PD09-04: A Phase Ib, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of the PI3-Kinase Inhibitor GDC-0941 in Combination with Paclitaxel and Bevacizumab in Patients with Locally Recurrent or Metastatic Breast Cancer.
Authors: Schöffski P , De Benedictis E , Gendreau S , Gianni L , Krop IE , Levy G , Ware J , Wildiers H , Winer EP 
Published: June 2012

Abstract
Background: GDC-0941 is a potent and selective oral pan-inhibitor of class I PI3K isoforms that demonstrates single-agent activity in xenograft models1,2,3. Increased phosphorylation of AKT has been observed in breast cancer (BC) cell lines treated with paclitaxel in vitro, suggesting dependence on the PI3K pathway for survival in response to chemotherapy treatment. GDC-0941 increases the antitumor activity of taxanes, associated with increased apoptotic cell death, in multiple BC xenograft models2.
Material and Methods: Patients (pts) with HER2−negative locally recurrent or metastatic BC (MBC) that received no more than 2 prior anti-cancer therapies for MBC (prior paclitaxel and/or bevacizumab permitted) were enrolled in a Phase Ib study (GDC4629g) of paclitaxel and GDC-0941 with and without bevacizumab using a 3+3 dose escalation design to evaluate the safety, tolerability, and PK and determine the MTD of the combination. Paclitaxel was given at 90 mg/m2 on Days 1, 8 and 15 and bevacizumab, if applicable, at 10 mg/kg on Days 1 and 15 every 28 days. Two dosing schedules of GDC-0941 were examined: GDC-0941 given once-daily on Days 1–21 (“21+7” schedule) or given for 5 consecutive days followed by a 2-day drug holiday (“5+2” schedule, implemented to potentially to improve the efficacy and safety of the combination treatment).
Results: We report data from 5 cohorts (25 pts). Sixteen of the 25 pts (64%) are hormone-receptor positive and 12 of 25 patients (48%) received prior treatment with a taxane, (all but one in the neo-adjuvant or adjuvant setting) and only one patient received prior treatment with bevacizumab. Pts in Cohort 1 received GDC-0941 60 mg given 21+7 with paclitaxel in Cycle 1; they were allowed to receive bevacizumab starting in Cycle 2. One DLT of Grade 3 subclavian vein thrombosis (in a pt with an indwelling catheter) was observed at this dose level. The cohort was expanded without any additional DLTs. In Cohorts 2 and 3, GDC-0941 was given 21+7 at 60 mg and 100 mg, respectively, with paclitaxel and bevacizumab starting in Cycle 1. In Cohort 4, GDC-0941 was given 5+2 at 165 mg with paclitaxel only. Cohort 5, with 250 mg GDC-0941 given 5+2 with paclitaxel only, is currently under evaluation. The most common drug-related AEs in 22 treated patients are in Table 1. Preliminary PK for GDC-0941, paclitaxel and 6-hydroxypaclitaxel were similar to historical profiles from previous studies of these molecules. One CR and 9 PRs (ORR 46%) have been observed to date.

Conclusions: GDC-0941 given 5+2 at doses up to 165 mg QD in combination with paclitaxel is well tolerated and dose escalation continues with encouraging clinical activity. Updated safety, PK and efficacy data will be presented.
1Junttila et al, Cancer Cell 2009
2Yao et al., CCR 2009
3O'Brien et al., CCR 2010
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-04.