A Phase 2/3, Randomized, Double Blind, Placebo-Controlled, Multicenter Study of NKTR-255 Vs Placebo Following CD-19 Directed CAR-T Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Background: Autologous T cells engineered to express a CD19-directed chimeric antigen receptor (CAR) have shown high overall response rates in treatment-refractory CD19+ B-cell non-Hodgkin lymphoma (NHL). However, over half of these patients will have lymphoma that fails to achieve remission or will relapse; thus, strategies to further improve the long-term efficacy of CAR-T cell products are needed. NKTR-255 is a novel investigational polymer-conjugated IL-15 agonist, designed to activate, proliferate and expand natural killer (NK) and CD8+ T-cells in vivo. NKTR-255 also promotes the survival and expansion of memory CD8+ T cells. Preclinical data in B-cell lymphoma xenograft models have shown that NKTR-255 enhanced expansion, survival, and anti-tumor activity of human CD19 CAR-T cells. Further, clinical studies have demonstrated that NKTR-255 promoted CD8+ T cell expansion in patients with relapsed/refractory (r/r) NHL who previously received CAR-T cell therapy (NCT04136756). Here, we describe a planned Phase 2/3 clinical trial of NKTR-255 following CAR-T cell therapy.

Methods: This is a phase 2/3, randomized, double blind, placebo-controlled, multicenter study of NKTR-255 vs placebo following CD-19 directed CAR-T therapy. Eligible patients who have r/r large B-cell lymphoma and are planned for treatment with an FDA-approved CAR-T product (axi-cel or liso-cel) will be enrolled. All patients will receive initial study drug administration of NKTR-255 intravenously, starting approximately 14 days following CAR-T therapy, with continued dosing every 21 days. The study will be comprised of two stages: 1) Phase 2: patients will be randomized to placebo or one of multiple dose cohorts of NKTR-255 (Stage 1) and 2) Phase 3: patients will be randomized to placebo or the selected NKTR-255 dose regimen (Stage 2). The primary objective for Stage 1 is to identify the dose of NKTR-255 for the Phase 3 part of the study based on the safety and tolerability of NKTR-255 as well as the complete response rate (CRR) at month 6. The primary efficacy endpoints of Stage 2 are CRR at month 6 and event-free survival. Efficacy analyses will be performed separately for Stage 1 and Stage 2. Efficacy, as measured by PET-CT, will be evaluated according to the Lugano Criteria (Cheson 2014). The key eligibility criteria following CD19 targeted CAR-T cell infusion include no grade ≥ 1 cytokine release syndrome (CRS) on the day of NKTR-255 administration, no grade ≥ 3 CRS within 72 hours proceeding NKTR-255 administration, no grade ≥ 3 immune effector cell-associated neurotoxicity (ICANS) of > 72 hours duration, no grade ≥ 2 ICANS on the day of NKTR-255 infusion and no tocilizumab and/or dexamethasone within 48 hours proceeding NKTR-255 administration.

Conclusions: Based on preclinical and clinical evidence, NKTR-255 has the potential to improve efficacy of currently approved cellular therapies. This trial evaluates safety and efficacy of NKTR-255 following commercial CD19 CAR-T therapy to enhance antitumor effect and durability of responses.