Safety, tolerability, and pharmacokinetics of single and multiple doses of intravenous cixutumumab (IMC-A12), an inhibitor of the insulin-like growth factor-I receptor, administered weekly or every 2 weeks in patients with advanced solid tumors

Background: Type 1 insulin-like growth factor receptor (IGF-IR) signaling is often dysregulated in cancer. Cixutumumab, a fully human IgG1 monoclonal antibody, blocks IGF-IR and inhibits downstream signaling. The current study determined the recommended dose, safety, and pharmacokinetic (PK) profile of weekly or every-2-week dosing of cixutumumab. Patients and Methods: Two open-label, multicenter phase I studies evaluated weekly (3–15 mg/kg) or every-2-weeks (6–15 mg/kg) dosing of cixutumumab in patients with advanced solid tumors. Serial blood samples for PK were collected up to 168–336 h (day 8–15) following the first administration of cixutumumab. Efficacy was evaluated as best overall tumor response. Results: A total of 24 and 16 patients were enrolled in the weekly and every-2-week dosing studies, respectively. Treatment-emergent adverse events (≥10 %) included hyperglycemia, fatigue, anemia, nausea, and vomiting. Severe adverse events (AE) were infrequent; one serious AE (grade 3 electrocardiogram QT prolongation) was deemed possibly cixutumumab-related (10 mg/kg every-2-weeks). One death occurred due to disease progression (6 mg/kg weekly cohort). Maximum serum concentrations increased with dose. A maximum tolerated dose was not identified; pre-determined target serum minimum concentrations (60 μg/mL) were achieved with ≥6 mg/kg weekly and ≥10 mg/kg every-2-week dosing. Cixutumumab terminal elimination half-life is approximately a week (individual range, t_1/2 = 4.58–9.33 days based upon 10 mg/kg every 2 weeks). Overall, stable disease was achieved in 25 % of all patients. Conclusions: Cixutumumab was associated with favorable safety and PK profiles. A dosing regimen of 10 mg/kg every 2 weeks was recommended for subsequent disease-focused clinical trials.