A Phase 2 Study of Loncastuximab Tesirine Plus Mosunetuzumab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background

While the majority of diffuse large B-cell lymphoma (DLBCL) patients are cured with frontline chemoimmunotherapy, up to 30-40% of patients will have refractory or relapsed (R/R) disease. Though treatment for R/R DLBCL has evolved with chimeric antigen-receptor (CAR) T, most of these patients will ultimately relapse with poor survival outcomes, and improved therapy for R/R DLBCL remains an unmet need.

Two novel therapies in DLBCL include loncastuximab tesirine (Lonca), an approved antibody-drug conjugate targeting CD19, and mosunetuzumab (Mosun), a CD3/CD20 bispecific antibody, which have both demonstrated promising response rates and safety in R/R DLBCL including in the post- CAR T setting. Here, we propose to combine Lonca and Mosun for the treatment of patients with R/R DLBCL. The rationale for combining these agents is multifold and includes 1) high responses seen with each agent (when used as single agent); 2) minimal overlapping toxicity profile; 3) distinct but potentially complementary mechanisms of action; 4) targeting of both CD19 and CD20, which may overcome antigen downregulation/escape mechanisms of resistance; and 5) outpatient administration.

We hypothesize that Lonca/Mosun will be safe and efficacious in R/R DLBCL.

Methods

This is a single-center, open-label, phase 2 investigator-initiated trial of Lonca/Mosun for patients with R/R DLBCL (NCT05672251). Eligibility includes R/RL DLBCL after ≥2 prior lines of therapy with CD20-positive, measurable disease . Patients who have received prior Lonca or CD3/CD20 bispecific antibodies, stem cell transplant or CAR T therapy within 30 days, active infection, systemic immunosuppression, or active central nervous system involvement are excluded.

The trial consists of a safety lead-in to evaluate the safety/tolerability of Lonca/Mosun and a Phase 2 stage to evaluate the anti-tumor activity of the regimen in the study population. During the safety lead-in, Lonca/Mosun will be administered at standard doses of both drugs in dose level 1. There will be a de-escalation dose level (dose level -1) where Mosun start is delayed to Cycle 2 Day 1, only if necessary. The safety lead-in segment (6 patients) will utilize a standard rolling six design based on observed toxicity during Cycles 1 & 2, and enrollment will be staggered for the first three patients in the safety lead-in. In the Phase 2 portion, study therapy will be administered at the final dose level deemed tolerable established during the safety lead-in. The phase 2 portion will use a Simon’s minimax two-stage design (total 26 patients). In the first stage, 12 patients will be enrolled (including the safety cohort), and if there is ≥ 6 responses the study will enroll an additional 14 patients in the second stage. The treatment will be considered encouraging if there are 15 or more responders in the 26 patients. Safety lead-in is ongoing at this time, with three patients enrolled thus far and no unacceptable toxicities or new safety signals.

Patients will receive up to 8-17 cycles of combined Lonca/Mosun therapy: participants who are in complete response (CR) after 8 cycles will stop protocol therapy after 8 cycles while patients who have partial response or stable disease after 8 cycles may continue protocol therapy for up to 17 cycles. Patients who were enrolled during the safety lead-in portion and treated at the final dose will also be included in the Phase 2 response evaluation if they are evaluable for response.

The primary objective is to evaluate the safety and preliminary activity of Lonca/Mosun in patients with R/R DLBCL, as measured by toxicities (type, timing, and severity) per the Common Terminology Criteria for Adverse Events v5.0 and overall response rate. The secondary objective of the study is to evaluate secondary measures of efficacy in patients with R/R DLBCL, as measured by CR rate, duration of response, progression-free survival, and overall survival. Lymphoma response will be evaluated using the 2014 Lugano classification.

Exploratory objective is to evaluate the tumor immune microenvironment (TME) and biomarkers of response to Lonca/Mosun. We will explore whether the response to Lonca/Mosun is associated with features of the TME, including density of and/or spatial relationships between immune cell populations, level of expression of CD19 and CD20, and genetic mutations particularly in immune-related genes.