On-target activity of neoadjuvant cixutumumab and combined androgen deprivation therapy for high-risk prostate cancer: A phase II trial.

153 Background: IMC-A12 (cixutumumab) is a fully human monoclonal antibody which targets the insulin-like growth factor receptor 1. Preclinical data suggests that the combination of androgen deprivation and IMC-A12 is much more effective than either treatment alone. This clinical trial tests the effectiveness of the combined treatment in a neoadjuvant fashion before radical prostatectomy. We have assayed serum samples from the first 18 patients to identify signs of on-target activity in this setting. Methods: Eligible men with high risk localized prostate cancer are defined by one of the following: Gleason score ≥ 8, PSA ≥ 20, Clinical Stage T2c-T3, or a risk for relapse exceeding 50% as defined by the Kattan nomogram. Men are treated for 3 months with goserelin, bicalutamide, and biweekly IMC-A12 infusions (10 mg/kg). The primary objective of the trial is to determine the rate of pathological complete response with an accrual goal of 28 men. Using samples from the first 18 patients on study, serum protein markers were assayed by ELISA and serum PSA and glucose levels were determined by clinical laboratory analysis. Results: Significant increases in c-peptide (1.7-fold, p<0.01), IGF-I (4.1-fold, p<0.01), IGF-II (1.32-fold, p<0.001), IGFBP-3 (1.9-fold, p<0.01), growth hormone (8-fold, p<0.01) were noted after initiation of ADT+IMC-A12, compared to pre-treatment levels. Non-significant increases of insulin (1.9-fold), IGFBP-1 (2-fold), and glucose (1.24-fold) levels were seen. Stratification of patients by nadir PSA levels correlated with residual tumor volume, likelihood of positive surgical margins and likelihood of lymph node metastases. Interestingly, patients with lower nadir PSA levels had smaller increases in c-peptide (50%, p<0.01), insulin (66%, p<0.02) and blood sugar (21%, P<0.01) compared to the patients with higher nadir PSA levels. Conclusions: Combined with ADT in the neoadjuvant setting, IMC-A12 effectively targets the IGF-1R axis in prostate cancer patients. Metabolic differences between patients may alter the efficacy of IMC-A12 in this setting. [Table: see text]