Phase I dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

Abstract

Purpose This phase I study endeavored to estimate the maximum tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors. Methods Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150mg/m2/day) on days 1-12 of a 21-day course. The Escalation with Overdose Control (EWOC) method guided irinotecan dose escalation (7 dose levels, range 5mg/m2/day to 40mg/m2/day). Results Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in 10 patients. Diagnoses included osteosarcoma (N=5), neuroblastoma (N=3), sarcoma (N=3), and others (N=5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N=2 and hypophosphatemia, N=1) at dose levels two (10mg/m2) and four (20mg/m2). One patient experienced grade 3 diarrhea (40mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35mg/m2). Of eleven patients receiving at least two courses of therapy, three had stable disease (SD) lasting two to four courses and one patient maintained a complete response through 18 courses. Conclusions The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.

Advances in emerging drugs for osteosarcoma

“…Irinotecan has been used in combination with other chemotherapeutics as salvage treatment for relapsed or refractory pediatric cancers. In OS, irinotecan has been evaluated in recurrent, metastatic patients in combination with gemcitabine [110] and in a Phase I dose escalation and pharmacokinetic study together with gefitinib [111] showing antitumor activity.…”

Continuous-infusion Ifosfamide and Doxorubicin Combination as Second-Line Chemotherapy for Recurrent or Refractory Osteosarcoma Patients in China: a Retrospective Study

“…Several new agents such as topotecan (Seibel et al, 2007), irinotecan (Crews et al, 2004;Bagatell et al, 2014), imatinib mesylate (Bond et al, 2008), gefitinib (Brennan et al, 2014), trabectedin (Chuk et al, 2012), pirarubicin (Qi et al, 2012), ifosfamide (Choeyprasert et al, 2014;Li et al, 2014) and gemcitabine (Qi et al, 2012) have been investigated in pediatric and adult patients, but the response rate is low and survival time is short. As a result, we undertook this retrospective study to investigate the activity of continuous-infusion ifosfamide and doxorubicin combination as secondline therapy for patients with relapsing and refractory osteosarcoma.…”

Innovations for phase I dose-finding designs in pediatric oncology clinical trials

“…The EWOC design has been used in one pediatric trial of escalation of irinotecan and gefitinib combination (23). In the trial, the target probability of toxicity defining the RP2D was set as τ=25%, and the risk of overdose was controlled to be less than α=30%.…”