Phase I study of OGX-011, a second generation antisense oligonucleotide (ASO) to clusterin, combined with cisplatin and gemcitabine as first-line treatment for patients with stage IIB/IV non-small cell lung cancer (NSCLC)

17078 Background: The clusterin gene is frequently expressed in NSCLC and encodes a cytoprotective chaperone protein that promotes cell survival and is upregulated in response to apoptotic stimuli such as chemotherapy. OGX-011 is an ASO that binds to clusterin mRNA thus potently regulating expression and chemosensitizing cancer cells. Previous Phase I studies of OGX-011 identified biologically active doses of 480mg to 640mg. The objective of this multi-center Phase I study was to define the Phase 2 dose of OGX-011 in combination with standard chemotherapy. Methods: Patients (pts) with chemotherapy-naive advanced stage IIIB/IV NSCLC were potentially eligible. OGX-011 is given as a 2hr IV infusion weekly after 3 loading doses (days -7, -5, and -3). OGX-011 dose escalation was planned to a maximum of 640mg. Cisplatin was given at 75 mg/m2 IV day 1 and gemcitabine 1250mg/m2 IV days 1 and 8, on a 21-day schedule up to 6 cycles. Pharmacokinetic profiling was done in cycle 1. Results: Between Jan 2004 and Apr 2005, 10 patients were enrolled. Median age 62 yrs (49–75); 4 female. ECOG 0/1: 3/7. Stage IIIB/IV: 1/9. 9 of 10 pts completed at least one cycle; 1 withdrew after one dose of OGX-011 due to progressive disease (PD). Of the 9 pts, 6 received ≥ 5 cycles and 3 received 2–4 cycles (2 patients discontinued due to PD and 1 at the pts request). Median follow-up: 5.0m (1.6 - 6.7m). As of Jan 2006, 2 pts had a PR; 5 had SD; 2 had PD. 4 pts had 5 serious adverse events: elevated creatinine, hypoxia, pneumonia, pleural effusion, and febrile neutropenia. 3 pts had Gr 3 hyponatremia. Gr 3/4 hematological toxicities in 10–40% and 10–20%, respectively. No dose-limiting toxicities noted; 7 pts received OGX-011 at 640 mg. A proportional increase in OGX-011exposure (Cmax and AUC0-inf) from 480 to the 640 mg was noted with no apparent effect on GEM/CIS. Conclusions: OGX-011 was well tolerated and can be given at biologically active doses (640 mg) with standard GEM/CIS chemotherapy for patients with advanced NSCLC. A multicenter Phase II trial of this combination is underway. Sponsored by OncoGenex Technologies, Inc. with Isis Pharmaceuticals Inc. [Table: see text]

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