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

• Published in: Molecular cancer therapeutics 2011-11, Vol.10 (11_Supplement), p.B154-B154
• Main Authors: Yan, Yibing, Wagle, Marie-Claire, Punnoose, Elizabeth, Musib, Luna, Budha, Nageshwar, Nannini, Michelle, Lin, Kui, Liederer, Bianca M., Murli, Sumati, Ramakrishnan, Vanitha, Patel, Premal, Cervantes, Andrs, Tabernero, Josep
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-B154

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