Abstract: NCIC CTG IND.147: A First in Man Dose Escalation and Pharmacokinetic Study of the Novel Nucleoside Analog OSI-7836 Given in a Day 1 and 8 Schedule.

Goss, G. (1); Siu, L (1); Powers, J (1); Adams, L (2); Trader, K (2); Seymour, L (1); (1) NCIC CTG, IND Program, Kingston, Canada; (2) OSI Pharmaceuticals, Boulder, Colorado, USA

Background: OSI-7836 (previously GS-7836, 4-thio-araC) is a nucleoside analog with a number of favorable characteristics. It is a weak substrate for both deoxycytidine kinase and deaminase resulting in reduced inactivation and prolonged intracellular activity. In several xenograft models antitumour effects were greater than gemcitabine at equitoxic doses. Toxicity in nonclinical models is consistent with that expected for this class of compounds.

Methods: An accelerated phase I design was used; starting dose was 100mg/m2 and 1-2 patients (pts) were entered at each dose level (DL) until > grade 1 clinically relevant toxicity was encountered, after which 3-6 pts were entered. Dose limiting toxicity (DLT) and recommended phase II dose followed standard criteria. All patients underwent full clinical, laboratory and pharmacokinetic testing.

Results: Nine pts have been entered to four DLs to date (100, 200, 400 and 600mg/m2). Median age was 55 years; 7 pts had a performance status of 1 or 2; 5 pts were female; all pts had had prior chemotherapy; 3 pts had colorectal cancer, 2 pts NSCLC, and 4 pts had other primaries. Grade 1 or 2 emesis necessitated the introduction of prophylactic 5-HT3 antiemetics at DL 3. Toxicities included mild transaminase increases and diarrhea, rash, lymphopenia, nausea and vomiting, herpes simplex reactivation and fatigue. No hematologic toxicity has been seen to date other than lymphopenia seen in all dose levels. At the 4th DL (600mg/m2) both patients entered experienced protocol defined DLTs. These included grade 3 rash, fever, seizure, and grade 3 fatigue (both patients had lymphopenia and herpes simplex). The 5th dose level has opened at 500mg/m2. One pt with lymphoepithelioma of the thymus showed evidence of tumour shrinkage in pulmonary lesions. Pharmacokinetic analyses are ongoing.

Conclusions: OSI-7836 is a promising nucleoside analog with excellent activity in nonclinical solid tumour models. Early evidence of antitumour activity has been seen in this clinical study