Phase I Dose Escalation Study of MEDI-573, a Bispecific, Anti-ligand Monoclonal Antibody against IGF-I and IGF-II, in Patients with Advanced Solid Tumors
Mené sur 43 patients atteints d'une tumeur solide de stade avancé et réfractaire aux traitements de référence, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale d'un composé appelé MEDI-573, un anticorps monoclonal bispécifique anti IGF-I et IGF-II
Purpose: This phase I, multicenter, open-label, single-arm, dose escalation, and dose expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10 or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. Pharmacokinetic evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGF-II were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis.