Phase I study of everolimus (RAD001) with irinotecan (Iri) and cetuximab (C) in second-line metastatic colorectal cancer: Hoosier Oncology Group GI05-102.

Abstract

523 Background: Preclinically, mTOR and EGFR inhibitors are synergistic. We hypothesize that the mTOR inhibitor RAD001 would enhance efficacy and prevent resistance when added to an anti-EGFR agent. The purpose of the phase I portion of this study was to determine the safety and maximum tolerated dose (MTD) of daily RAD001 combined with weekly Iri and C in mCRC. Methods: Pts who failed first-line therapy, including an Iri-regimen, were treated with Iri 125 mg/m2 weekly x 2 every 3 weeks, C 400 mg/m2 loading dose, then 250 mg/m2 weekly, and escalating doses of RAD001 orally: 5 mg qod, 5 mg qd and 10 mg qd during 21-day cycles, with a “3+3” design. The study was amended after the first 9 pts enrolled, to include stopping rules for excessive toxicity beyond what was expected for diarrhea, nausea/vomiting and febrile neutropenia due to Iri, and skin rash due to C. Enrollment excluded pts with UGT1A1*28, but allowed KRAS mutated mCRC. RAD001 PK was done on C2D1, and archival tumors were analyzed for pharmacodynamic markers. Results: 28 pts were enrolled, median age 61 y (25-77), 15 male, ECOG PS 0/1 (19/9). Reasons for treatment discontinuation were: PD (7), adverse events (AEs) (6), pt withdrawal, symptomatic deterioration and non-compliance (1 each). Prior to study's amendment* (n=9), 3 pts were not evaluable for DLT due to: Iri intolerance after one dose (1), non-compliance (1) and gr 3 C infusion reaction (1). DLTs and number of cycles are listed in Table. Following protocol amendment, 2 pts had DLT in cohort 3 (gr 3 mucositis), thus the MTD was 5 mg RAD001. The most common grade 3/4 AEs were: diarrhea (10), neutropenia (5), fatigue (4), acne-rash (4), mucositis (2), nausea (2), vomiting (1). Among 19 pts evaluable for response, there were 1 CR, 2 PR, (RR 16%), 9 SD (47%), 7 PD (37%). PK and pharmacodynamic data is ongoing. Conclusions: The MTD of RAD001 of 5 mg QD with Iri/C weekly is safe and clinically active. A randomized phase II study is near starting accrual. [Table: see text] [Table: see text]