Nemtabrutinib and Lisocabtagene Maraleucel for the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCT07194980 | Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: RG1125624NCI-2025-0640620853
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well the addition of nemtabrutinib to lisocabtagene maraleucel in treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Nemtabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lisocabtagene maraleucel is a type of treatment called chimeric antigen receptor (CAR) T-cell therapy, in which a patient's T-cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T-cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T-cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T-cells are grown in the laboratory and given to the patient by infusion for treatment. Adding nemtabrutinib to lisocabtagene maraleucel may be an effective treatment for relapsed/refractory CLL/SLL.

Conditions

Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (1)

• Complete response (CR)

  Will be defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Binary proportions will be estimated along with 95% confidence intervals. Confidence intervals for binary proportions will be estimated using the Wilson Score method.

  Up to 5 years after completion of study treatment

Secondary Outcomes (12)

• Overall response rate

  Up to 5 years after completion of study treatment

• Overall survival (OS)

  From first dose of protocol treatment to documentation of the first sign of disease progression or death from any cause, assessed up to 5 years after completion of study treatment

• Progression free survival (PFS)

  From first dose of protocol treatment to documentation of the first sign of disease progression or death from any cause, assessed up to 5 years after completion of study treatment

• Time to response (TTR)

  From start of protocol treatment to first documentation of response among participants documented to have a response, assessed up to 5 years after completion of study treatment

• Time to next treatment (TTNT)

  From start of protocol treatment to the start of a subsequent treatment, assessed up to 5 years after completion of study treatment

Study Arms (1)

Treatment (nemtabrutinib, lisocabtagene maraleucel)

EXPERIMENTAL

Patients receive nemtabrutinib PO daily on days 1-28 of each cycle (NOTE: nemtabrutinib is not given during lymphodepleting therapy). Cycles repeat every 28 days for up to 1 year after lisocabtagene maraleucel infusion in the absence of disease progression or unacceptable toxicity. Patients undergo leukapheresis 7 days after start of nemtabrutinib treatment. Patients receive SOC lymphodepleting therapy consisting of cyclophosphamide IV and fludarabine IV on approximately the 5th, 4th, and 3rd day prior to lisocabtagene maraleucel infusion. Patients then receive lisocabtagene maraleucel IV 36-96 hours after completion of SOC lymphodepleting therapy. Patients also undergo TTE or MUGA during screening, and PET/CT scans, bone marrow biopsy and aspiration, lymph node biopsy, and blood sample collection throughout the study.

Drug: Nemtabrutinib; Biological: Lisocabtagene Maraleucel

Interventions

Nemtabrutinib DRUG

Given PO

Also known as: ARQ 531, ARQ-531, ARQ531, Bruton's Tyrosine Kinase Inhibitor ARQ 531, BTK Inhibitor ARQ 531, MK-1026

Treatment (nemtabrutinib, lisocabtagene maraleucel)

Lisocabtagene Maraleucel BIOLOGICAL

Given IV

Also known as: Anti-CD19-CAR Genetically Engineered Autologous T Lymphocytes JCAR017, Anti-CD19-CAR Genetically Engineered Autologous T-lymphocytes JCAR017, Autologous Anti-CD19-EGFRt-4-1BB-zeta-modified CAR CD8+ and CD4+ T-lymphocytes JCAR017, Breyanzi, JCAR 017, JCAR-017, JCAR017, Liso-cel

Treatment (nemtabrutinib, lisocabtagene maraleucel)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed diagnosis of CLL/SLL per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) classification
• Measurable disease by imaging (lymph node \[LN\] \> 1.5cm) or absolute lymphocyte count (ALC) (\> 5000/μL) or marrow involvement of at least 30% by flow cytometry
• Eligible for lisocabtagene maraleucel (liso-cel) as standard-of-care per Food and Drug Administration (FDA) label for CLL/SLL
• At least 18 years of age at time of study enrollment
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• The ability to swallow and retain oral medication
• NOTE: Administration of nemtabrutinib is not permitted through a percutaneous endoscopic gastro-jejunal (J PEG) tube
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization
• Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis B screening tests should include HBsAg and anti-HBV. Hepatitis B screening tests are not required unless:
• Known history of HBV infection,
• As mandated by local health authority
• Absolute neutrophil count (ANC) ≥ 500/µL
• Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed
• No lower limit if cytopenia is related to bone marrow involvement
• Hemoglobin ≥ 8 g/dL

You may not qualify if:

• Diagnosis of Richter Transformation
• Active infection and uncontrolled infection
• Active HBV/hepatitis C virus (HCV) infection
• Participants must have completed curative anti-viral therapy for HCV at least 4 weeks prior to study enrollment
• Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to study enrollment
• Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention
• HIV with a detectable viral load or a CD4 count ≤ 350 cells/µL at time of screening
• Participants with HIV who do not meet the above criteria are eligible if they are on a stable antiretroviral therapy (ART) regimen (ART must not be strong CYP3A4 inducers) for at least 4 weeks prior to study entry and are compliant with ART are eligible
• Patients with an AIDS defining opportunistic infection in the past 12 months prior to screening
• Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy)
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Corrected QT interval (QTc) prolongation (defined as a QTc \> 450 msecs) or other significant electrocardiogram (ECG) abnormalities including second degree atrioventricular (AV) block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min)
• Known allergy/sensitivity to nemtabrutinib or any of the excipients
• Known prior progressive disease while on nemtabrutinib
• NOTE: Refer to the investigator's brochure (IB) for details regarding prior recipients of nemtabrutinib

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: collaborator
• Fred Hutchinson Cancer Center: lead

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ARQ531

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Mazyar Shadman, MD, MPH

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Fred Hutch Immunotherapy Intake

CONTACT

206-606-4668; immunotherapy@fredhutch.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 19, 2025
• First Posted: September 26, 2025
• Study Start (Estimated): May 29, 2026
• Primary Completion (Estimated): October 20, 2029
• Study Completion (Estimated): October 20, 2029
• Last Updated: May 1, 2026

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)