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

Abstract

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.

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

“…One case of transient grade three blurred vision was reported at DL4 (0.50 mg/kg irofulven), with the remainder of the events restricted to grade 1-2, and resolving in less than 1 week in five patients (start date not available for three patients). Despite reports of capecitabine being associated with visual toxicity (eye irritation, blurred vision, increased tears and decreased visual acuity related to keratitis secondary to corneal deposits of capecitabine) the incidence in this study was no higher than that observed in previous studies of biweekly irofulven over a similar dose range [19]. Grade 1-2 hand-foot syndrome, a characteristic fluoropyrimidine toxicity, was observed in 25% of patients at the RD, without ever reaching grade 3 severity, consistent with the incidence of this toxicity following capecitabine monotherapy at a dose of 2,000 mg/m 2 /day [30], and lower than the 50 to 90% reported for capecitabine administered at a dose of 2,500 mg/m 2 /day for 2 weeks out of every 3 [30,31].…”

“…Subsequent single-agent studies explored weekly and biweekly schedules of irofulven; the recommended biweekly regimen became 0.5 mg/kg as a 30-min infusion [10,27]. Consequently, the irofulven dose recommended for use in combination with capecitabine represents 80% of the single agent recommended dose for biweekly administration and the same as that recommended for use in combination with cisplatin [19]. The recommended dose of capecitabine in combination with irofulven is also 80% of the single agent dose, 2,500 mg/m 2 /day [28].…”

“…Two prior phase II studies of irofulven as monotherapy or combined with prednisone reported 13 to 16% PSA response rates, with median duration 2.9 to 3.4 months, and two partial responses in 18 RECIST evaluable patients [13,14]. In combination with cisplatin, three PSA responses were observed in nine prostate cancer patients [19]. Based on the evidence of activity of irofulven in prostate cancer patients in these trials, and in the present trial, a randomized phase II trial in docetaxel-pretreated HRPC patients is currently evaluating irofulven combined with prednisone or capecitabine and prednisone [32].…”

“…Phase II studies of single-agent irofulven employing both daily and weekly schedules have demonstrated promising antitumor activity in patients with heavily pretreated ovarian cancer, androgen-independent prostate cancer, advanced pancreatic cancer, and hepatocellular carcinoma [11][12][13][14][15]. Dose-finding studies of irofulven in combination with irinotecan, docetaxel, gemcitabine, cisplatin and oxaliplatin have been completed or are ongoing [16][17][18][19].…”

Highlights of Natural Products in Prostate Cancer Drug Discovery

“…Irofulven has demonstrated activity against PC-3 and DU145 cells as monotherapy and enhanced efficacy was displayed in combination with mitoxantrone or docetaxel (Van Laar et al, 2004) and these results highlighted its potential to be used in combination regimens in clinical trials. Thus a phase I and pharmacokinetic study of irofulven (0.4 mg/kg) and cisplatin (30 mg/m 2 ) in patients with solid tumors concluded that the regimen was adequately tolerated with substantial evidence of antitumor activity observed (Hilgers et al, 2006). Combination regiments of the same dosage of irofulven with capecitabine (2,000mg/m 2 /day) were also found safe on phase I clinical trials in patients with solid tumors (Alexandre et al, 2007).…”