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Phase I and Pharmacokinetic Study of Irofulven Administered Weekly or Biweekly in Advanced Solid Tumor Patients

¹ Service de Médecine Interne 1, Hôpital Cochin, Paris, France; ² Institut Gustave Roussy, Villejuif, France; ³ Cvitkovic et Associés Consultants, Le Kremlin-Bicetre, France; ⁴ Centre René Huguenin, Saint Cloud, France; ⁵ MGI PHARMA, Inc., Bloomington, Minnesota; and ⁶ Hôpital Saint Louis (AP-HP), Paris, France

Purpose: We performed a Phase I and pharmacokinetic study to determine the maximum tolerated dose of irofulven (6-hydroxymethylacylfulvene; MGI-114, MGI PHARMA, Inc.), administered in intermittent weekly schedules in patients with advanced solid tumors.

Experimental Design: Three schedules were tested: A, days 1, 8, and 15 every 4 weeks; B, days 1 and 8 every 3 weeks; C, days 1 and 15 every 4 weeks. Drugs were administered as 5- and 30-min (schedules B and C) infusions. Dose levels of 10, 12, and 14 mg/m²/week were explored.

Results: Ninety-nine patients received 256 cycles. Fifteen of 74 patients evaluable for maximum tolerated dose experienced 16 dose-limiting toxicities (5 of 17 patients on schedule A, 2 of 25 on schedule B, and 8 of 32 on schedule C), principally treatment delay for thrombocytopenia. Schedule A was considered unsuitable because of frequent thrombocytopenia and treatment discontinuations. Twenty-three percent of the overall population (22 patients with grade 1–2, and 1 patient with grade 3), including 37% of patients on dose level 3, experienced unexpected dose-limiting visual toxicity, which included color perception and visual field alterations linked to retinal cone cell toxicity; the visual toxicity had an early onset, was mostly reversible, and was related to higher dose per infusion. Safety profiles were similar for 5- and 30-min infusions. The relationships between dose and area under the plasma concentration–time curve and maximum plasma concentration were linear for both 5- and 30-min infusions in the 78 patients evaluated for pharmacokinetics. The area under the plasma concentration–time curve and clearance were comparable between infusion durations. Responses included one complete (ovarian), one partial (renal), and seven disease stabilizations lasting >4 months.

Conclusions: We recommend doses of 18 mg/m²/infusion for schedule B and 24 mg/m²/infusion for schedule C, limited to 0.55 mg/kg and a total dose of 50 mg/infusion, administered over 30-min.

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