Abstract B153: A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamic (PD) activity of the dual PI3K/mTOR inhibitor GDC-0980 administered once weekly (QW).
Authors: Hollebecque Antoine , Clamp Andrew , Horsley Laura , Morgan Jeffrey A. , Bahleda Rastilav , George Suzanne , Shaw Danielle , Lauchle Jennifer O. , Ware Joseph , Desai Rupal , Wu Jenny , Fu Ling , Jayson Gordon C. , Soria Jean-Charles , Wagner Andrew J. 
Published: June 2012

Abstract
Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 is a potent, selective, oral inhibitor of class I PI3K and mTOR kinase demonstrating broad activity in xenograft cancer models (breast, ovarian, lung, and prostate).
Methods: A Phase I dose escalation study using a 3+3 design has been initiated in patients (pts) with advanced solid tumors or non-Hodgkin's lymphoma. GDC-0980 is administered QW. The objectives are to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD), evaluate PK and PD effects, and describe observed anti-tumor activity of GDC-0980 on this schedule. PD assessments include evaluating pAKT levels in platelet-rich plasma (PRP), biomarker pS6 in paired pre- and on-treatment tumor biopsies, tumor FDG avidity via PET imaging (FDG-PET), and tumor vasculature changes via DCE-MRI. Archival tumor tissue is evaluated for PTEN expression and PIK3CA mutations.
Results: Thirty-two pts have been enrolled in 7 successive cohorts evaluating 6 to 200 mg of GDC-0980 QW. Drug-related adverse events (AEs) reported in ≥10% of pts were nausea, diarrhea, hyperglycemia, vomiting, and fatigue. The only Grade (g) ≥3 drug-related AEs have been g3 hyperglycemia at ≥150 mg GDC-0980. Hyperglycemic events have been asymptomatic and generally well managed after initiation of an oral diabetic agent. One patient each at 150 and 200 mg GDC-0980 experienced the DLT of a repeat fasting g3 hyperglycemia following a subsequent dose of GDC-0980 during the DLT assessment period despite initiation of oral diabetic therapy. The patient with the DLT at 150 mg has continued on-treatment for more than 8 months with isolated g3 events. Analyses of PK data suggest dose-proportional increases in fasting mean Cmax and AUC. Levels of pAKT in PRP were inversely correlated with GDC-0980 plasma concentrations. All patients treated at ≥25 mg with evaluable-paired tumor biopsies demonstrated significant decreases in pS6 IHC staining of up to 100%. Signs of clinical activity include 3 pts [gastrointestinal stromal tumor (GIST), solitary fibrous tumor, and ovarian cancer] treated at 150 mg QW who are all currently on study after 7 months. Clinical and PD activity was also observed in a pt with epithelioid sarcoma who was treated at 25 mg QW for 11 mo with a 22% decrease in tumor FDG avidity and a pt with ovarian cancer who was treated at 100 mg for 6.2 months and demonstrated a 22% decrease in tumor lesions by RECIST and 48% decrease in serum CA-125. By DCE-MRI, the pt with GIST on 150 mg QW demonstrated a 60% decrease in the blood-normalized area under the signal intensity-time curve (AUCBN) in liver lesions as assessed by DCE-MRI after 2 doses of GDC-0980 suggesting a potential anti-angiogenic effect.
Conclusions: GDC-0980 is generally well tolerated when administered QW up to 200 mg with signs of anti-tumor activity. Decreases in the PD markers pAKT and pS6 are consistent with downstream modulation of the PI3K pathway. Dose-escalation continues and updated PK/PD data will be presented.
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 B153.