Phase I study of safety and pharmacokinetics (PK) of GDC-0917, an antagonist of inhibitor of apoptosis (IAP) proteins in patients (Pts) with refractory solid tumors or lymphoma.

Abstract

2503 Background: GDCE0917 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing IAP proteins. Preclinical studies demonstrated antitumor efficacy of GDC-0917 alone or in combination with chemotherapeutic agents. Methods: Oral GDC-0917 was given on Day (d) 1 followed by 2d off and a 2-week (w) on/ 1w off treatment (tx) schedule (21d cycle) starting d4. A modified continual reassessment method was used for dose escalation. Dose-limiting toxicity (DLT, assessed d1-24), PK, adverse events (AEs), pharmacodynamics (PD), and clinical activity were evaluated. Results: 42 pts of age 36-86 (median 60.5) were enrolled in 11 cohorts (5-600 mg) and received 1-15 cycles (median 2) of GDC-0917. One DLT, Grade (G) 3 fatigue, was observed at 450 mg. The maximum tolerated dose was not determined although plasma concentrations of preclinically defined IC90 were reached. The most frequent AEs were diarrhea, fatigue and nausea (26.2% each), vomiting (23.8%), and constipation (19%). The most frequent AEs reported as tx-related were mostly G1-2 and included fatigue and nausea (21.4% each), vomiting (14.3%), rash (11.9%) and pruritus (9.5%). AEs reported as tx-related that were ≥ G3 in > 1 pt were elevated AST and ALT (2 pts, at 450 and 600 mg). AEs reported as tx-related that resulted in tx discontinuation were G3 fatigue, G2 QTc prolongation, G2 drug hypersensitivity, G2 pneumonitis (1 pt each), and G3 pruritus/G2 rash (same pt). GDC-0917 peak concentrations were observed 2-3h post dosing. Exposure was dose-proportional with a mean plasma elimination t 1/2 of 4-8h and no apparent accumulation at steady state. Rapid down-modulation of cIAP1 was observed in PBMCs at all dose levels. Evaluation of tumor biopsies demonstrated decreases in cIAP1 (2 pts total, at 40 and 200 mg) and increases in activated caspase-3 and cPARP (1 pt at 200 mg). Two pts (4.8%) had a complete response (both unconfirmed, ovarian Ca and MALT lymphoma [PET]); 4 pts (9.5%) had stable disease for ≥ 3 months. Conclusions: GDC-0917 had a favorable safety, PK and PD profile in pts with advanced malignancies. These encouraging results support further clinical evaluation of this agent. Clinical trial information: NCT01226277.