gdc-0068 and Neoplasm-Metastasis

Ipatasertib is a selective AKT kinase inhibitor currently in development for the treatment of several solid tumors, including breast and prostate cancers. This study was undertaken to characterize pharmacokinetic profiles of ipatasertib and its metabolite M1 (G-037720) and to understand the sources of variability. Population pharmacokinetic models of ipatasertib and M1 were developed separately using data from 342 individuals with cancer from 5 phase 1 and 2 studies. The final population pharmacokinetic models for ipatasertib and M1 were 3-compartmental, with first-order elimination and sequential zero- and first-order absorption. Ipatasertib bioavailability and M1 formation increased after multiple dosing, resulting in an increase in exposure beyond that expected from accumulation alone. Covariate effects of ipatasertib include decreased oral clearance with increasing age and with coadministration of abiraterone, as well as decreased bioavailability with increasing weight. For ages 37 and 80 years, steady-state area under the curve (AUC

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Neoplasm Metastasis; Neoplasms; Paclitaxel; Piperazines; Prednisolone; Pyrimidines

PI3K-Akt-mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase Ib/II study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC.. rPFS was prolonged in the ipatasertib cohort versus placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors versus those without. The combination was well tolerated, with no treatment-related deaths.. In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Neoplasm Metastasis; Piperazines; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyrimidines; Treatment Outcome