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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

  • 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

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.

Keywords

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

References

  1. 1.
    MacDonald JR, Muscoplat CC, Dexter DL, et al: Preclinical antitumor activity of 6-hydroxymethylacylfulvene, a semisynthetic derivative of the mushroom toxin Illudin S. Cancer Res 57:279–83, 1997PubMedGoogle Scholar
  2. 2.
    Kelner MJ, McMorris TC, Taetle R: Preclinical evaluation of illudins as anticancer agents: Basis for selective cytotoxicity. J Natl Cancer Inst 82:1562–565, 1990CrossRefPubMedGoogle Scholar
  3. 3.
    Woynarowski J, Napier C, Koester S, et al: Effects on DNA integrity and apoptosis induction by a novel antitumor sesquiterpene drug, 6-hydroxymethylacylfulvene (HMAF). Biochem Pharmacol 54:1181–193, 1997CrossRefPubMedGoogle Scholar
  4. 4.
    Woynarowska B, Woynarowski J, Herzig M, Roberts K, Higdon AL, MacDonald JR: Differential cytotoxicity and induction of apoptosis in tumor and normal cells by hydroxymethylacylfulvene (HMAF). Biochem Pharmacol 59:1217–226, 2000CrossRefPubMedGoogle Scholar
  5. 5.
    Herzig M, Trevino AV, Liang H, et al: Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent. Biochem Pharmacol 65:503–13, 2003CrossRefPubMedGoogle Scholar
  6. 6.
    Herzig M, Arnett B, MacDonald J, Woynarowski J: Drug uptake and cellular targets of hydroxymethylacylfulvene (HMAF). Biochem Pharmacol 58:217–25, 1999CrossRefPubMedGoogle Scholar
  7. 7.
    Kelner MJ, McMorris TC, Estes L, Samson K, Bagnell CR, Taetle R: Efficacy of MGI 114 (6-hydroxymethylacylfulvene, HMAF) against the mdr1/gp170 metastatic MV522 lung carcinoma xenograft. Eur J Cancer 34:908–13, 1998CrossRefPubMedGoogle Scholar
  8. 8.
    Kelner MJ, McMorris TC, Estes L, et al: Efficacy of MGI 114 (HMAF) against the MRP+ metastatic MV522 lung carcinoma xenograft. Anti-Cancer Drugs 11:217–24, 2000CrossRefPubMedGoogle Scholar
  9. 9.
    Eckhardt S, Baker SD, Britten C, et al: Phase I and pharmacokinetic study of irofulven, a novel mushroom- derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies. J Clin Oncol 18:4086–097, 2000PubMedGoogle Scholar
  10. 10.
    Alexandre J, Raymond E, Ould-Kaci M, et al: Phase I and pharmacokinetic study of irofulven administered weekly or biweekly in advanced solid tumor patients. Clin Cancer Res 10:3377–385, 2004CrossRefPubMedGoogle Scholar
  11. 11.
    Reed E, Sarosy G, Gordon A, Weems G, Herdrich L: Clinical activity of irofulven in pretreated advanced ovarian cancer (AOC) patients. Clin Cancer Res 7:3697s, 2001Google Scholar
  12. 12.
    Von Hoff DD, Cox JV, Tempero M, et al: Phase II trial of irofulven (MGI 114) in patients with advanced pancreatic cancer who have progressed on gemcitabine. Proc Am Soc Clin Oncol 19:309a, 2000Google Scholar
  13. 13.
    Senzer N, Arseneau J, Richards D, Berman B, MacDonald JR, Smith S: Irofulven demonstrates clinical activity against metastatic hormone-refractory prostate cancer in a phase 2 single-agent trial. Am J Clin Oncol 28:36–2, 2005CrossRefPubMedGoogle Scholar
  14. 14.
    Tombal B, Tourani JM, Fizazi K, et al: Randomized phase II trial of irofulven (IROF) with or without prednisone in hormone-refractory prostate cancer (HRPC) patients (pts). Proc Am Soc Clin Oncol 22:407, 2003Google Scholar
  15. 15.
    Stuart K, Eder J, Proper J, et al: Phase II trial of irofulven in patients with unresectable hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 21:127b, 2002Google Scholar
  16. 16.
    Debono J, Rowinsky E, Hidalgo M, et al: Irofulven in combination with irinotecan: A Phase I study examining 3 schedules in patients with advanced cancers. Clin Cancer Res 7:3796s, 2001Google Scholar
  17. 17.
    McCreery H, Rowinsky E, Tolcher AW, et al: Phase I trial of irofulven and CPT-11 in patients with advanced cancers. Proc Am Soc Clin Oncol 21:82b, 2002Google Scholar
  18. 18.
    Alexandre J, Bertheault-Cvitkovic F, Hilgers W, Yovine A, Weems G, Herait P: Phase I and pharmacokinetic (PK) study of irofulven (IROF) and capecitabine (CAP) in combination using an intermittent schedule in advanced solid tumors. Proc Am Soc Clin Oncol 22:154, 2003Google Scholar
  19. 19.
    Witta S, Eckhardt G, Rothenberg M, et al: A phase I combination trial of irofulven and gemcitabine in patients with advanced solid malignancies. Proc Am Soc Clin Oncol 22:138, 2003Google Scholar
  20. 20.
    Go RS, Adjei AA: Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 17:409–22, 1999PubMedGoogle Scholar
  21. 21.
    Koeppel F, Poindessous V, Lemke K, Skladanwski A, Raymond E, Larsen A: Irofulven-resistant colon carcinoma cells show little or no cross-resistance with several anticancer drug types. Clin Cancer Res 7:3696s, 2001Google Scholar
  22. 22.
    Poindessous V, Koeppel F, Raymond E, Cvitkovic E, Waters JS, Larsen A: Enhanced antitumor activity of irofulven in combination with 5-fluorouracil and cisplatin in human colon and ovarian carcinoma cells. Int J Oncol 23:1347–355, 2003PubMedGoogle Scholar
  23. 23.
    Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creartinine. Nephron 16:31–1, 1976CrossRefGoogle Scholar
  24. 24.
    Patnaik A, Rowinsky E, Tammara BK, et al: Phase I and pharmacokinetic study of the differentiating agent vesnarinone in combination with gemcitabine in patients with advanced cancer. J Clin Oncol 18:3974–985, 2000PubMedGoogle Scholar
  25. 25.
    Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–16, 2000CrossRefPubMedGoogle Scholar
  26. 26.
    Leroy AR, Wehling ML, Sponseller HL, et al: Analysis of Platinum in Biological Materials by Flameless Atomic Absorbtion Spectrophotometry. Biochem Med 18:184–91, 1977CrossRefPubMedGoogle Scholar
  27. 27.
    Urien S, Alexandre J, Raymond E, et al: Phase I population pharmacokinetics of irofulven. Anticancer Drugs 14:353–58, 2003CrossRefPubMedGoogle Scholar
  28. 28.
    Raymond E, Kahatt C, Rigolet MH, et al: Characterization and multiparameter analysis of adverse events in irofulven single-agent phase I and II trials. Clin Cancer Res 10:7566–574, 2004CrossRefPubMedGoogle Scholar
  29. 29.
    Lee MS, Gupta N, Penson R, et al: Cone damage in patients receiving high-dose irofulven treatment. Arch Ophthalmol 123:29–4, 2005CrossRefPubMedGoogle Scholar
  30. 30.
    Cvitkovic E, Spaulding JT, Bethune V, Martin J, Whitmore W: Improvement of Cisdichlorodiamine Platinum (NSC 119875) therapeutic index in an animal model. Cancer 39:1357–361, 1977CrossRefPubMedGoogle Scholar
  31. 31.
    Johnson S, O’Dwyer P: Cisplatin and its analogues. In: De Vita VT, Hellman S, Rosenberg S (eds.), Cancer. Principles & practice of oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 2005, pp. 344–58Google Scholar
  32. 32.
    Moore M, Troner M, DeSimone P, Birch R, Irwin L: Phase II evaluation of weekly cisplatin in metastatic hormone-resistant prostate cancer: A Southeastern cancer study group trial. Cancer Treat Rep 70:541–43, 1986PubMedGoogle Scholar
  33. 33.
    Qazi R, Khandeker J: Phase II study of cisplatin for metastatic prostate carcinoma. An Eastern Cooperative Oncology Group study. Am J Clin Oncol 6:203–05, 1983CrossRefPubMedGoogle Scholar
  34. 34.
    Rossof A, Talley R, Stephens R: Phase II evaluation of cis-dischlorodiammineplatinum (II) in advanced malignancies of the genitourinary and gynecological organs: A Southwest Oncology Group study. Cancer Treat Rep 63:1557–564, 1979PubMedGoogle Scholar
  35. 35.
    Osborne CK, Blumenstein B, Crawford ED, Weiss G, Bukowski RM, Larrimer N: Phase II study of platinum and mitoxantrone in metastatic prostate cancer: A Southwest Oncology Group Study. Eur J Cancer 28:477–78, 1999CrossRefGoogle Scholar
  36. 36.
    Huan S, Stewart DJ, Aitken S, Segal R, Yau JC: Combination of epirubicin and cisplatin in hormone-refractory metastatic prostate cancer. Am J Clin Oncol 22:471–74, 1999CrossRefPubMedGoogle Scholar

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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