Abstract B154: A first-in-human trial of GDC-0068: A novel, oral, ATP-competitive Akt inhibitor, demonstrates robust suppression of the Akt pathway in surrogate and tumor tissues.

摘要: GDC-0068 is a highly selective ATP-competitive small molecule that inhibits all three isoforms of Akt with IC50 values 5 to 30 nM. selectively cancer cells activated signaling (e.g. via PTEN loss or PIK3CA mutations). Patients advanced solid tumors were treated using 3+3 escalation design. was dosed PO QD on 21-day on, 7-day off schedule; endpoints included safety, pharmacokinetics (PK) and determination pathway knockdown. Pharmacodynamics (PD) in surrogate tissue [platelet rich plasma (PRP)] evaluated patients. In addition, at least two patients per cohort had pre- on-treatment (day 15) tumor biopsies doses ≥100mg QD. The samples reverse phase protein array (RPPA). Thirty enrolled across 7 cohorts (25, 50, 100, 200, 400, 600 800 mg QD). generally well-tolerated ≤ mg. Preliminary PK analyses show dose proportional increase exposure over the range tested. clinical exposures ≥ 200 met exceeded associated stasis multiple null preclinical xenograft models. PK/PD evaluation showed dose-dependent inhibition PRP assay, ≥70% pGSK3 Pre- ≥50% decrease pPRAS40 cyclin D1 higher. evidence feedback activation MAP kinase after treatment observed biopsy samples. One patient low/ H1047R/ KRAS wt CRC prolonged stable disease suppression by downstream markers. well tolerated favorable safety profile pharmacokinetics. Treatment results substantial knockdown both tissues Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings AACR-NCI-EORTC International Conference: Molecular Targets Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Ther 2011;10(11 Suppl):Abstract nr B154.