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Cancer Therapy: Clinical

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

Charles A. Kunos, Steven Waggoner, Vivian von Gruenigen, Elisa Eldermire, John Pink, Afshin Dowlati and Timothy J. Kinsella
Charles A. Kunos
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Steven Waggoner
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Vivian von Gruenigen
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Elisa Eldermire
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John Pink
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Afshin Dowlati
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Timothy J. Kinsella
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DOI: 10.1158/1078-0432.CCR-09-2469 Published February 2010
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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

Keywords
  • Triapine
  • cervical cancer
  • ribonucleotide reductase
  • radiosensitization

Footnotes

    • Received September 10, 2009.
    • Revision received December 4, 2009.
    • Accepted December 8, 2009.
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Clinical Cancer Research: 16 (4)
February 2010
Volume 16, Issue 4
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Phase I Trial of Pelvic Radiation, Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC #663249) for Locally Advanced Cervical Cancer
Charles A. Kunos, Steven Waggoner, Vivian von Gruenigen, Elisa Eldermire, John Pink, Afshin Dowlati and Timothy J. Kinsella
Clin Cancer Res February 15 2010 (16) (4) 1298-1306; DOI: 10.1158/1078-0432.CCR-09-2469

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Phase I Trial of Pelvic Radiation, Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC #663249) for Locally Advanced Cervical Cancer
Charles A. Kunos, Steven Waggoner, Vivian von Gruenigen, Elisa Eldermire, John Pink, Afshin Dowlati and Timothy J. Kinsella
Clin Cancer Res February 15 2010 (16) (4) 1298-1306; DOI: 10.1158/1078-0432.CCR-09-2469
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Clinical Cancer Research
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