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/m2 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/m2) and 467 ng/mL (50 mg/m2). Median methemoglobin levels peaked at 1% (25 mg/m2) and 6% (50 mg/m2) 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/m2 dose during cisplatin and pelvic radiation. Clin Cancer Res; 16(4); 1298–306
- Triapine
- cervical cancer
- ribonucleotide reductase
- radiosensitization
Footnotes
- Received September 10, 2009.
- Revision received December 4, 2009.
- Accepted December 8, 2009.
Volume 16, Issue 4
