A phase I study of cetuximab and irinotecan in pediatric patients (pts) with refractory solid tumors

Abstract

9547 Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adults with colorectal cancer, combining irinotecan with cetuximab enhances clinical activity as compared to treatment with irinotecan alone. We implemented this first-in- pediatrics phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of cetuximab and irinotecan in pediatric patients. Methods: 35 heavily pre-treated pts with refractory solid tumors were enrolled: brainstem glioma/astrocytoma (16), hepatoblastoma (4), neuroblastoma (2), other (13). Weekly cetuximab was escalated in 3 sequential dose levels: 75, 150 or 250mg/m2; Irinotecan was given at 16 or 20 mg/m2/day over 1 hour [daily × 5] for two weeks, every 21 days. Correlative EGFR expression (immunohistochemistry and FISH) and/or mutations, pharmacokinetics (PK) of and immune response to cetuximab were performed. Results: Pts were treated in two age cohorts (ages 1–12 yrs = Group A, and 13–18 yrs = Group B). PK analyses show linearity, with similar t1/2, clearance, and volume of distribution between groups. Irinotecan-related DLT in 2/6 pts in Group A/dose 2 necessitated dose de-escalation. Three pts experienced Grade 3 hypersensitivity infusion reaction and were discontinued. A pt with an EGFR-negative high-grade glioma (dose level 1) achieved a >70% reduction in tumor size and remains on study for 16+ months (24 cycles). A pt with ependymoma experienced a partial response (PR) and continues on cycle 12+. 9 pts received ≥4 cycles of therapy. 16 pts had a best response of stable disease or PR (mean 17 wks, range 5–66+ wks) for a clinical benefit rate of 45%. Conclusions: The combination of cetuximab and irinotecan is well-tolerated over multiple repeat cycles without cumulative toxicity in children with refractory CNS and non-CNS solid tumors. Promising preliminary anti-cancer activity was observed in a variety of pediatric solid tumors. Detailed biologic correlative and PK data will be presented. [Table: see text] No significant financial relationships to disclose.