A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of the oral pan-phosphoinositide-3 kinase (PI3K) inhibitor GDC-0941.

Abstract

2613 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral pan-inhibitor of class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and demonstrates activity in preclinical xenograft models (breast, ovarian, lung, and prostate). Material and Methods: Patients (pts) with histologically confirmed advanced solid tumors and performance status 0–1 were enrolled in a phase I study (GDC4254g) of GDC-0941 using a 3+3 escalation design. Treatment was a single dose of GDC-0941 with a 1-week washout, followed by GDC-0941 QD on a 3-wk on, 1-wk off schedule. Phase I objectives included an evaluation of PD endpoints in surrogate tissue (pAKT in platelet-rich plasma [PRP]) and tumor tissue (pS6 in paired tumor biopsies) and FDG-PET. Results: Twenty-six pts have been enrolled in 7 successive cohorts (15–130 mg QD). GDC- 0941 was generally well tolerated with no DLT observed to date. The most frequently occurring drug-related adverse events (AEs) have been grade 1–2 nausea, diarrhea, vomiting, fatigue, and dysgeusia. There has been one drug-related grade 4 AE of hyperglycemia in a cholangiocarcinoma pt at the 130 mg dose level during cycle 2 in the setting of concomitant steroid use. GDC-0941 displays dose-proportional increases in mean Cmax and AUCinf. Decreases in pS6 staining of >50% have been observed in paired tumor biopsies in addition to decreases of >90% in pAKT levels assayed in PRP from pts treated at 80 mg and higher. Signs of biologic activity have been observed in 3 pts (ovarian cancer, triple negative breast cancer, and ocular melanoma) treated at ≥100 mg GDC-0941 with reductions (≥30% in mean SUVmax) in tumor FDG avidity observed on PET scan and an ∼80% decrease in CA-125 in the ovarian cancer pt, who remained on-study for ∼5 months. Conclusions: GDC-0941 is generally well tolerated at 15 to 130 mg QD. Decreases in pAKT levels in PRP and decreases in pS6 staining in paired tumor biopsies are consistent with downstream modulation of the PI3K pathway. FDG-PET reductions have been observed along with a CA-125 decrease in a pt with ovarian cancer. Dose-escalation continues and updated PK/PD data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Institute of Cancer Research Arno Therapeutics, AstraZeneca, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer Roche Arno Therapeutics, AstraZeneca, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer Genentech