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A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors

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Summary

Purpose

To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics of irofulven combined with capecitabine in advanced solid tumor patients.

Experimental design

Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15. Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m2/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000.

Results

Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3 thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of 14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade 3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1, DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug–drug interactions.

Conclusions

Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m2/day.

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Acknowledgments

The authors thank Scott Lunos for statistical analysis, Scott Slough for aid in preparation of the manuscript, and the Department of Pharmacology of René Huguenin Cancer Centre for performing the drug assays. Supported by MGI PHARMA, INC., Bloomington, MN, USA.

Authors’ disclosure of potential conflicts of interest

John R. MacDonald, Ajit Shah and Garry Weems are employees and stockholders of MGI PHARMA, INC., Bloomington, MN, the sponsor of this trial. Esteban Cvitkovic is CEO and a stockholder of CAC, Kremlin-Bicêtre, France, the clinical research organization which was contracted by MGI PHARMA to conduct this and other trials of irofulven. Carmen Kahatt is an employee and stockholder of CAC.

Author information

Authors and Affiliations

  1. Hôpital Cochin, Université Paris 5, Paris, France

    Jérôme Alexandre

  2. CAC Oncology, Kremlin-Bicêtre, France

    Carmen Kahatt & Esteban Cvitkovic

  3. Centre René Huguenin, Saint-Cloud, France

    Frédérique Bertheault-Cvitkovic

  4. Institut Gustave Roussy, Villejuif, France

    Sandrine Faivre

  5. City of Hope National Medical Center, Duarte, CA, USA

    Stephen Shibata

  6. Hôpital Saint-Louis, Paris, France

    Werner Hilgers & Eric Raymond

  7. CHU Cochin, Paris, France

    François Goldwasser

  8. Centre René Huguenin, Saint-Cloud, France

    François Lokiec

  9. MGI PHARMA, INC., Bloomington, MN, USA

    Garry Weems, Ajit Shah & John R. MacDonald

  10. Cvitkovic & Associés Consultants, 18-20 rue Pasteur, 94278, Kremlin-Bicêtre, France

    Esteban Cvitkovic

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  1. Jérôme Alexandre
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  9. Eric Raymond
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  13. Esteban Cvitkovic
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Correspondence to Esteban Cvitkovic.

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Alexandre, J., Kahatt, C., Bertheault-Cvitkovic, F. et al. A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors. Invest New Drugs 25, 453–462 (2007). https://doi.org/10.1007/s10637-007-9071-6

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  • DOI: https://doi.org/10.1007/s10637-007-9071-6

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