Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors

• Published in: Clinical cancer research 2014-09, Vol.20 (18), p.4747-4757
• Main Authors: Haluska, Paul, Menefee, Michael, Plimack, Elizabeth R, Rosenberg, Jonathan, Northfelt, Donald, LaVallee, Theresa, Shi, Li, Yu, Xiang-Qing, Burke, Patricia, Huang, Jiaqi, Huang, Jaiqi, Viner, Jaye, McDevitt, Jennifer, LoRusso, Patricia
• Format: Article
• Language: English
• Subjects: Aged; Antibodies, Bispecific - administration & dosage; Antibodies, Bispecific - adverse effects; Antibodies, Bispecific - pharmacokinetics; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Dose-Response Relationship, Drug; Female; Humans; Insulin-Like Growth Factor I - antagonists & inhibitors; Insulin-Like Growth Factor II - antagonists & inhibitors; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms - drug therapy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-0114

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. 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 (PK), pharmacodynamics, immunogenicity, and antitumor activity. 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. PK 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 IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. 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.