A phase I study of the recombinant human IgG1 anti-IGF-IR monoclonal antibody (Mab) IMC-A12, administered on a weekly basis to patients with advanced solid tumors: Interim analysis

B19 Background: The insulin-like growth factor-I receptor (IGF-IR) plays a critical role in tumor cell proliferation and survival, and is overexpressed in multiple tumor types. IMC-A12 is a recombinant human Mab of the immunoglobulin G, subclass 1, which targets the IGF-IR with high affinity. In preclinical studies, IMC-A12 has been shown to inhibit the growth of multiple tumor types in vivo and in vitro. Methods: This multicenter, first-in-human trial enrolled patients age ≥ 18 with advanced refractory or untreatable solid tumors, ECOG PS ≤ 2, and measurable disease. All patients received intravenous IMC-A12 once a week for 4 weeks, with a 2-week observation period following the first 4 week cycle only. The starting dose for the first cohort was 3 mg/kg; dose escalation in subsequent cohorts was to be 6 mg/kg, 10 mg/kg, and 15 mg/kg. Radiological evaluation of tumor response was performed following the 2 week observation period after the first treatment cycle, and every 8 weeks thereafter until documentation of progressive disease (PD), withdrawal of consent, or toxicity necessitating study cessation. Blood samples for pharmacokinetic and serum pharmacodynamic marker analyses and evaluation of any antibodies against IMC-A12 were drawn throughout the study. Results: A total of 24 patients were enrolled (14m/11f), including seven, nine, six, and two in the 3 mg/kg, 6 mg/kg, 10 mg/kg, and 15 mg/kg dose groups, respectively. Eleven patients (46%) had a best overall response of stable disease (SD), including five of nine (56%) treated at 6 mg/kg. The patients with stable disease included a heavily pretreated male patient with breast cancer (SD of approximately 9 months), a patient with hepatocellular carcinoma (SD approximately 10 months), and a patient with pheochromocytoma (SD > 7 months). A total of 18 patients (75%) experienced at least one adverse event (AE) thought to be possibly, probably, or definitely related to IMC-A12; the most common of these was hyperglycemia, which affected a total of four patients (17%), was grade ≥ 3 in two patients, and resulted in study discontinuation in one patient in the 3 mg/kg cohort and one patient in the 10 mg/kg cohort. Infusions of 6 mg/kg and above produced IMC-A12 serum concentrations at or above those associated with activity in preclinical models (trough concentration of approximately 60 to 158 μg/mL). Pharmacodynamic analysis showed that IGF-I levels increased following infusion and remained elevated in the presence of IMC-A12. No evidence of anti-IMC-A12 antibody development has been detected in clinical study to date. Conclusions: In this phase I study of IMC-A12 in patients with advanced, treatment-refractory solid tumors, disease stabilization was observed in nearly half of enrolled patients, with several patients experiencing stable disease > 6 months. Treatment with IMC-A12 produced sustained elevation in IGF-I levels, suggesting successful blockade of the IGF-IR. Dose escalation has been completed for this trial. Because target IMC-A12 serum concentrations have been met or exceeded at a weekly dose of 6 mg/kg, and because IMC-A12 was well-tolerated at this dose level, 6 mg/kg has been selected as the recommended dose for phase 2 study of weekly IMC-A12.