A phase I trial of RAD001 in combination with cetuximab in patients with advanced solid tumors

Abstract

14075 Background: Cetuximab is a selective epidermal growth factor (EGFR) inhibitor approved for use in EGFR expressing advanced colorectal cancers. RAD001 inhibits mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway. Preclinical studies suggest that RAD001 may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination it may augment anti-tumor activity. We assessed safety, pharmacokinetics (PK), and pharmacodynamic (PD) endpoints for mTOR inhibition and tumor vascular permeability in a phase I combination study. Methods: Pts with EGFR-expressing advanced solid tumors were randomized to a 3 week run-in of single agent RAD001 or cetuximab Q wk, followed by RAD001 + cetuximab Qwk. RAD001 was dosed at 30–70 mg PO. Standard dosing of cetuximab was used (400 mg/m2 IV loading, followed by 250 mg/m2 IV Qwk). DLT was defined as any grade 4 hematologic or =grade 3 non-hematologic toxicity associated with treatment during cycle 1. In addition to plasma analysis for the PK of RAD001, we performed 18FDG-PET and dynamic contrast-enhanced (DCE) MRI before and during combination therapy, to assess for early changes in tumor metabolic activity and vascular permeability. Phosphorylation of p70S6K, a biomarker for RAD001 activity, was measured in peripheral blood mononuclear cells. Results: 12 pts (median age 56, 5 M/7F, median PS 0) were treated at dose levels 1–2 (RAD001 30–50mg/cetuximab 250 mg/m2), with 3 per dose order. Observed toxicities were all grade 1–2, and included mucositis (2/12), rash (8/12), fatigue (6/12), anorexia (4/12), nausea (5/12), and vomiting (5/12). 2 pts (parotid and ovarian CA) had SD (4+ mos) as best response, with decreased serum CA-125 in the ovarian CA pt. PET findings in pts with SD confirm decreased tumor metabolic activity. Conclusions: At these doses, neither drug appears to increase the toxicity of the other. Analysis of full dose RAD001 in the combination is nearing completion. Preliminary PET findings suggest biological activity of the combination. No significant financial relationships to disclose.