AFFILIATIONS
1 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
2 Fred Hutchinson Cancer Center, Seattle, Washington, United States
3 Fred Hutchinson Cancer Center, Seattle, Washington, United States
4 Fred Hutchinson Cancer Center, Seattle, Washington, United States
5 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
6 University of Washington, Seattle, Washington, United States
7 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
8 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
9 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
10 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
11 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
12 Fred Hutchinson Cancer Center, Seattle, Washington, United States
13 Fred Hutchinson Cancer Center, Seattle, Washington, United States
14 Fred Hutchinson Cancer Center, Seattle, Washington, United States
15 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
16 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
17 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
18 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
19 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
20 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
21 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
22 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
23 Fred Hutchinson Cancer Center, Seattle, Washington, United States, University of Washington, Seattle, Washington, United States
ABSTRACT
Background
Lisocabtagene maraleucel (liso-cel) is approved for the treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) after exposure to a Bruton tyrosine kinase inhibitor (BTKi) and a BCL-2 inhibitor. Its approval for CLL/SLL was based on the TRANSCEND CLL 004 clinical trial, which showed a complete response (CR) or CR with incomplete marrow recovery rate of 20%. This leaves room for improving the efficacy of liso-cel.
Multiple pre-clinical studies have demonstrated the benefit of combining the first-generation BTKi ibrutinib with CAR T-cells to enhance efficacy and reduce toxicity, potentially by promoting CAR T-cell expansion and decreasing T-cell exhaustion. Additional data suggest that ibrutinib-mediated improvement in T-cell exhaustion may involve both BTK dependent and independent pathways.
Clinical studies have further supported the benefit of concurrent BTKi treatment. In a phase 1/2 clinical trial evaluating ibrutinib in combination with an investigational CAR T-cell product in patients with CLL who had progressed on ibrutinib, the combination was associated with lower CRS severity. The ibrutinib cohort of the TRANSCEND CLL 004 clinical trial also showed improved efficacy over liso-cel monotherapy. Real-world studies have also demonstrated the potential benefit of bridging with BTK inhibitors (Huang, et al., ASH 2025).
Nemtabrutinib is a non-covalent BTKi and represents the ideal partner in combination with liso-cel given its potential monotherapy activity in patients who are either intolerant to BTKis or have developed resistance mutations to covalent BTKis. In contrast to pirtobrutinib, another non-covalent BTKi, nemtabrutinib targets BTK dependent and independent pathways, both mechanisms through which ibrutinib improves CAR T-cell fitness. We thus propose the addition of nemtabrutinib to liso-cel to assess whether it can improve CAR T-cell efficacy without increasing toxicity.
Study Design and Methods
NemCAR is a single-arm, single-center, phase II study (NCT07194980) to assess the efficacy of nemtabrutinib in combination with lisocabtagene maraleucel (liso-cel). Liso-cel will be administered per FDA-approved dosing. Nemtabrutinib 65mg will be started at least 7 days prior to leukapheresis and continue until 1 year after liso-cel infusion or disease progression, intolerance, or unacceptable toxicity, whichever occurs first. This work was supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme LLC.
Inclusion/Exclusion Criteria
Patients must have a confirmed diagnosis of CLL/SLL and meet criteria for treatment per iwCLL criteria and have measurable disease. They also must be eligible for standard-of-care liso-cel per the FDA label. Patients must have an ECOG status of 0-2. Patients with Richter Transformation and symptomatic CNS disease are excluded.
Objectives
Primary Objective:
To evaluate the rate of complete response per iwCLL criteria of the addition of nemtabrutinib to lisocabtagene maraleucel in patients with R/R CLL/SLL.
Secondary Objectives:
To evaluate the efficacy of clinical endpoints including overall response rate, overall survival, progression free survival, time to response, and time to next treatment.
To assess adverse events that occur during combination therapy.
To evaluate the incidence, time to onset, and resolution of cytokine release syndrome and immune effector-cell associated neurotoxicity syndrome.
Exploratory Objectives:
To assess measurable disease status by flow cytometry and next generation sequencing.
To identify any BTK resistance mutations, if any, that may occur at time of progression.
Statistical Considerations
The design of the study is a 2-stage phase design with 90% power to rule out a 20% complete response rate at the one-sided 5% level if the true response rate were 52%. The planned sample size is 20 participants evaluable for response, enrolled in two stages with 10 evaluable participants enrolled in the first stage.
With 20 participants, binary proportions can be estimated within 22% with 95% confidence and will be estimated using the Wilson Score method. The distribution of time to event outcomes will be estimated using the method of Kaplan-Meier.
Summary
NemCAR will evaluate the safety and efficacy of the combination of nemtabrutinib with liso-cel for patients with R/R CLL/SLL. This trial is actively enrolling at Fred Hutch Cancer Center/University of Washington.