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

  • Werner Hilgers
  • Sandrine Faivre
  • Stéphanie Chieze
  • Jérôme Alexandre
  • François Lokiec
  • François Goldwasser
  • Eric Raymond
  • Carmen Kahatt
  • Abdelkrim Taamma
  • Garry Weems
  • John R. MacDonald
  • Jean-Louis Misset
  • Esteban Cvitkovic
Phase I Studies


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.


MGI 114 HMAF platinum drugs phase I trial solid tumors prostate cancer 


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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Werner Hilgers
    • 1
  • Sandrine Faivre
    • 2
  • Stéphanie Chieze
    • 3
  • Jérôme Alexandre
    • 4
  • François Lokiec
    • 5
  • François Goldwasser
    • 4
  • Eric Raymond
    • 1
  • Carmen Kahatt
    • 6
    • 8
  • Abdelkrim Taamma
    • 6
  • Garry Weems
    • 7
  • John R. MacDonald
    • 7
  • Jean-Louis Misset
    • 1
  • Esteban Cvitkovic
    • 6
  1. 1.Hôpital Saint-LouisParisFrance
  2. 2.Institut Gustave RoussyVillejuifFrance
  3. 3.CHU La MilétriePoitiersFrance
  4. 4.CHU CochinParisFrance
  5. 5.Centre René HugueninSaint-CloudFrance
  6. 6.CACKremlin-BicetreFrance
  7. 7.MGI Pharma, Inc.BloomingtonUSA
  8. 8.Cvitkovic et Associés ConsultantsKremlin-BicêtreFrance

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