Phase I Dose-Escalation Study of MEDI-573, a Bispecific, Antiligand Monoclonal Antibody against IGFI and IGFII, in Patients with Advanced Solid Tumors

Abstract

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 (PK), 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. 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. 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.

Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade

“…The growing appreciation of INSR mediated signaling in the IGF pathway has led to two novel strategies to target the IGF-1R pathway in patients with advanced breast cancer, sarcoma, and NSCLC: combined IGF-1R and insulin receptor inhibition (8) and therapeutic antibodies directed against the IGF-1 and IGF-2 ligands (50, 51). …”

“…MEDI-573, a mAb to both IGF-1 and IGF-2, has demonstrated the ability to suppress IGF signaling through both IGF-1R and INSR-A without affecting normal INSR-B mediated signaling in cancer cell lines, leading to its use in an early clinical trial in patients with advanced, heavily pretreated solid tumors (50). In this trial, the disease stabilization rate was 30% with no PRs or CRs observed.…”

“…In this trial, the disease stabilization rate was 30% with no PRs or CRs observed. Based on preclinical studies showing increased INSR-A:INSR-B mRNA ratios in tumor tissue from patients with hormone receptor positive, ERBB2 negative tumors, there is now a phase I/II clinical trial underway assessing the impact of MEDI-573 combined with hormonal therapy in this subset of breast cancer patients (NCT01446159) (50). …”

Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist

“…One problem appears to be the underestimated effects of IGF1(R) blockade on activation of a central nervous system negative feedback loop, resulting in increased systemic GH driving total IGF1 production from the liver, GH-mediated insulin resistance, and increased insulin supply, resulting in antagonism of the IGF1R inhibitor and systemic metabolic toxicity (20). Similar compensatory feedback responses are also observed with anti-IGF ligand antibodies when administered at therapeutic levels, likely related to the lack of selectivity and subsequent sequestration of free IGF1 (48,49 (14,(50)(51)(52). It is well established that for ligand trap molecules to be functional, a >10-fold higher affinity than that for the signaling receptor appears to be necessary to achieve maximal antagonistic activity (53).…”

Mechanisms of action of therapeutic antibodies for cancer

“…MEDI-573, a humanized antibody that neutralizes the IGF-1R ligands IGF-1 and IGF-2 has shown anti-tumor efficacy in pre-clinical models[49, 50]. In a phase I trial MEDI-573 was well tolerated but failed to achieve partial or complete responses in HCC patients[51]. A study in Japanese patients with advanced solid tumors produced similar results[52].…”