A phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of the OX40 agonist MEDI0562 in combination with tremelimumab or durvalumab in adult aubjects with advanced solid tumors.

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TPS3100 Background: Recent advances in treatment of solid tumors include single or combined use of monoclonal antibodies (mAbs) against the immune checkpoints CTLA-4 or PD-1/PD-L1 that can reactivate antitumor cytotoxic tumor-infiltrating lymphocytes (TILs) and significantly improve OS (Menon S, et al. Cancers (Basel). 2016;8:E106.) (Antonia S, et al. Lancet Oncol. 2016; 17:299-308). Activation of TILs via the costimulatory OX40 (CD134) molecule, may offer an alternative and non-redundant pathway for increasing antitumor immunity. OX40 costimulation promotes effector T cell expansion and longevity, overcomes regulatory T cell suppression and provides survival benefit in animal models of tumor challenge (Linch SN, et al. Front Oncol. 2015;5:34). MEDI0562 is an investigational, humanized IgG1κ anti-OX40 mAb that triggers OX40 signaling. Coadministration of an OX40 agonist and either a CTLA-4 or PD-1/PD-L1 pathway inhibitor may promote synergistic effects against certain solid tumors and may be tolerable administered in combination. Methods: A Phase 1, multicenter, open-label study (NCT02705482) is underway to evaluate safety (primary endpoint), pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity (secondary endpoints) of MEDI0562 in combination with either anti-PD-L1 mAb durvalumab or anti-CTLA-4 mAb tremelimumab in adult subjects with previously treated advanced solid tumors. Subjects with primary CNS tumors and hematologic malignancies are excluded. The study includes a dose escalation and expansion phase, with 2 treatment arms in each: MEDI0562/durvalumab combination (Arm A) and MEDI0562/tremelimumab combination (Arm B). Safety assessments include AEs, serious AEs, dose-limiting toxicities, abnormal laboratory parameters, vital signs, and electrocardiogram results. Antitumor efficacy will be assessed as OR, disease control, duration of response, PFS, and OS using RECIST Version 1.1. Subjects will remain on treatment until unacceptable toxicity, progressive disease or other reasons for discontinuation. Clinical trial information: NCT02705482.