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A phase I and pharmacokinetic study of irofulven and cisplatin administered in a 30-min infusion every two weeks to patients with advanced solid tumors

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Summary

Background: To determine maximum tolerated dose (MTD), recommended dose, safety and pharmacokinetics of irofulven combined with cisplatin in advanced solid tumor patients. Patients and methods: Cisplatin and irofulven were given sequentially i.v. over 30 min on day 1 and 15 every 4 weeks. Four dose levels (DL) were explored: irofulven (mg/kg)/cisplatin (mg/m2): DL1: 0.3/30; DL2: 0.4/30; DL3: 0.4/40; DL4: 0.5/40. Dose-limiting toxicity (DLT) included dosing omission and delay >1 week. MTD was the DL with DLT in 2/2 or ≤2/6 patients during cycle 1–2. Results: Between March 2002 and April 2003, 33 patients were treated. DLT occurred in 1/6 patients in DL1 (hypomagnesemia, hypocalcemia); 1/6 in DL2 (thrombocytopenia); 2 heavily pretreated patients out of 6 patients in DL3 (neutropenic infection, thrombocytopenia, stomatitis); 2/3 in DL4 (asthenia, blurred vision). Three DLT occurred in 12 additional patients treated at DL2. No toxic deaths occurred; grade 4 toxicity and grade 3 non-hematological toxicity were infrequent. Six patients reported grade 1–2 visual events. Antitumor activity was observed over a broad spectrum of tumor types in all DLs: 1 partial response in bulky sarcoma (DL1); 1 clinical response in endometrial carcinoma (DL1); 2 partial responses not confirmed due to discontinuation (ovarian DL2, renal DL4); 8 stabilizations >3 months; PSA response: 3/9 prostate cancer patients. Irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions. Conclusion: Irofulven with cisplatin was adequately tolerated and substantial evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and cisplatin 30 mg/m2.

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Author information

Authors and Affiliations

  1. Hôpital Saint-Louis, Paris, France

    Werner Hilgers, Eric Raymond & Jean-Louis Misset

  2. Institut Gustave Roussy, Villejuif, France

    Sandrine Faivre

  3. CHU La Milétrie, Poitiers, France

    Stéphanie Chieze

  4. CHU Cochin, Paris, France

    Jérôme Alexandre & François Goldwasser

  5. Centre René Huguenin, Saint-Cloud, France

    François Lokiec

  6. CAC, Kremlin-Bicetre, France

    Carmen Kahatt, Abdelkrim Taamma & Esteban Cvitkovic

  7. MGI Pharma, Inc., Bloomington, MN, USA

    Garry Weems & John R. MacDonald

  8. Cvitkovic et Associés Consultants, 18-20 rue Pasteur, 94278, Kremlin-Bicêtre, France

    Carmen Kahatt

Authors
  1. Werner Hilgers
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  2. Sandrine Faivre
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  3. Stéphanie Chieze
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  4. Jérôme Alexandre
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  7. Eric Raymond
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  13. Esteban Cvitkovic
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Corresponding author

Correspondence to Carmen Kahatt.

Additional information

Supported by MGI PHARMA, INC., Bloomington, MN, USA.

Work previously presented in part at the Annual Conference of the American Society for Clinical Oncology, Chicago, IL, 2003.

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Hilgers, W., Faivre, S., Chieze, S. et al. A phase I and pharmacokinetic study of irofulven and cisplatin administered in a 30-min infusion every two weeks to patients with advanced solid tumors. Invest New Drugs 24, 311–319 (2006). https://doi.org/10.1007/s10637-005-5055-6

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  • DOI: https://doi.org/10.1007/s10637-005-5055-6

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