Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2009

01-05-2009 | Clinical Trial Report

A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors

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

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2009

Login to get access

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/m2 and Triapine® 25 mg/m2. 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/m2, Triapine® 45 mg/m2), 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/m2) with Triapine® 45 mg/m2. 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/m2, 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/m2 on day 1 and Triapine® 25 mg/m2 on days 1–4 of a 21-day cycle.
Literature
1.
Cory JG, Cory AH, Rappa G, Lorico A, Liu MC, Lin TS, Sartorelli AC (1994) Inhibitors of ribonucleotide reductase. Comparative effects of amino- and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. Biochem Pharmacol 48:335–344PubMedCrossRef
2.
Alvero AB, Chen W, Sartorelli AC, Schwartz P, Rutherford T, Mor G (2006) Triapine (3-amino-2-carboxaldehyde thiosemicarbazone) Induces Apoptosis in Ovarian Cancer Cells. J Soc Gynecol Investig 13(2):145–152PubMedCrossRef
3.
Elford HL, Freese M, Passamani E, Morris HP (1970) Ribonucleotide reductase and cell proliferation. I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas. J Biol Chem 245:5228–5233PubMed
4.
Yu Y, Wong J, Lovejoy DB, Kalinowshi DS, Richardson DR (2006) Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res 12(23):6876–6883PubMedCrossRef
5.
Nordlund P, Sjoberg B-M, Eklund H (1990) Three-dimensional structure of the free radical protein of ribonucleotide reductase. Nature 345:593–598PubMedCrossRef
6.
Cory JG, Chiba P (1989) Combination chemotherapy directed at the components of nucleoside diphosphate reductase. In: Cory JG, Cory AM (eds) International encyclopedia of pharmacology and therapeutics—inhibitors of ribonucleotide diphosphate reductase activity. Pergamon Press, NY, pp 245–264 Sect. 128
7.
Wright JA, Chan AK, Choy BK et al (1990) Regulation and drug resistance mechanisms of mammalian ribonucleotide reductase, and the significance to DNA synthesis. Biochem Cell Biol 68:1364–1371PubMedCrossRef
8.
Antholine WE, Lyman S, Petering DH, Pickart L (1985) In: Karlin KD, Zubieta J (eds) Biological and inorganic copper complexes. Adenine Press, USA, pp 125–137
9.
Richardson DR et al (2006) Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity. J Med Chem 49:6510–6521PubMedCrossRef
10.
Shao J, Zhou B, Chu B, Yen Y (2006) Ribonucleotide reductase inhibitors and future drug design. Curr Cancer Drug Targets 6(5):409–431PubMedCrossRef
11.
Shao J, Zhou B, Di Bilio AJ, Zhu L, Wang T, Qi C, Shih J, Yen Y (2006) A ferrous-triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase. Mol Cancer Ther 5:586–592PubMedCrossRef
12.
Finch RA, Liu M, Grill SP, Rose WC, Loomis R, Vasquez KM, Cheng Y, Sartorelli AC (2000) Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone): a potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol 59:983–991PubMedCrossRef
13.
Feun L, Modiano M, Lee K, Mao J, Marini A, Savaraj N, Plezia P, Almassian B, Colacino E, Fischer J, MacDonald S (2002) Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule. Cancer Chemother Pharmacol 50:223–229PubMedCrossRef
14.
Murren J, Modiano M, Clairmont C, Lambert P, Savaraj N, Doyle T, Sznol M (2003) 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 9:4092–4100PubMed
15.
Giles FJ, Fracasso PM, Kantarjian HM, Cortes JE, Brown RA, Verstovsek S, Alvarado Y, Thomas DA, Faderl S, Garcia-Manero G, Wright LP, Samson T, Cahill A, Lambert P, Plunkett W, Sznol M, DiPersio JF, Gandhi V (2003) Phase I and pharmacodynamic study of Triapine, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia. Leuk Res 27(12):1077–1083PubMedCrossRef
16.
Dorr RT, Van Hoff DD (1994) Cancer chemotherapy handbook, 2nd edn. Appleton and Lange, pp 500–514, 524–526
17.
Rubin EH, de Alwis DP, Pouliquen I, Green L, Marder P, Lin Y, Musanti R, Grospe SL, Smith SL, Toppmeyer DL, Much J, Kane M, Chaudhary A, Jordan C, Burgess M, Slapak CA (2002) A phase I trial of a potent P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), administered orally in combination with doxorubicin in patients with advanced malignancies. Clin Cancer Res 8(12):3710–3717PubMed
18.
Attia S, Kolesar J, Mahoney MR, Pitot HC, Laheru D, Heun J, Huang W, Eickhoff J, Erlichman C, Holen KD (2008) A phase 2 consortium (P2C) trial of 3 aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. Invest New Drugs 26(4):369–379PubMedCrossRef
19.
Kolesar J, Huang W, Eickhoff J, Hahn K, Alberti D, Attia S, Schelman W, Holen K, Traynor A, Ivy P, Wilding G (2008) 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. doi: 10.​1007/​s00280-008-0845-0
20.
Greeno E, Kindler HL, Peeters M, Trowbridge RC, Chong G, Valle JW, Johnson B, Allain EL, Burris HA (2006) A phase II study of triapine in combination with gemcitabine (G) in patients (pts) with unresectable or metastatic pancreatic cancer (PC). JCO. 2006 ASCO annual meeting proceedings part I. vol 24, no. 18S (June 20 Supplement): 4123
21.
22.
Blum RH, Carter SK (1974) Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med 80(2):249–259PubMed
23.
Buzdar AU, Marcus C, Smith TL, Blumenschein GR (1985) Early and delayed clinical cardiotoxicity of doxorubicin. Cancer 55(12):2761–2765PubMedCrossRef
24.
Watts RG (1991) Severe and fatal anthracycline cardiotoxicity at cumulative doses below 400 mg/m2: evidence for enhanced toxicity with multiagent chemotherapy. Am J Hematol 36(3):217–218PubMedCrossRef
25.
Bepler G, Sharma S, Cantor A et al (2004) RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol 22:1878–1885PubMedCrossRef
26.
Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A, Simon G (2006) RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 28:4731–4736CrossRef
27.
Goan YG, Zhou B, Hu E, Mi S, Yen Y (1999) Overexpression of ribonucleotide reductase as a mechanism of resistance to 2, 2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res 59:4204–4207PubMed
28.
Tanno S, Nakano Y, Koizumi K et al (2007) Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br J Cancer 96:457–463PubMedCrossRef
29.
Lewis WH, Srinivasan PR (1983) Chromosome-mediated gene transfer of hydroxyurea resistance and amplification of ribonucleotide reductase activity. Mol Cell Biol 3:1053–1061PubMed
30.
Cocking JM, Tonin PN, Stokoe NM, Wensing EJ, Lewis WH, Srinivasan PR (1987) Gene for M1 subunit of ribonucleotide reductase is amplified in hydroxyurea-resistant hamster cells. Somatic Cell Mol Genet 13:221–233CrossRef
31.
McClarty GA, Chan AK, Wright JA (1986) Characterization of a mouse cell line selected for hydroxyurea resistance by a stepwise procedure: drug-dependent overproduction of ribonucleotide reductase activity. Somatic Cell Mol Genet 12:121–131CrossRef
32.
Finch RA, Liu M, Grill SP et al (2000) Triapine (3-aminopyridine-2-carboxaldehydethiosemicarbazone): a potent inhibitor of ribonucleotide reductase activity with broadspectrum antitumor activity. Biochem Pharmacol 59:983–991PubMedCrossRef
33.
Kayyali R, Porter JB, Liu ZD et al (2001) Structure-function investigation of the interaction of 1- and 2-substituted 3-hydroxypyridin-4-ones with 5-lipoxygenase and ribonucleotide reductase. J Biol Chem 276:48814–48822PubMedCrossRef
Metadata
Title
A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors
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
Publication date
01-05-2009
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-008-0890-8

Other articles of this Issue 6/2009

Cancer Chemotherapy and Pharmacology 6/2009 Go to the issue

Original Article

Successful re-challenge with panitumumab in patients who developed hypersensitivity reactions to cetuximab: report of three cases and review of literature

Short Communication

Extended survival of a HER-2-positive metastatic breast cancer patient with brain metastases also treated with intrathecal trastuzumab

Original Article

Diverse cross-resistance phenotype to ET-743 and PM00104 in multi-drug resistant cell lines

Original Article

Growth inhibitory activity of a novel lectin from Cliona varians against K562 human erythroleukemia cells

Original Article

Multiple-pool cell lifespan models for neutropenia to assess the population pharmacodynamics of unbound paclitaxel from two formulations in cancer patients

Short Communication

Lenalidomide: in vitro evaluation of the metabolism and assessment of cytochrome P450 inhibition and induction
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits