458P - 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

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Johanna Bendell
Authors J. Bendell1, D. Roda2, J. Mateo3, A. Hollebecque4, L. De Mattos-Arruda5, R. Meng6, S.J. Isakoff7, L.R. Molife8, J. Tabernero9, A. Cervantes Ruiperez10
  • 1Drug Development Unit, Sarah Cannon Research Institute, 37203 - Nashville/US
  • 2Department Of Hematology And Medical Oncology, Hospital Clinico, 46010 - Valencia/ES
  • 4Dept. Of Medicine, Institut Gustave Roussy, FR-94805 - Villejuif CEDEX/FR
  • 5Medical Oncology, Vall d'Hebron Hospital, 08035 - Barcelona/ES
  • 6Exploratory Clinical Development, Genentech, So San Francisco/US
  • 7Department Of Hematology And Medical Oncology, Massachusetts General Hospital, Boston/US
  • 8Drug Development Unit, Royal Marsden Hospital, SM25BH - London/UK
  • 9Medical Oncology Department, Vall d'Hebron University Hospital, ES-08035 - Barcelona/ES
  • 10Serv. Hematologia Y Oncologia Medica, Hospital Clinico Universitario de Valencia, ES-46010 - Valencia/ES



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.


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.


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 (<10%). All GDC-0068-related AEs were Grade 1-2, except Grade 3 diarrhea (n = 1), leukopenia (n = 1), hypophosphatemia (n = 2) in Arm A, and thrombocytopenia (n = 1), nausea (n = 1), fatigue (n = 1) in Arm B. No Grade ≥ 4 AEs due to GDC-0068 or DLTs occurred up to GDC-0068 600 mg. Preliminary data show comparable PK of GDC-0068, 5FU, OX, and D to single agents. 6 pts had ≥30% tumor reduction per RECIST, including pts with prior taxanes or 5FU/platinum, or with PI3K/Akt pathway alterations assessed by investigators, such as Akt1 mutant breast cancer (Arm A) and PTEN-loss colon cancer, PI3K mutant cervical cancer, and HER2+ esophageal cancer (Arm B).


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.


R. Meng: Employee of Genentech.

All other authors have declared no conflicts of interest.