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

  • Clinical Trial Report
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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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Acknowledgments

The authors would like to thank the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center (UWCCC) Analytical Instrumentation Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics (3P Lab) for support in the acquisition of pharmacokinetic data for this research. The authors also would like to thank the patients who participated in this clinical trial, and the nurses and research specialist of the UWCCC phase I program for their efforts in conducting and managing this trial. UO1 CA062491, Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis, NCI; CTEP Translational Research Initiative, Contract 24XS090; and 1UL 1RR025011, Clinical and Translational Science Award, National Center for Research Resources, NIH.

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Authors and Affiliations

  1. University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue, K6/568, Madison, WI, 53792, USA

    William R. Schelman, Rebecca Marnocha, Fred Lee, Jens Eickhoff, Wei Huang, Marcia Pomplun, Zhisheng Jiang, Dona Alberti, Jill M. Kolesar, George Wilding & Anne M. Traynor

  2. Southern Cancer Center, Mobile, AL, USA

    Sherry Morgan-Meadows

  3. Clinical Trials Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Percy Ivy

Authors
  1. William R. Schelman
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  2. Sherry Morgan-Meadows
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  3. Rebecca Marnocha
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  4. Fred Lee
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  5. Jens Eickhoff
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  6. Wei Huang
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  7. Marcia Pomplun
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  8. Zhisheng Jiang
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  9. Dona Alberti
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  10. Jill M. Kolesar
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  11. Percy Ivy
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  12. George Wilding
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  13. Anne M. Traynor
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Corresponding author

Correspondence to Anne M. Traynor.

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Schelman, W.R., Morgan-Meadows, S., Marnocha, R. et al. A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemother Pharmacol 63, 1147–1156 (2009). https://doi.org/10.1007/s00280-008-0890-8

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  • DOI: https://doi.org/10.1007/s00280-008-0890-8

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