A Phase I Pharmacologic Study of Necitumumab (IMC-11F8), a Fully Human IgG1 Monoclonal Antibody Directed Against EGFR in Patients with Advanced Solid Malignancies

Abstract

Purpose: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. Experimental Design: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. Results: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with ≥600 mg necitumumab achieved target trough concentrations (≥40 μg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. Conclusion: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting. Clin Cancer Res; 16(6); 1915–23

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

“…The tolerability of necitumumab in the clinic was assessed in solid tumor cancer patients, investigating doses of 100 mg up to 1,000 mg in a weekly or biweekly schedule,18 and the maximum tolerated dose (MTD) was defined as 800 mg. The major dose‐limiting toxicity (WHO Grade 3+) observed was severe headaches.…”

Antibody-based therapeutics to watch in 2011

“…The maximum tolerated dose was established as 800 mg; the half-life was approximately 7 days at this dose. 22 The most common drug-related toxicity was mild skin toxicity that was dose-related. Target trough concentrations were achieved by all patients who were administered 600 mg or more of necitumumab.…”

Clinical potential of necitumumab in non-small cell lung carcinoma

“…In a first-in-human, dose-escalation, Phase I trial, the maximum tolerated dose of necitumumab was identified to be 800 mg; at this dose, the half-life of necitumumab was ≈7 days; additionally, its mean clearance decreased in a less than dose-proportional pattern, while its maximum serum concentration and area under the concentration versus time curve extrapolated from time 0 to infinity values increased disproportionately to the dose of necitumumab. These nonlinear pharmacokinetics findings suggest a saturable clearance mechanism for this drug; additionally, its metabolism is not apparently related to height or weight, indicating fixed dose as the most suitable choice for necitumumab 12,13…”