Phase I trial of pelvic radiation, weekly cisplatin, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) for locally advanced cervical cancer.
OBJECTIVE
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.


METHODS
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. Clin Cancer Res; 16(4); 1298-306.
Kunos
Charles A
CA
Department of Radiation Oncology, Case Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, Ohio, USA.
Waggoner
Steven
S
von Gruenigen
Vivian
V
Eldermire
Elisa
E
Pink
John
J
Dowlati
Afshin
A
Kinsella
Timothy J
TJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008706:Methemoglobin / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013882:Thiosemicarbazones / Q000008:administration & dosage* / Q000009:adverse effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*
D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D008706:Methemoglobin; D012264:Ribonucleotide Reductases; D002945:Cisplatin