Abstract OT1-1-16: A randomized, multicenter, phase II study of ipatasertib (Ipat, GDC-0068), an inhibitor of Akt, in combination with paclitaxel (Pac) as front-line treatment for patients (pts) with metastatic triple-negative breast cancer (TNBC)
Authors: Isakoff Steven J , Kim Sung-Bae , Im Seock-Ah , Dent Rebecca A , Traina Tiffany A , Valero Vicente , Saura Cristina , Yalamanchili Sreeni , Patel Premal , Oliveira Mafalda 
Published: May 2015

Abstract
Background: The PI3K/Akt pathway is often activated in TNBC through loss of PTEN expression, low INPP4B expression, and/or increased AKT3 amplification. Activation of Akt may then lead to chemoresistance; thus, inhibition of Akt signaling may result in improved efficacy of chemotherapy in TNBC. Ipat (GDC-0068) is a potent ATP-competitive small molecule inhibitor of all Akt isoforms. In preclinical breast cancer models, the combination of Ipat with taxanes enhanced efficacy, and in a Phase Ib study, the combination of Ipat with Pac was well-tolerated and resulted in clinical responses.
Trial Design: This is a randomized, double-blinded, placebo controlled, international, multicenter, Phase II study designed to estimate the efficacy and safety profile of Ipat combined with Pac versus placebo combined with Pac in pts with metastatic TNBC. Pts will receive Ipat or placebo 400 mg orally once daily on Days 1 to 21 of each 28-day cycle with Pac 80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle. Treatment will continue until disease progression, intolerable toxicity, withdrawal, or study completion. Pts will then be followed every 3 months for survival. Archival tumors will be assessed for PTEN expression by immunohistochemistry.
Key Eligibility: Pts ≥ 18 years, ECOG 0 or 1, with histologically documented TNBC that is inoperable locally advanced or metastatic and not amenable to curative resection are eligible. Additional eligibility criteria include availability of a tumor specimen, measurable disease per RECIST v1.1, and adequate hematologic and organ function within 14 days of study. Any previous therapy for TNBC is excluded, except for prior neoadjuvant or adjuvant chemotherapy and/or radiation completed 6 months prior to study. Pts with known brain or spinal cord metastases are also excluded.
Objectives: The primary objective is progression-free survival (PFS) in all TNBC pts and in TNBC pts with PTEN-low tumors. Secondary objectives include estimation of overall survival (OS), objective response rate (ORR), duration of ORR, safety, pharmacokinetics (PK), patient-reported outcomes (PROs), and biomarkers.
Statistical Methods: Approximately 120 pts will be randomized 1:1 and stratified by prior adjuvant/neoadjuvant treatment including chemotherapy and/or radiation (yes vs. no), disease free interval from last dose of chemotherapy (≤ 12 months vs. &gt; 12 months), and tumor PTEN status (low/null vs. moderate vs. high). Primary and secondary efficacy analyses will include all randomized pts, grouped by treatment at randomization. Kaplan−Meier curves will be produced for analyses of PFS, OS, and duration of response, and stratified log rank tests will be used to compare treatments.
Accrural: This study is open for accrual.
Citation Format: Steven J Isakoff, Sung-Bae Kim, Seock-Ah Im, Rebecca A Dent, Tiffany A Traina, Vicente Valero, Cristina Saura, Sreeni Yalamanchili, Premal Patel, Mafalda Oliveira. A randomized, multicenter, phase II study of ipatasertib (Ipat, GDC-0068), an inhibitor of Akt, in combination with paclitaxel (Pac) as front-line treatment for patients (pts) with metastatic triple-negative breast cancer (TNBC) [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 OT1-1-16.