Escalating weekly doses of cetuximab: A phase I trial in advanced solid tumors

Abstract

13012 Background: Cetuximab, an IgG1 monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is FDA-approved at a 400 mg/m2 loading dose, followed by 250 mg/m2 weekly maintenance. Clinical activity of cetuximab has been reported to correlate with grade of skin toxicity, and skin toxicity is reported to increase with increasing dose. We therefore examined the safety and feasibility of escalating weekly cetuximab doses. We hypothesized that increased dose would correlate with rash severity as a surrogate for tumor response. Methods: Four dose levels were tested: cetuximab loading 400 mg/m2 and 250,300,350,400 mg/m2 weekly maintenance. Dose limiting toxicity (DLT) was defined as: grade 4 platelets, grade 3 platelets with bleeding, febrile neutropenia, grade 4 cutaneous toxicity, grade 3 cutaneous toxicity necessitating holding cetuximab for > 4 weeks or any other grade ≥ 3 non-hematologic toxicity. Rash was evaluated using two additional validated dermatology methods: acne lesion counting and global acne grading scale (Int J Derml.1997;36:416–18, J Am Acad Derm.1996;35:559–65, Arch Derm.1982;118:23–25). Results: Twelve patients with advanced solid tumors were treated, including 3 H&N, 2 pancreas, 2 breast, 2 lung, 2 colorectal and 1 bladder. Patient characteristics: age range 44–84, median 62; gender: 10 M; KPS ≥80/<80=7/5; prior chemo ≤1:>1=5:7; median cycles 2 (1–8). Treatment was generally well tolerated. There were no DLTs. The most common grade 3/4 toxicities were acneiform rash (1) and lymphopenia (2). The majority of patients (6) had a Grade 2 rash. In 10 evaluable patients, there were no responses; 3 patients had stable disease. Correlative science studies are ongoing evaluating EGFR expression and polymorphisms, pEGFR, pMAPK, pAKT, Ki67, p27 levels and K-ras mutations. Conclusions: 1) Cetuximab 400 mg/m2 loading dose and 400 mg/m2 weekly maintenance is feasible and well tolerated. Doses up to 400 mg/m2 did not portend increased toxicity and a MTD was not reached on this schedule. 2) Grade of rash did not increase with increasing doses of weekly cetuximab in this limited population. 3) To date, cetuximab has not demonstrated RECIST response in this cohort of pretreated patients with solid tumors. 20 additional patients are being evaluated at the highest dose level. No significant financial relationships to disclose.