Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.
Purpose-To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine ® administered in combination with doxorubicin.Study Design-Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine ® IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m 2 and Triapine ® 25 mg/m 2 . PK analysis was performed at various time-points before and after treatment.Results-Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m 2 , Triapine ® 45 mg/m 2 ), 2 patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/ m 2 ) with Triapine ® 45 mg/m 2 . The 2 patients enrolled on this level had 2 DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine ® were reduced to 45 mg/m 2 and 25 mg/m 2 , respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drugrelated toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer.Conclusions-Pretreated patients with advanced malignancies can tolerate the combination of Triapine ® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m 2 on day 1 and Triapine ® 25 mg/m 2 on days 1-4 of a 21 day cycle.
KeywordsTriapine ® ; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; doxorubicin; phase I; ribonucleotide reductase * Corresponding author and address for reprint requests: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue, K6/568. Madison, WI 53792, Phone (608) Fax (608)
InroductionTriapine ® (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a potent small molecule ribonucleotide reductase (RR) inhibitor that exerts its antineoplastic activity by inhibiting DNA synthesis and repair (1). Ribonucleotide reductase is an enzyme that is important for cell division and tumor growth (2-4), and the human RR has a tetrameric structure, composed of two non-identical homodimers (5). The RRM1 subunit contains a nucleotide binding site, and the RRM2 subunit contains a metal binding site. The RRM2 subunit is comprised of a non-heme iron and a tyrosine free radical, which are required for the enzymatic reduction of ribonucleotides (6). Therapeutic agents that inhibi...
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