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

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.

• 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 63 Issue 6 Pg. 1147-56 (May 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19082825 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Pyridines
• Thiosemicarbazones
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• Doxorubicin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Doxorubicin (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Drug Administration Schedule
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Thiosemicarbazones (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)