446PD - Phase Ib dose-escalation study of the Akt inhibitor ipatasertib (Ipat) with paclitaxel (P) in patients (pts) with advanced solid tumors

Date 28 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Anti-Cancer Agents & Biologic Therapy
Drug Development
Translational Research
Presenter Steven Isakoff
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors S.J. Isakoff1, J.R. Infante2, D. Juric1, W.Y. Chan3, S. Jia3, L. Musib3, J. Zhu3, R. Meng4, P.H. Patel4, J. Bendell5
  • 1Department Of Hematology And Medical Oncology, Massachusetts General Hospital, 02114 - Boston/US
  • 2Drug Development, Sarah Cannon Research Institute, 37203 - Nashville/US
  • 3Exploratory Clinical Development, Genentech, INC., 94080 - So San Francisco/US
  • 4Exploratory Clinical Development, Genentech, 94080 - So San Francisco/US
  • 5Drug Development Unit, Sarah Cannon Research Institute, 37203 - Nashville/US




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.


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.


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).


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.


W.Y. Chan, S. Jia, L. Musib, J. Zhu, R. Meng and P.H. Patel: Employee of Genentech, Inc. All other authors have declared no conflicts of interest.