A phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders.

Triapine is a potent ribonucleotide reductase (RR) inhibitor that depletes intracellular deoxyribonculeotide pools, especially dATP. We designed a Phase I trial of Triapine followed by the adenosine analog fludarabine in adults with refractory acute leukemias and aggressive myeloproliferative disorders (MPD). Two schedules were examined: (A) Triapine 105 mg/m(2)/day over 4 h followed by fludarabine daily x 5 (24 patients, fludarabine 15-30 mg/m(2)/dose); (B) Triapine 200 mg/m(2) over 24h followed by 5 days of fludarabine 30 mg/m(2)/day (9 patients). Complete and partial responses (CR, PR) occurred in Schedule A (5/24, 21%), with CR occurring at the 2 highest fludarabine doses (2/12, 17%). In contrast, no CR or PR occurred in Schedule B. Four of the 5 responses occurred in patients with underlying MPD (4/14, 29%). Drug-related toxicities included fever and metabolic acidosis. Triapine 105 mg/m(2) followed by fludarabine 30 mg/m2 daily x 5 is active in refractory myeloid malignancies and warrants continuing study for patients with aggressive MPD.

Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies.

Triapine, a potent inhibitor of ribonucleotide reductase, has demonstrated anti-leukemia activity in pre-clinical models. We conducted a Phase I study of Triapine administered as a 2 h infusion for 5 days in 25 adults with advanced leukemias. We established that Triapine at 96 mg/m2 once a day can be given safely on days 1-5 and 15-19 or 1-5 and 8-12 of a 4-week cycle. When administered twice a day on days 1-5 and 8-12, the maximum tolerated dose of Triapine appears to be 64 mg/m2, although the true criteria for DLT were not met by protocol definition. No CR or PR were observed, but 76% of patients had a >50% reduction in white blood cell counts. At all dose levels, the peak plasma concentration of Triapine (2.2-5.5 microM) was above levels required to achieve in vitro/in vivo leukemia growth inhibition. Based on these data, we conclude that Triapine warrants further investigation in hematologic malignancies.

Transdermal delivery of desmopressin using a coated microneedle array patch system.

Desmopressin is a synthetic peptide hormone chiefly used for treatment of enuresis in young children. It is available in injectable, intranasal, and oral formulations. While administration by injection is poorly suited for routine use in young children, intranasal and oral administration result in low and variable bioavailability. This study therefore explored the feasibility of administering desmopressin transdermally using Macroflux technology, which uses a microneedle array to overcome the skin barrier. The tips of microneedles in 2-cm2 arrays were covered with a solid coating of various amounts of desmopressin and applied to the skin of hairless guinea pigs for 5 or 15 min. Pharmacologically relevant amounts of desmopressin were delivered after 5 min. Bioavailability was as high as 85% and showed acceptable variability (30%). Immunoreactive serum desmopressin reached peak levels after a Tmax of 60 min. Elimination kinetics for serum desmopressin was similar after transdermal and intravenous (IV) delivery, suggesting the absence of a skin depot. Only 10% of the desmopressin dose loaded onto the microneedle array was found on the skin surface after application. Additionally, the patches were well tolerated. These results suggest that transdermal delivery of desmopressin by Macroflux is a safe and efficient alternative to currently available routes of administration.

A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer.

PURPOSE: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer. STUDY DESIGN: 3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m(2). Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m(2) in cohorts of three to six patients. Following the gemcitabine 1000 mg/m(2) dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m(2). RESULTS: 3-AP at 105 mg/m(2) administered over 2 h followed in 1-4 h by gemcitabine at 1000 mg/m(2) produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m(2) administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis. CONCLUSIONS: 3-AP at 105 mg/m(2) infused over 2-4 h followed by gemcitabine at 1000 mg/m(2) on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.