A Phase I Study of Triapine in Combination with Doxorubicin in Patients with Advanced Solid Tumors

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2008 Dec 17

PMID 19082825

Citations 16

Authors

William R Schelman

Sherry Morgan-Meadows

Rebecca Marnocha

Fred Lee

Jens Eickhoff

Wei Huang

Marcia Pomplun

Zhisheng Jiang

Dona Alberti

Jill M Kolesar

Percy Ivy

George Wilding

Anne M Traynor

Affiliations

Soon will be listed here.

Abstract

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)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three 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 two patients enrolled on this level had two 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 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related 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.

Citing Articles

Antiproliferative Activity and DNA Interaction Studies of a Series of N4,N4-Dimethylated Thiosemicarbazone Derivatives.

Montalbano S, Buschini A, Pelosi G, Bisceglie F Molecules. 2023; 28(6).

PMID: 36985750 PMC: 10058200. DOI: 10.3390/molecules28062778.

Harnessing microbial iron chelators to develop innovative therapeutic agents.

Ribeiro M, Sousa C, Simoes M J Adv Res. 2022; 39:89-101.

PMID: 35777919 PMC: 9263657. DOI: 10.1016/j.jare.2021.10.010.

Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present.

Huff S, Winter J, Dealwis C Biomolecules. 2022; 12(6).

PMID: 35740940 PMC: 9221315. DOI: 10.3390/biom12060815.

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance.

Babak M, Ahn D Biomedicines. 2021; 9(8).

PMID: 34440056 PMC: 8389626. DOI: 10.3390/biomedicines9080852.

Targeting iron metabolism in cancer therapy.

Morales M, Xue X Theranostics. 2021; 11(17):8412-8429.

PMID: 34373750 PMC: 8344014. DOI: 10.7150/thno.59092.

References

Lewis W, Srinivasan P . Chromosome-mediated gene transfer of hydroxyurea resistance and amplification of ribonucleotide reductase activity. Mol Cell Biol. 1983; 3(6):1053-61. PMC: 368634. DOI: 10.1128/mcb.3.6.1053-1061.1983. View

Nakano Y, Tanno S, Koizumi K, Nishikawa T, Nakamura K, Minoguchi M . Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br J Cancer. 2007; 96(3):457-63. PMC: 2360025. DOI: 10.1038/sj.bjc.6603559. View

Nordlund P, SJOBERG B, Eklund H . Three-dimensional structure of the free radical protein of ribonucleotide reductase. Nature. 1990; 345(6276):593-8. DOI: 10.1038/345593a0. View

Murren J, Modiano M, Clairmont C, Lambert P, Savaraj N, Doyle T . Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors. Clin Cancer Res. 2003; 9(11):4092-100. View

Yu Y, Wong J, Lovejoy D, Kalinowski D, Richardson D . Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res. 2006; 12(23):6876-83. DOI: 10.1158/1078-0432.CCR-06-1954. View

McClarty G, Chan A, Wright J . Characterization of a mouse cell line selected for hydroxyurea resistance by a stepwise procedure: drug-dependent overproduction of ribonucleotide reductase activity. Somat Cell Mol Genet. 1986; 12(2):121-31. DOI: 10.1007/BF01560659. View

Buzdar A, Marcus C, Smith T, Blumenschein G . Early and delayed clinical cardiotoxicity of doxorubicin. Cancer. 1985; 55(12):2761-5. DOI: 10.1002/1097-0142(19850615)55:12<2761::aid-cncr2820551206>3.0.co;2-p. View

Feun L, Modiano M, Lee K, Mao J, Marini A, Savaraj N . Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule. Cancer Chemother Pharmacol. 2002; 50(3):223-9. DOI: 10.1007/s00280-002-0480-0. View

Shao J, Zhou B, Chu B, Yen Y . Ribonucleotide reductase inhibitors and future drug design. Curr Cancer Drug Targets. 2006; 6(5):409-31. DOI: 10.2174/156800906777723949. View

10.

Finch R, Liu M, Grill S, Rose W, LOOMIS R, Vasquez K . Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol. 2000; 59(8):983-91. DOI: 10.1016/s0006-2952(99)00419-0. View

11.

Wright J, Chan A, Choy B, Hurta R, McClarty G, Tagger A . Regulation and drug resistance mechanisms of mammalian ribonucleotide reductase, and the significance to DNA synthesis. Biochem Cell Biol. 1990; 68(12):1364-71. DOI: 10.1139/o90-199. View

12.

Cocking J, Tonin P, STOKOE N, Wensing E, Lewis W, Srinivasan P . Gene for M1 subunit of ribonucleotide reductase is amplified in hydroxyurea-resistant hamster cells. Somat Cell Mol Genet. 1987; 13(3):221-33. DOI: 10.1007/BF01535204. View

13.

Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A . RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol. 2006; 24(29):4731-7. DOI: 10.1200/JCO.2006.06.1101. View

14.

Giles F, Fracasso P, Kantarjian H, Cortes J, Brown R, Verstovsek S . Phase I and pharmacodynamic study of Triapine, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia. Leuk Res. 2003; 27(12):1077-83. DOI: 10.1016/s0145-2126(03)00118-8. View

15.

Bepler G, Sharma S, Cantor A, Gautam A, Haura E, Simon G . RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol. 2004; 22(10):1878-85. DOI: 10.1200/JCO.2004.12.002. View

16.

Kolesar J, Huang W, Eickhoff J, Hahn K, Alberti D, Attia S . Evaluation of mRNA by Q-RTPCR and protein expression by AQUA of the M2 subunit of ribonucleotide reductase (RRM2) in human tumors. Cancer Chemother Pharmacol. 2008; 64(1):79-86. PMC: 3043989. DOI: 10.1007/s00280-008-0845-0. View

17.

Blum R, Carter S . Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med. 1974; 80(2):249-59. DOI: 10.7326/0003-4819-80-2-249. View

18.

Watts R . Severe and fatal anthracycline cardiotoxicity at cumulative doses below 400 mg/m2: evidence for enhanced toxicity with multiagent chemotherapy. Am J Hematol. 1991; 36(3):217-8. DOI: 10.1002/ajh.2830360314. View

19.

Attia S, Kolesar J, Mahoney M, Pitot H, Laheru D, Heun J . A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. Invest New Drugs. 2008; 26(4):369-79. PMC: 4461052. DOI: 10.1007/s10637-008-9123-6. View

20.

Alvero A, Chen W, Sartorelli A, Schwartz P, Rutherford T, Mor G . Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) induces apoptosis in ovarian cancer cells. J Soc Gynecol Investig. 2006; 13(2):145-52. DOI: 10.1016/j.jsgi.2005.11.004. View