancer types. In colorectal cancer (CRC), ∼30% of the tumors harbor PIK3CA mutations, and ∼20% of tumors have PTEN loss. GDC-0980 has demonstrated synergy with fluoropyrimidines, a common therapeutic agent in colorectal and advanced breast cancers. Methods This was a standard 3 + 3 dose escalation design to determine the recommended phase 2 dose (RP2D) of GDC-0980 with capecitabine (CPC) (Arm A) or with mFOLFOX6 + Bev (Arm B) in patients (pts) with advanced solid tumors. In Arm A, GDC-0980 and CPC are given daily for 14 consecutive days in each 21-day cycle. In Arm B, GDC-0980 is given for 7 consecutive days in a 14-day cycle with mFOLFOX6 given on the first day. Bev is given on Day 1 starting in Cycle 5 during the dose escalation stage. Results In Arm A 6 pts received 25mg GDC-0980 and 1650mg/m2 bid of CPC (A1); 3 pts received 40mg GDC-0980 and 1650mg/m2 CPC (A2); and 9 pts received 40mg GDC-0980 and 2000mg/m2 CPC (A3). Common adverse events (AEs) in >20% pts were nausea, fatigue, decreased appetite, hyperglycemia, vomiting, diarrhea, stomatitis, mucositis and rash. One dose limiting toxicity (DLT) of G3 AST/ALT was observed in A1. The RP2D in Arm A is 40mg GDC-0980 + 2000mg/m2 CPC. One pt in A2 with HNSCC experienced a confirmed partial response (cPR, ≥6mo). In Arm B, 4 pts received 25 mg (B1) and 6 pts received 40mg GDC-0980 (B2) in combination with mFOLFOX6 and Bev (10 mg/kg). The RP2D in Arm B is 40mg GDC-0980 + mFOLFOX6 + Bev. Common AEs in >20% pts were nausea, vomiting, decreased appetite, diarrhea, fatigue, peripheral neuropathy and thrombocytopenia. One DLT of G4 thrombocytopenia was observed in cohort B2. Cohort expansion with CRC pts in Arm B is ongoing. Two pts in cohort B1 (cholangiocarcinoma, anal cancer) experienced cPRs (≥6mo). The PK of GDC-0980 and CPC or 5-FU, oxaliplatin and leucovorin suggests minimal drug-drug interaction. Biomarker analysis is ongoing. Conclusions GDC-0980 combined with fluoropyrimidine-based regimens is well tolerated, with confirmed antitumor activity. The RP2Ds are identified. Disclosure L.S. Rosen: Research support received from Genentech, the study sponsor. J. Goldman: Research support received from Genentech, the study sponsor. W. Lin: Genentech Employee. G. Shankar: Genentech Employee. S. Leong: Presently receiving research support for clinical trials from: Genentech, Pfizer, Astra Zeneca Presently recieving laboratory research support from Pfizer. All other authors have declared no conflicts of interest.