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

Abstract

3587 Background: Preclinically, mTOR and EGFR inhibitors are synergistic. We hypothesize that the mTOR inhibitor RAD001 would enhance clinical efficacy when added to C. The main purpose of this study was to determine the safety, and maximum tolerated dose (MTD) of daily RAD001 combined with Iri and C in mCRC. Methods: Pts were treated with Iri 125 mg/m2 weekly (qw) x 2 every 3 wks, C 400 mg/m2 loading, then 250 mg/m2 qw, 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. Eligibility allowed KRAS mutated (MUT) mCRC. The study was amended after the first 9 pts*, to include stopping rules for excessive toxicity beyond expected rates for diarrhea, nausea/vomiting and febrile neutropenia due to Iri, and skin rash due to C. PK (Cmin) for RAD001 was done on C2D1, and archival tumors were analyzed for pharmacodynamic (PD) markers of EGFR and mTOR pathway activation. Results: 30 pts were enrolled (KRAS WT 12; MUT 15; unknown 3), median age 60.5 y (25-77), 16 male, ECOG PS 0/1 (20/10). Reasons for treatment discontinuation were: PD (13), adverse events (AEs) (8), pt withdrawal (2), symptomatic deterioration and non-compliance (1 each). Prior to study’s amendment*, 3 pts were not evaluable for DLT due to: gr 3 Iri and C infusion reactions with 1st infusion (1 each), non-compliance (1). DLTs and number of cycles are listed in Table. The most common gr 3/4 AEs were diarrhea (9), rash (6), mucositis, ANC, fatigue (4 each), nausea (3), vomiting, anorexia, febrile neutropenia (2 each). RAD001 mean Cmin at MTD was 8.5 ng/mL, similar to that seen with RAD001 alone. Among pts evaluable for response (n=24), there were 1 CR, 4 PR (21%, including 1PR in KRAS MUT pt for 26 mos), 9 SD (37%). Median PFS and OS were 6 and 28 mos for KRAS WT, and 3.3 and 12 mos for KRAS MUT pts, respectively. PD markers will be presented. Conclusions: The MTD of RAD001 of 5 mg QD with Iri/C qw is safe and clinically active. A phase II study is ongoing. Cohort (# pts) RAD001 # DLT DLT # Cycles median (range) 1* (9) 5 mg QOD 2 Gr 3 diarrhea Gr 3 febrile neutropenia 2 (1-34) 1 (3) 5 mg QOD 0 6 (2-10) 2 (MTD) (4) 5 mg QD 0 5 (1-13) 3 (4) 10 mg QD 2 Gr 3 mucositis 2 (2-6) 2 expansion (10) 5 mg QD 1 Gr 3 diarrhea 2 (1-9+)