A phase II study of triapine in combination with gemcitabine (G) in patients (pts) with unresectable or metastatic pancreatic cancer (PC)

Abstract

4123 Background: Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone [T]) is a small molecule that inhibits ribonucleotide reductase at a site distinct from G. In tumor cell lines, pre-exposure to T enhances G uptake and DNA incorporation, and yields synergistic cytotoxicity. A phase I trial of T + G showed that the combination was well-tolerated and produced T serum concentrations sufficient to modulate G activity in vitro (Ca Chemother Pharmacol, 2004). Methods: We conducted a phase II trial of T + G in advanced PC pts at 7 centers. Eligible pts were untreated, had measurable disease and ECOG PS 0–2. T was given by 4-hr infusion followed by G 1000 mg/m2 on days 1, 8, and 15 of a 4-week schedule. Since preclinical studies showed longer exposure of T maximized synergy between the agents, the protocol was amended to administer T over 24 hrs continuously (CI) prior to G. Pts were assessed for response q 2 cycles and retreated to progression or toxicity. Results: Sixty pts (median age 62, range 37–88) were treated with T by 4-hr infusion (median 4 cycles, range 1–18). Pt characteristics included M:F 39/21; PS 0/1/2 = 25 (42%)/34 (57%)/1 (2%); metastatic/locally advanced 72/28%. Eight (15%) patients achieved PR; and 32 (60%) had stable disease. Median survival was 8 mos; 13% are alive at 1 yr. The next 6 pts (median age 54, range 50–69, M/F: 3/3) received T at a fixed dose of 400mg CI + G. Two pts were evaluable for response; 1 pt had PD, 1 pt is on treatment after 14 cycles. Due to excessive myelosuppression the dose of T CI was reduced to 105 mg/m2. Of 7 pts (median age 60, range 34–73) treated, 2 had PD, 1 was unevaluable, and 4 remain on tx. T toxicity included hypotension, hypoxia, rash and dyspnea in < 10% of pts. In the 2 CI groups (N=13), the only toxicity attributed to T was excessive myelosuppression, requiring G dose reduction in all pts. Survival data on CI pts pending. Conclusions: T + G shows activity in PC. As predicted by preclinical studies, prolonged exposure (CI) enhances biological effect of T + G evidenced by increased myelosuppression without additional toxicities. Further studies are warranted to define the optimal dose of T CI with G. [Table: see text]