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A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors.
- Source :
-
Cancer discovery [Cancer Discov] 2017 Jan; Vol. 7 (1), pp. 102-113. Date of Electronic Publication: 2016 Nov 21. - Publication Year :
- 2017
-
Abstract
- Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1-2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI <subscript>90</subscript> , and pharmacodynamic studies confirmed that multiple targets (i.e., PRAS40, GSK3β, and mTOR) were inhibited in paired on-treatment biopsies. Preliminary antitumor activity was observed; 16 of 52 patients (30%), with diverse solid tumors and who progressed on prior therapies, had radiographic stable disease, and many of their tumors had activation of AKT.<br />Significance: Potent inhibition of AKT signaling with ipatasertib was associated with a tolerable safety profile and meaningful disease control in a subgroup of patients. Targeting pAKT with an ATP-competitive inhibitor provides a greater therapeutic window than allosteric inhibitors. Further investigation with ipatasertib is ongoing in phase II studies. Cancer Discov; 7(1); 102-13. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Administration, Oral
Adult
Aged
Cell Line, Tumor
Drug Administration Schedule
Female
Humans
Male
Middle Aged
Neoplasms genetics
Piperazines adverse effects
Piperazines pharmacology
Protein Kinase Inhibitors adverse effects
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Pyrimidines adverse effects
Pyrimidines pharmacology
Xenograft Model Antitumor Assays
Neoplasms drug therapy
Piperazines administration & dosage
Protein Kinase Inhibitors administration & dosage
Pyrimidines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 27872130
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-16-0512