Preclinical studies demonstrated antitumor efficacy of GDC-0917 (CUDC-427) alone or in combination with other anticancer agents including chemotherapy. In October 2010, Genentech initiated an open-labeled, uncontrolled, dose-escalation, Phase I clinical study of GDC-0917 (NCT01226277; IAM4914g) in patients with refractory solid tumors or lymphoma. The study was designed to assess safety, tolerability and pharmacokinetics of daily, oral doses of GDC-0917. The presentation at ASCO focused on results from this Phase I trial, in which oral GDC-0917 was administered once daily for two weeks on and one week off treatment schedule.

Forty two patients were enrolled across 11 cohorts, in which patients received GDC-0917 at doses ranging between 5 mg - 600 mg daily. Unconfirmed complete responses were observed in one ovarian cancer patient and one patient with MALT lymphoma. In addition, a mixed response was observed in one patient with a carcinoma of unknown primary origin and stable disease was observed for greater than three months in four additional patients. GDC-0917 drug levels in patient plasma were dose-proportional with an average half-life of approximately four to eight hours. No apparent drug accumulation was seen at steady state levels. Biomarker changes in the peripheral blood cells (at all dose levels) and in tumor biopsies analyzed (n=2) were consistent with the drug candidate's mechanism of action. 

The maximum tolerated dose for GDC-0917 has not been determined, although plasma concentrations of preclinically defined ED90 were reached. Adverse events (AEs) reported as treatment-related that were equal to or greater than Grade 3 in severity in more than one patient were elevated levels of AST and ALT liver enzymes (two patients at 450 and 600 mg dose). AEs that resulted in treatment discontinuation were Grade 3 fatigue, Grade 2 QTc prolongation, Grade 2 drug hypersensitivity, Grade 2 pneumonitis (one patient each), and Grade 3 pruritus/Grade 2 rash.

About CUDC-427 (previously referred to as GDC-0917)

CUDC-427 is an orally bioavailable small molecule that triggers tumor cell apoptosis by selectively antagonizing IAP proteins. CUDC-427 was designed to mimic the endogenous IAP antagonist, second mitochondria-derived activator of caspases/direct IAP-binding protein (Smac/DIABLO) that is released into the cytoplasm in response to pro-apoptotic stimuli.

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