First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas

Abstract

Background: GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.

Methods: Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10-1500 mg) or GWN323+spartalizumab (GWN323 10-750 mg+spartalizumab 100-300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1.

Results: Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures.

Conclusions: GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.

Trial registration number: NCT02740270.

Keywords: antibodies; clinical trials as topic; combination; drug therapy; investigational; neoplasm; therapies.

Figure 1

Best percentage change and best overall response by investigator assessment (RECIST V.1.1) in patients with target lesions in the single-agent arm. n is the number of patients with ≥1 baseline and postbaseline assessment of target lesions. CR, complete response; GWN, GWN323; PD, progressive disease; PR, partial response; q3w, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; UNK, unknown.

Figure 2

Best percentage change and best overall response by investigator assessment (RECIST V.1.1) in patients with target lesions in the combination arm. # indicates percentage changes from baseline of >100% are set to 100%. n indicates the number of patients with ≥1 baseline and postbaseline assessment of target lesions. CR, complete response; GWN, GWN323; PD, progressive disease; PR, partial response; q3w, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; UNK, unknown.

Figure 3

Effect of treatment on (A) proliferating CD8 and NK cells and (B) effector memory CD8 cells (flow cytometry data). Blood was collected and PBMCs were isolated at screening, C1D8 and C2D1. PBMCs were stained to identify the percentages of proliferating CD8 and NK cells (A) as well as effector memory T cells (B). BOR categories are indicated by shape, and doses of GWN±spartalizumab are color coded. BOR, best overall response; C, cycle; CR, complete response; D, day; GITR, glucocorticoid-induced tumor necrosis factor receptor; GWN, GWN323; NK, natural killer; PBMC, peripheral blood mononuclear cell; PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown.

Figure 4

Immunohistochemistry data for the (A) single-agent and (B) combination arms. Immunohistochemistry was performed on paraffin-embedded sections of the tumor samples collected at screening, C2D1 and C4/5/6D1. Visits are color coded. BPC, best percent change in tumor size; C, cycle; CR, complete response; D, day; PD, progressive disease; PR, partial response; SD, stable disease; TMB, tumor mutational burden; UNK, unknown.