1020O A phase I, first-in-human, open-label, dose escalation study of MGD019, an investigational bispecific PD-1 x CTLA-4 DART® molecule in patients with advanced solid tumours

Background MGD019 is a bispecific, Fc-bearing (IgG4) DART molecule that blocks PD-1 and CTLA-4, with increased activity on dual PD-1/CTLA-4-expressing cells. MGD019 enhances in vitro T-cell responses to levels achieved by a combination of nivolumab and ipilimumab replicas. MGD019 was well tolerated in cynomolgus monkeys, with biological evidence of CTLA-4 antagonism but a safety profile similar to PD-1 blockade alone. MGD019 may offer risk/benefit improvements vs PD-1 plus CTLA-4 combinations. Methods This study characterizes safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and preliminary antitumor activity of MGD019 in patients (pts) with advanced solid tumors. Dose Escalation enrolled pts in a 3+3+3 design up to 10 mg/kg. Cohort Expansion will further characterize safety and antitumor activity per RECIST v1.1 in pts treated at the MTD/MAD. Results At data-cutoff, 33 pts (39% checkpoint-experienced, 3 median prior lines of therapy) were treated in Dose Escalation from 0.03 to 10 mg/kg. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 26/33 (78.8%) pts, most commonly fatigue (24%), nausea, arthralgia, pruritus, and rash (18% each). The rate of Grade ≥ 3 TRAEs was 24.2%. Immune-related SAEs included enteritis, enterocolitis, pneumonitis, and myocarditis (n=1 each). Half-life was 12 days; full on-target binding to circulating T cells sustained through trough was observed at doses ≥ 3.0 mg every 3 weeks. Among 25 response-evaluable pts, 4 objective responses were observed (microsatellite stable colorectal cancer, metastatic thymoma [both confirmed PRs], anti-PD-L1-refractory serous fallopian tube carcinoma [unconfirmed PR with \u3e50% reduction of CA-125], and prostatic adenocarcinoma [confirmed CR with resolution of PSA]); 9 pts had stable disease. Dose-dependent ICOS upregulation on circulating CD4+ T cells was evident, consistent with CTLA-4 engagement. Potential correlative biomarkers are being investigated. Conclusions MGD019 has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Clinical trial identification NCT03761017