Phase I Trial of Pelvic Radiation, Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC #663249) for Locally Advanced Cervical Cancer

Abstract

Purpose: This study assessed the safety/tolerability, pharmacokinetics, and clinical activity of three times weekly i.v. 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in combination with once-weekly i.v. cisplatin and daily pelvic radiation in patients with gynecologic malignancies. 3-AP is a novel small-molecule inhibitor of ribonucleotide reductase (RNR) and is being tested as a potential radiosensitizer and chemosensitizer.Experimental Design: Patients with stage IB2 to IVB cervical cancer (n = 10) or recurrent uterine sarcoma (n = 1) were assigned to dose-finding cohorts of 2-hour 3-AP infusions during 5 weeks of cisplatin chemoradiation. Pharmacokinetic and methemoglobin samples and tumor biopsy for RNR activity were obtained on day 1 and day 10. Clinical response was assessed.Results: The maximum tolerated 3-AP dose was 25 mg/m 2 given three times weekly during cisplatin and pelvic radiation. Two patients experienced manageable 3-AP-related grade 3 or 4 electrolyte abnormalities. 3-AP pharmacokinetics showed a 2-hour half-life, with median peak plasma concentrations of 277 ng/mL (25 mg/m 2 ) and 467 ng/mL (50 mg/m 2 ). Median methemoglobin levels peaked at 1%(25 mg/m 2 ) and 6% (50 mg/m 2 ) at 4 hours after initiating 3-AP infusions. No change in RNR activity was found on day 1 versus day 10 in six early complete responders, whereas elevated RNR activity was seen on day 10 as compared with day 1 in four late complete responders (P = 0.02). Ten (100%) patients with stage IB2 to IVB cervical cancer achieved complete clinical response and remained without disease relapse with a median 18 months of follow-up (6-32 months). Conclusions: 3-AP was well tolerated at a three times weekly i.v. 25 mg/m 2 dose during cisplatin and pelvic radiation.

Reduced Level of Ribonucleotide Reductase R2 Subunits Increases Dependence on Homologous Recombination Repair of Cisplatin-Induced DNA Damage

“…This clinical trial reported that 100% of patients with advanced cervical cancer exhibited a complete clinical response and remained disease-free for 18 months with the combination regimen of cisplatin, radiation, and triapine (Kunos et al, 2010). A follow-up phase II trial is currently under way.…”

Chemoradiotherapy for Cervical Cancer in 2010

“…Topotecan is a promising addition to radiation and cisplatin for locally advanced cervical cancer given the overall survival benefit of topotecan in the metastatic or recurrent setting [27][28][29]. Topotecan (2 mg/m 2 ) was given together with radiation therapy and weekly cisplatin in a phase 2 trial for locally advanced cervical cancer [30].…”

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

“…1A), has been examined in more than 20 phase I and II clinical trials for cancer treatment (Murren et al, 2003;Wadler et al, 2004;Gojo et al, 2007;Knox et al, 2007;Kunos et al, 2010). In general, studies using 3-AP report limited antitumor activity or no response (Murren et al, 2003;Wadler et al, 2004;Gojo et al, 2007;Knox et al, 2007;Kunos et al, 2010).…”

“…In general, studies using 3-AP report limited antitumor activity or no response (Murren et al, 2003;Wadler et al, 2004;Gojo et al, 2007;Knox et al, 2007;Kunos et al, 2010). However, other studies suggest some positive results after 3-AP was coadministered with cisplatin and daily pelvic radiation in patients with locally advanced cervical and vaginal cancer (Kunos et al, 2010). The notable side effects of 3-AP include hypoxia and methemoglobinemia (Yen et al, 2004;Gojo et al, 2007;Knox et al, 2007;Odenike et al, 2008;Traynor et al, 2010), which are major concerns for patients with compromised cardiopulmonary function.…”