Abstract P6-12-02: Phase Ib dose-escalation study of an Akt inhibitor ipatasertib (Ipat) in combination with docetaxel (Doc) or paclitaxel (Pac) in patients (pts) with metastatic breast cancer (MBC)
Authors: Isakoff Steven J , Bendell Johanna C , Cervantes Andrés , Soria Jean-Charles , Molife L R , Sanabria-Bohorquez Sandra M , Punnoose Elizabeth A , Jia Shidong , Patel Premal , Saura Cristina 
Published: May 2015

Abstract
Background: The Akt pathway is frequently aberrantly activated in MBC (e.g. via PTEN loss, and/or alterations of PIK3CA, AKT1, or AKT3); additionally, Akt activation may occur in response to chemotherapy, leading to cell survival and chemoresistance. Ipat (GDC-0068) is a potent oral, ATP-competitive inhibitor of all Akt isoforms. In preclinical models, Ipat synergistically combined with taxanes. In the Phase I dose-escalation single agent study, Ipat was given to pts including MBC, and downregulated Akt signaling at doses ≥ 100 mg.
Methods: Eligible pts with MBC, treated with up to 3 prior systemic chemotherapy regimens, received Doc 75 mg/m2 intravenously (IV) on Day 1 with escalating doses of Ipat PO QD on Days 2-15 every 21 days or received Pac 90 mg/m2 IV on Days 1, 8, and 15 with escalating doses of Ipat PO QD on Days 1-21 every 28 days. A standard 3+3 does-escalation design was used, with an expansion cohort of HER2-negative/hormone receptor positive [HER2-/HR+] MBC patents (including triple-negative MBC [TNBC]) in the Pac cohort at the recommended phase II dose. Pharmacokinetic (PK) and circulating tumor cell (CTC) samples were collected. Archival tumors were assessed for PTEN by immunohistochemistry and for pathway-relevant mutations.
Results: As of 1 Apr 2014, 54 patients with multiple solid tumors, including 19 pts with MBC (TNBC: n=13, HER2-/HR+: n=4, and HER2-positive: n=2) were enrolled, and pts with MBC received Ipat with Doc (n=5) or Pac (n=14). The common Grade ≥ 2 adverse events (AEs) related to Ipat in combination with Doc (≥ 10% and &gt; 1 patient) were diarrhea (80%), nausea (60%) and vomiting (40%), versus in combination with Pac (≥ 10% of pts) were diarrhea (43%), fatigue (29%) and hyperglycemia (14%). The PKs of Ipat, Doc, or Pac were comparable to the single agents. Partial responses by RECIST v1.1 were seen in 5 pts, including pts with HER2-/HR+ (n=2) or TNBC (n=3) who had previously progressed on Pac (n=4) or PI3K inhibitors (n=2) or had tumors with PI3K/Akt alterations [PTEN loss (n=1), PIK3CA mut (n=2), or AKT1 mut (n=1)]. Time on study &gt; 9 months occurred in 4 pts (HER2-/HR+ and TNBC) who had progressed on prior Pac (n=3) or PI3K inhibitors (n=3), and/or had tumors with PIK3CA mut (n=3).
Conclusions: Ipat in combination with Doc or Pac is well-tolerated and has a safety profile generally consistent with the single agent. Anti-tumor activity with Ipat in combination with taxanes was seen in MBC, including HER2-/HR+ or TNBC with baseline PI3K/Akt alterations. Updated safety, efficacy, and biomarker data will be presented.
Citation Format: Steven J Isakoff, Johanna C Bendell, Andrés Cervantes, Jean-Charles Soria, L R Molife, Sandra M Sanabria-Bohorquez, Elizabeth A Punnoose, Shidong Jia, Premal Patel, Cristina Saura. Phase Ib dose-escalation study of an Akt inhibitor ipatasertib (Ipat) in combination with docetaxel (Doc) or paclitaxel (Pac) in patients (pts) with metastatic breast cancer (MBC) [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 P6-12-02.