Phase IB Dose-Escalation Study of the Akt Inhibitor Gdc-0068 with Docetaxel (D) or Modified Folfox6 (F) in Patients (PTS) with Advanced Solid Tumors

ABSTRACT Background Aberrant activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway occurs in cancers and may lead to chemoresistance. GDC-0068 is a potent ATP-competitive small molecule inhibitor of all Akt isoforms. In preclinical models, GDC-0068 synergistically combined with taxanes and 5FU/platinum. This study evaluated safety, pharmacokinetics (PK), and efficacy of GDC-0068 combined with D or F. Methods Eligible pts with metastatic solid tumors, treated with up to 3 regimens, received either D, 75 mg/m2 Day1 and escalating GDC-0068 daily (QD) Days 2-15 every 21 days (Arm A); or F, bolus 5FU 400 mg/m2, leucovorin 400 mg/m2, oxaliplatin (OX) 85 mg/m2 Day 1, infusional 5FU 2400 mg/m2 for 46 hours and GDC-0068 QD Days 1-7 every 14 days (Arm B). GDC-0068 dose was capped at 600 mg QD, the single-agent MTD. Secondary endpoints were PK and predictive biomarker assessment. Results 47 pts enrolled as of May 2012: Arm A (GDC-0068 in mg): 100 (n = 3), 200 (n = 4), 400 (n = 7), 600 (n = 10, with expansion), and Arm B: 100 (n = 6), 200 (n = 9), 400 (n = 6), 600 (n = 2, ongoing). Grade ≥ 2 adverse events (AEs) related to GDC-0068 in ≥ 10% of pts were nausea (17%), diarrhea (13%), fatigue (13%) in Arm A and nausea (17%) and diarrhea (13%) in Arm B. Fasting hyperglycemia due to GDC-0068 was only Grade 1 ( Conclusions GDC-0068, combined with D or F, is safe and well tolerated up to 600 mg. Anti-tumor activity occurred, particularly in cancers with PI3K/Akt pathway alterations. Updated safety, efficacy, PK, and biomarker data, including expansion cohorts, will be presented. Disclosure R. Meng: Employee of Genentech. All other authors have declared no conflicts of interest.