Background:

GDC-0941 is a potent and selective oral inhibitor of class I PI3K kinases that demonstrates broad activity in diverse xenograft cancer models and increases the anti-tumor activity of taxanes, associated with increased apoptotic cell death, in multiple BC xenografts.

Methods:

In the Phase Ib dose-escalation study, GDC4629g, GDC-0941 was administered in combination with paclitaxel dosed at 90 mg/m2 intravenous [IV] weekly for 3 out of 4 weeks, bevacizumab at 10 mg/kg IV biweekly, and trastuzumab 2−4 mg/kg IV weekly in 28-day cycles. The study was conducted in 2 parts: Part 1 evaluated oral doses of 60 and 100 mg GDC-0941 on a "21+7" (21 days on/7 days off) dosing schedule in combination with paclitaxel with and without bevacizumab. Part 2 evaluated GDC-0941 on a "5+2" schedule (5 days on/2 days off in a repeating pattern), at doses of 165 - 330 mg, in combination with paclitaxel (Arm A), paclitaxel plus bevacizumab (Arm B) or paclitaxel plus trastuzumab (Arm C). The primary objective was to evaluate safety, tolerability, and pharmacokinetics (PK), and to determine the maximum tolerated dose (MTD) for each combination. Anti-tumor activity was evaluated by RECIST v1.0 and available archival tumor samples were analyzed to assess PI3K related biomarkers.

Results:

63 patients were enrolled: 20 in Part 1 and 43 in Part 2 (18 in Arm A, 16 in Arm B, and 9 in Arm C). The most frequent grade ≥3 drug-related adverse events (AEs) were: Part 1, neutropenia (45%), peripheral neuropathy and nail disorder (15% each); Part 2, Arm A, neutropenia (38%), pneumonia and rash (11% each); Arm B, neutropenia and rash (25% each); Arm C, rash and hypertension (11% each). The most common AEs assessed as being related to GDC-0941 were as follows:

Most common AEs related to GDC-0941

Adverse EventAll GradesGrade ≥ 3
DIARRHEA 45 (71.4%) 2 (3.2%) 
NAUSEA 33 (52.4%) 
NEUTROPENIA 29 (46.0%) 17 (27.0%) 
RASH 29 (46.0%) 7 (11.1%) 
FATIGUE 28 (44.4%) 
STOMATITIS 19 (30.2%) 
DECREASED APPETITE 15 (23.8%) 1 (1.6%) 
VOMITING 15 (23.8%) 
Adverse EventAll GradesGrade ≥ 3
DIARRHEA 45 (71.4%) 2 (3.2%) 
NAUSEA 33 (52.4%) 
NEUTROPENIA 29 (46.0%) 17 (27.0%) 
RASH 29 (46.0%) 7 (11.1%) 
FATIGUE 28 (44.4%) 
STOMATITIS 19 (30.2%) 
DECREASED APPETITE 15 (23.8%) 1 (1.6%) 
VOMITING 15 (23.8%) 

In Part 1, the MTD was not reached, the maximum administered dose (MAD) of GDC-0941 was 100 mg, a dose-limiting AE was subclavian vein thrombosis. In Part 2, Arm A, the MTD was 250 mg, Grade 3 febrile neutropenia, bacteremia, and rash were DLTs. In Arm B and Arm C, the MAD was 260 mg, Grade 3 rash was a DLT in both arms. No differences in the PK of either GDC 0941 or paclitaxel were observed when administered in combination compared to historical single-agent data. Best tumor response by RECIST was as follows: Part 1, 1 (5%) complete (CR) and 4 (21%) partial responses (PR); Arm A, 1 (6%) CR and 3 (17%) PR; Arm B, 7 (47%) PR; Arm C, 1 (11%) PR.

Conclusions:

GDC-0941 was generally well-tolerated in combination with paclitaxel with or without bevacizumab or trastuzumab at dose ranges of up to 330 mg at the "5+2" dosing schedule. Anti-tumor activity has been observed in combination with paclitaxel with and without bevacizumab or trastuzumab. Updated biomarker data and associations with clinical outcomes will be presented.

Citation Format: Patrick Schöffski, Sara Cresta, Ingrid A Mayer, Hans Wildiers, Isabelle Rooney, Doris Apt, Steve Gendreau, Kari Morrissey, Mark Lackner, Jill Spoerke, Eric Winer. Tolerability and anti-tumor activity of the oral PI3K inhibitor GDC-0941 in combination with paclitaxel, with and without bevacizumab or trastuzumab in patients with locally recurrent or metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-10.