A phase I dose escalation trial of BCD-145 in patients with unresectable or metastatic melanoma.

9526 Background: BCD-145 (nurulimab) is a fully human IgG1 mAb with modified Fc-fragment (the 1 st Gln is replaced by Glu in the heavy chain sequence, and there is no terminal dipeptide composed by Gly and Lys residues) that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction between CTLA-4 and its ligands. This allows to stimulate T-cell proliferation, cytokine production and induces antitumor immune response. Here we present the results of multicenter open-label single-arm multi-cohort phase I trial of pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity of BCD-145 in pts with unresectable/metastatic melanoma (unr/mM). Methods: BCD-145 monotherapy in 3+3 dose escalation 0.1, 0.3, 1, 3, 10 mg/kg intravenously Q3W was given to 15 pts with unr/mM with measurable disease, who had failed prior therapy, ECOG 0-2. Pts with brain mts, previous therapy with aCTLA-4 and/or aPD-1/PD-L1 drugs were not allowed. The main objective of the study was to evaluate PK, PD, tolerability, immunogenicity, safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) identification. Secondary objectives included tumor response rate (irRECIST). Results: BCD-145 proved safety and overall was well tolerated. DLT and MTD were not reached. Any grade (Gr) adverse events (AEs) occurred in 100% (15/15) of pts. 33.3% (5/15) of pts had AE/SAE of Gr 3-4, including hypertension Gr 3 (1 at 1 mg/kg), hypercalcemia Gr 4 (2 at 1 mg/kg), hypokalemia Gr 3 (2 at 1 mg/kg), neutropenia Gr 3 (1 at 0.3 mg/kg), anemia Gr 3 (1 at 1 mg/kg), lung infection Gr 3 with hospitalization (1 at 1 mg/kg). Only 2 pts had a treatment-related AE Gr 3-4. Immuno-related AE were identified in 46.7% (7/15), manifested by symptoms of thyroiditis (mainly Gr 1) and diarrhea Gr 2 (1 at 10 mg/kg). There was 1 death (at 1 mg/kg) due to progression. There is dose-dependent peak study drug serum concentrations and systemic exposure. Two dosage regimens (1 mg/kg, 3 mg/kg Q3W) allowed to achieve the optimal concentration. BCD-145 increased subpopulations of activated HLA-DR+ CD4+ and CD8+ T lymphocytes, CD4+ICOS+ T-lymphocytes, absolute lymphocyte counts in all cohorts without significant differences. Binding and neutralizing Abs against BCD-145 were detected in 2 pts from different dose cohorts (0.3 mg/kg, 1 mg/kg). PR and SD were registered in 2 pts of each response group. 30.8% of pts achieved disease control, which is consistent with published data on other CTLA-4 inhibitors. A dose of 1 mg/kg is determined as recommended phase 2 dose (RP2D). Conclusions: BCD-145 demonstrated a tolerable safety profile and preliminary anti-tumor activity in pts with unr/mM. Anti-tumor effects of BCD-145 were observed in pts who had progressed on prior treatment. Further co-targeting PD-1 and CTLA-4 simultaneously will achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Clinical trial information: NCT03472027 .