Results of 2 phase I studies of intravenous (iv) pelitrexol (AG2037), a glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, in patients (pts) with solid tumors

Abstract

3075 Background: AG2037 is a rationally designed, novel inhibitor of GARFT, which is an essential enzyme in the de novo synthesis of purines, a critical process for cell growth. Methods: The primary objectives of these studies were to determine the maximum-tolerated dose (MTD) and recommended safe dose of AG2037 for Phase II studies (RP2D). AG2037 was given by bolus or slow iv push (every 3 weeks in Study-002 and weekly for 3 consecutive weeks every 4 weeks in Study-003) to pts with advanced solid tumors in cohorts of at least 3 patients at each dose level. The dose for the next cohort was increased by 100% if no drug related Grade 3 or worse toxicity was encountered, and by ∼50% if Grade 2 toxicity was observed. Results: 45 pts in Study-002 were treated at doses ranging from 1 to 576 mg/m2 and 49 were treated in Study-003 at doses ranging from 1 to 760 mg/m2. Study-002 was terminated before MTD was determined since mechanism-based toxicities appeared to correlate to drug exposure and not to peak concentration. For Study-003, at the highest dose (720 mg/m2), Grade 3 anemia, thrombocytopenia, diarrhea, fatigue, mucosal inflammation, dehydration, hyponatremia, confusion, or mental status changes were observed in 1 or 2 of 6 pts. There were no grade 4 toxicities. The MTD was 540 mg/m2/infusion. Grade 3 nausea was the only Grade 3 or 4 related adverse events in the 7 patients treated at MTD. The pharmacokinetics of AG2037 were linear over the studied dose range; plasma concentrations declined in a triexponential manner with a terminal half-life of 85 hours and were inversely proportional to creatinine clearance. RBC polyglutamate increased with dose to a maximum concentration and showed minimal decline between doses. One pt with colorectal cancer had a partial response by RECIST at 6 mg/m2 (Study-003). Conclusions: The RP2D for AG2037 is 540 mg/m2/week for 3 consecutive weeks, every 4 weeks. Expected adverse events on this schedule include mild to moderate myelosuppression, mucositis, diarrhea, anorexia, fatigue, and peripheral neuropathy. Further study in colorectal and other solid tumors is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Inc. Pfizer, Inc. Pfizer, Inc. Pfizer, Inc.