452P - A phase 1b study to evaluate the safety and pharmacology of the dual PI3K-mTOR inhibitor GDC-0980 in combination with a fluoropyrimidine, oxaliplati...

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Lee Rosen
Authors L.S. Rosen1, J.W. Goldman2, S. Stewart2, J.M. Hubbard3, M. Roos3, W. Lin4, G. Shankar5, J. Capdevila6, E. Freas7, S. Leong7
  • 1Medicine, UCLA, 90404 - Santa Monica/US
  • 2Division Of Hematology Oncology, UCLA, 90404 - Santa Monica/US
  • 3Oncology, Mayo Clinic, Rochester/US
  • 4Bioocology Early Clinical Development, Genentech Inc, 94080 - South San Francisco/US
  • 5Biooncology Early Clinical Development, Genentech Inc, 94080 - South San Francisco/US
  • 6Medical Oncology, Hospital Vall d'Hebrón, Barcelona/ES
  • 7Medicine/oncology, University of Colorado, Denver/US



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.


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.


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.


GDC-0980 combined with fluoropyrimidine-based regimens is well tolerated, with confirmed antitumor activity. The RP2Ds are identified.


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.