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Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti–angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy. Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5–1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed. Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively. Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749–57. ©2018 AACR.

Background This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo–sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab–sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review. Key secondary end points included progression-free survival, overall survival, and objective response. Results In total, 101 patients were randomized (placebo–sorafenib arm: N = 51; mapatumumab–sorafenib arm: N = 50). There was no significant difference in median TTP between both arms [5.6 versus 4.1 months, respectively; adjusted hazard ratio (one-sided 90% confidence interval) 1.192 (0–1.737)]. No mapatumumab-related benefit was identified when TTP was evaluated in the stratified subgroups. The addition of mapatumumab to sorafenib did not demonstrate improvement in the secondary efficacy end points. The reported frequency of adverse events (AEs) and serious AEs was comparable in both treatment arms. Conclusions The addition of mapatumumab to sorafenib did not improve TTP or other efficacy end points, nor did it substantially change the toxicity profile of sorafenib in patients with advanced HCC. Based on these results, further development of the combination of mapatumumab and sorafenib in HCC is not planned.

Background: MEDI0680 (AMP-514) is a humanized immunoglobulin gamma 4, kappa (IgG4κ) monoclonal antibody (mAb) specific for human programmed cell death-1 (PD-1), developed for the treatment of cancer. The primary objectives of this analysis were to (a) describe the pharmacokinetics (PK) of MEDI0680 and quantitate the impact of patient/disease characteristics on PK variability (b) to compare body weight (WT)-based and fixed dosing regimens of MEDI0680 and (c) to characterize PK-pharmacodynamic (receptor occupancy) relationship. Methods: A total of 905 serum concentration records from 58 patients in Phase 1 study (D6020C00002) designed to evaluate safety, tolerability and PK following 0.1, 0.5, 2.5, 10, and 20 mg/kg every 3 weeks (Q3W), every 2 weeks (Q2W) or weekly doses (QW) as intravenous (IV) infusion of MEDI0680 were included in this analysis. The population PK analysis was performed using a non-linear mixed effects modeling approach in NONMEM (version 7.2) software. Impact of patient demographics, clinical indices and biomarkers on PK parameters were explored. The appropriateness of the final model was tested using visual predictive check (VPC). A sequential PK-PD analysis was performed using receptor occupancy (RO) data from 35 subjects. Results: MEDI0680 PK profiles were best described using a 2-compartment model with linear clearance. The clearance (CL), volume of distribution (Vc) were 0.27 L/day, 5.07 L with a modest between-subject variability of 30% and 19%, respectively. None of the evaluated covariates showed any impact on PK parameters except a minor (not clinically relevant) impact of body weight on volume of distribution. VPC results demonstrated good predictability of the final population PK model. A direct Emax model described the PK-PD relationship of MEDI0680. The estimate of EC50 was approximately 9.3 µg/mL. PK/PD simulations indicate that following 20 mg/kg Q2W dose, >90% receptor occupancy can be maintained in all subjects. Based on preclinical/clinical PK, PD, and safety data, a dose of 20 mg/kg Q2W was selected for phase 2 studies. Conclusions: A population PK model of MEDI0680 was developed and validated. Modeling results indicate no need for dose adjustment based on patient/disease characteristics. Similar PK is expected following both WT-based and fixed dosing regimens. PK/PD findings support the dose of 20 mg/kg Q2W. Clinical studies are ongoing in various tumor types. Citation Format: Xuyang Song, Xizhe Gao, Bo Zheng, Chelsea Black, Matthew Gribbin, Joyson Karakunnel, Lorin Roskos, Rajesh Narwal. Pharmacokinetics and pharmacodynamics of MEDI0680, a fully human anti-PD1 monoclonal antibody, in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5045. doi:10.1158/1538-7445.AM2017-5045

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.