Phase Ib Dose-Escalation Study of the Akt Inhibitor Ipatasertib (Ipat) with Paclitaxel (P) in Patients (Pts) with Advanced Solid Tumors

Abstract

Abstract Aim Solid tumors, including breast cancers, may have aberrant activation of PI3K/Akt signaling, which may cause chemoresistance; thus, inhibition of Akt signaling may improve chemotherapeutic efficacy. Ipat (GDC-0068) is a potent ATP-competitive small molecule inhibitor of all Akt isoforms (maximum tolerated dose 600 mg oral once daily [QD] with downregulation of Akt signaling > 100 mg). In preclinical models, Ipat synergistically combined with P. Methods Eligible pts with metastatic solid tumors, treated with up to 3 prior chemotherapy regimens, and an expansion cohort of HER2-negative (neg) breast cancer (BC) pts, received P 90 mg/m2 on Days 1, 8, and 15, with escalating doses of Ipat QD on Days 1-21 every 28 days. Pharmacokinetic (PK) samples were collected, and archival tumors were assessed for PTEN status by immunohistochemistry and PIK3CA mutations (mut) by PCR. Results As of 1 April 2014, 27 pts with median age 58 (range 41-80), ECOG PS 0-1, enrolled at 400 mg (n = 21) or 600 mg (n = 6) and received median 3 cycles of Ipat (range 1-12). Grade ≥ 2 adverse events (AEs) related to Ipat in ≥ 10% of pts were diarrhea (44%), fatigue (22%), and hyperglycemia (11%). Grade 3 AEs related to Ipat occurred mostly at 600 mg (83%) vs 400 mg (14%), including diarrhea (n = 6), hyperglycemia (n = 3), dehydration (n = 2), anemia (n = 1), neutropenia (n = 1), and rash (n = 1). No dose-limiting toxicities occurred, but based on cumulative safety, the recommended phase II dose (RP2D) is Ipat 400 mg with P. There was comparable PK of Ipat and P to single agents. Partial responses by RECIST v1.1 were seen in 6 pts (22%), including HER2-neg or triple-neg BC (TNBC) pts who had progressed on P (n = 4) or PI3K inhibitors (n = 2) or had tumors with PI3K/Akt alterations [PTEN loss (n = 1) or PIK3CA mut (n = 2)]. Time on study > 6 months occurred in 5 pts, including HER2-neg BC with PIK3CA mut (n = 3). Conclusions The RP2D of Ipat with P is 400 mg, which is well-tolerated with a safety profile consistent with the single agent. Anti-tumor activity was seen, including HER2-neg or TNBC with PI3K/Akt activation. Updated safety, efficacy, PK, and biomarker data will be presented.