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01.05.2009 | Clinical Trial Report

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2009

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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.

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Titel: A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors
verfasst von: 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
Publikationsdatum: 01.05.2009
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2009
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0890-8

Springer Medizin

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