A Phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and gemcitabine in advanced pancreatic carcinoma. A trial of the Princess Margaret Hospital Phase II consortium

Abstract

3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®, Vion Pharmaceuticals, New Haven, CT) is an inhibitor of the M2 subunit of ribonucleotide reductase (RR). Preclinical testing demonstrates synergy between 3-AP and gemcitabine. Phase I studies of the combination have suggested tolerability and some initial evidence of efficacy. Therefore, a phase II study of gemcitabine plus 3-AP in advanced pancreatic carcinoma was undertaken. In this two-step phase II trial, patients with advanced pancreatic adenocarcinoma who had not received prior chemotherapy for advanced disease were treated with 3-AP 105 mg/m² given over 2 h. Four hours after the 3-AP infusion was completed, gemcitabine 1,000 mg/m² was given over 30 min. Both drugs were given on days 1, 8 and 15 of a 28-day cycle. Twenty-six patients were enrolled to the study. One patient withdrew consent prior to receiving any treatment and is excluded from all further analyses. Four patients discontinued treatment due to adverse effects. Grade 3/4 hematological adverse events included neutropenia, thrombocytopenia, lymphopenia, leukopenia and anemia and the most frequent non-hematological adverse events were fatigue and pain. No objective responses were observed. Eleven patients had stable disease (SD). In five of these eleven patients, SD lasted for more than 6 months. The median time to progression was 4.1 months and the 6 month progression-free survival rate was 29%. The median survival was 9.0 months with a 1-year survival of 28.0%. The combination of 3-AP and gemcitabine is associated with moderate toxicity in patients with advanced pancreatic cancer. This two-stage trial was stopped after stage I due to lack of antitumour activity. On the basis of this clinical trial, the combination of gemcitabine and 3-AP at this dose and schedule does not warrant further study in this patient population.