Trial in progress: A phase 1b study evaluating the safety, tolerability, and preliminary anti-tumor activity of NT-I7 (efineptakin alfa), a long-acting human IL-7, post-tisagenlecleucel in subjects with relapsed/refractory large B-cell lymphoma.

Abstract

TPS7596 Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy with tisagenlecleucel (Kymriah) is standard of care (SOC) for patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). CAR-T expansion is a strong predictor of response to this therapy. NT-I7 (efineptakin alfa) is a first in-class, long-acting human IL-7 previously shown clinically in solid tumor studies to increase the number and functionality of T-cells in peripheral blood and within tumors. In a CD19+ lymphoma xenograft mouse model that received anti-CD19 universal CAR-T infusion, NT-I7 treatment prolonged survival and enhanced CAR-T gene expression of functional markers, proliferation, persistence, and tumor killing. We hypothesize that NT-I7 administration after tisagenlecleucel SOC for subjects with r/r LBCL may increase expansion and persistence of CAR-T, leading to increased tumor response rate and improved clinical outcomes without safety concerns. Methods: This phase 1b study consists of a dose-escalation phase followed by a dose expansion. In dose escalation, subjects receive tisagenlecleucel infusion on Day 0 and a single dose of NT-I7 on Day 21, at 7 dose levels (DLs 1-7): 60, 120, 240, 360, 480, 600, and 720 μg/kg. DLs 1 and 2 will enroll 1 subject each, followed by a 3+3 design for the remaining DLs. Up to 42 subjects will be enrolled for the dose-escalation phase and up to 15 subjects in the dose-expansion phase, treated at the recommended phase 2 dose (RP2D). Eligible subjects are ≥18 years of age with biopsy-proven diagnosis of r/r LBCL after ≥2 lines of systemic therapy, including diffuse LBCL (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Subjects must be eligible for tisagenlecleucel as SOC. Subjects who have received prior CD19-directed therapy are ineligible. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) and/or RP2D for NT-I7 with this regimen. Secondary objectives are to explore the anti-tumor activity of this regimen for r/r LBCL. The effect of NT-I7 after tisagenlecleucel infusion on the safety profile regarding Grade ≥3 Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) will also be evaluated. Exploratory objectives are to assess pharmacokinetic parameters of tisagenlecleucel with NT-I7 administration, and correlative studies will evaluate the effects of this regimen not limited only to the expansion of lymphocytes and serum cytokines. As of January 3, 2022, 2 subjects have received NT-I7 in the dose-escalation phase at DL1 and DL2. Clinical trial information: NCT05075603.