A phase I study of triapine in combination with irinotecan in refractory tumors

Abstract

12011 Background: Triapine is a small molecule inhibitor of ribonucleotide reductase and has anti-tumor activity alone and in combination with other agents in advanced solid tumors. Based on its ability to limit DNA repair, Triapine has been postulated to act synergistically with irinotecan. This study was conducted to determine the toxicities and efficacy of Triapine with irinotecan. Correlative studies included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy. Methods: This study used standard eligibility criteria with the following exceptions: patients must have had no prior irinotecan and no G6PD deficiency. The treatment plan consisted of irinotecan on day 1 with Triapine on days 1- 3 of a 21-day cycle. Starting dose (level 1) was irinotecan (150 mg/m2) and Triapine (85 mg/m2/day). RECIST was used to measure response. Results: 10 patients have been enrolled; 5 men, 5 women. Tumor types: 4 pancreatic, 2 cholangio, 1 esophageal, 1 sarcoma, 1 lung, 1 ovarian. Grade 3–4 toxicities at least possibly related to Triapine at any dose level were as follows: neutropenia (3), leukopenia (2), fatigue, hypoxia, nausea, vomiting, thrombocytopenia, abdominal cramping, hypocalcemia, and thrombosis. The first patient enrolled at level 1 developed a DLT (Grade 3 hypoxia). Consequently, irinotecan and Triapine doses were reduced to 100 mg/m2 and 60 mg/m2/day, respectively (level -1). One of 6 patients experienced a DLT at this dose level. Further patients were then enrolled at level 1. There were 2 DLTs of 4 patients at level 1. One partial response (NSCLC) was seen. Conclusions: Unacceptable toxicities were seen at dose level 1; however, dose level -1 was well tolerated. The trial has therefore been amended in order to evaluate a higher dose of irinotecan (150 mg/m2) with the level -1 dose of Triapine (60 mg/m2/day). Accrual continues at this dose level. Antitumor activity in NSCLC was noted at level 1. [Table: see text]