GNC-038, a tetra-specific antibody, in patients with R/R non-Hodgkin lymphoma or acute lymphoblastic leukemia: A phase 1 study design and rationale

TPS2668 Background: Bispecific T cell engagers can mediate single antigen-specific cell cytolysis, but cannot preempt clonal relapse, or modify the immunosuppressive cancer cell surfaceome. The first-in-class octavalent, CD19xCD3x4-1BBxPD-L1 tetra-specific antibody, GNC-038, functions as a CD19-specific T cell engager by mediating direct antitumor activity, but further, GNC-038 overcomes inhibition of T cells by PD-L1 based on its 4 binding sites. The antitumor activity of GNC-038 is mediated by activating CD3 and 4-1BB signaling on T cells and targeting high expression of CD19 or PD-L1 on tumor cells. Preclinical studies showed GNC-038 has robust anti-tumor activity. Considering its favorable tolerance and pharmacokinetics in cynomolgus monkeys, we developed a phase I study to investigate GNC-038 for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL) and relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: Patients diagnosed with relapsed/refractory non-Hodgkin lymphoma or acute lymphoblastic leukemia are currently being enrolled in this phase I study to evaluate the safety, tolerability and pharmacokinetics of GNC-038. This study will be conducted in two phases, dose-escalation (Ia) and dose-expansion (Ib). During the dose escalation phase, R/R-NHL patients will receive GNC-038 (0.016-6 μg/kg/d) as continuous intravenous (cIV) infusion for 8 weeks. Further escalation will be conducted with step-up dosing: cIV infusion of 3.6 μg/kg/d GNC-038 will be administered during week 1 followed by higher doses on subsequent weeks (9, 13.5, 20.25 or 30 μg/kg/d). R/R-ALL patients will receive GNC-038 by cIV infusion for 8 weeks (0.016-16 μg/kg/d). During the dose-expansion phase, one or more dosages will be chosen for further investigation in specific indications. The primary endpoints are dose limiting toxicity (DLT), maximum tolerated dose (MTD), treatment emergent adverse events (TEAE) and recommended phase 2 dose (RP2D). Secondary endpoints are adverse events (AEs), pharmacokinetics, objective response rate (ORR), duration of response (DOR), progression free survival (PFS) and overall survival (OS). Exploratory endpoints are biomarker assessment, anti-drug antibody (ADA) and pharmacodynamics. The dose expansion phase (Ib) has been initiated. Clinical trial information: NCT04606433 .