Nemtabrutinib plus lisocabtagene maraleucel for relapsed or refractory CLL/SLL

Safety and Efficacy of the Addition of Nemtabrutinib to Lisocabtagene Maraleucel in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

This will test whether adding the oral drug nemtabrutinib to lisocabtagene maraleucel (CAR T‑cell therapy) helps people with CLL/SLL that has come back or stopped responding to prior treatment.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fred Hutchinson Cancer Center (other)
• Drugs / interventions: nemtabrutinib, radiation, prednisone, CAR T, chimeric antigen receptor, cyclophosphamide, fludarabine
• Locations: 1 site (Seattle, Washington)
• Trial ID: NCT07194980 on ClinicalTrials.gov

What this trial studies

This phase II study combines oral nemtabrutinib with lisocabtagene maraleucel (liso‑cel), a CAR T‑cell therapy, for adults with relapsed or refractory CLL/SLL. Nemtabrutinib is taken daily in 28‑day cycles, with leukapheresis performed about 7 days after starting the drug and nemtabrutinib held during lymphodepleting chemotherapy. Patients receive standard cyclophosphamide and fludarabine lymphodepletion followed by liso‑cel infusion 36–96 hours later, and may continue nemtabrutinib for up to one year after infusion if there is no progression or unacceptable toxicity. Participants undergo imaging, biopsies, and blood monitoring during treatment and are followed for five years after completion of study treatment.

Who should consider this trial

Good fit: Adults (≥18 years) with confirmed relapsed or refractory CLL/SLL who have measurable disease, are eligible for lisocabtagene maraleucel per label, have ECOG 0–2, and can swallow oral medication are the intended candidates.

Not a fit: Patients who cannot undergo leukapheresis, are not candidates for lymphodepleting chemotherapy or CAR T infusion, or who have uncontrolled organ dysfunction or active severe infection are unlikely to benefit from this approach.

Why it matters

Potential benefit: If successful, the combination could produce deeper or longer remissions for people with relapsed or refractory CLL/SLL compared with CAR T therapy alone.

How similar studies have performed: CAR T‑cell therapy has produced durable remissions in some CLL patients, and early work combining BTK inhibitors with CAR T approaches is promising, but this specific nemtabrutinib plus liso‑cel combination remains under investigation.

Eligibility criteria

Inclusion Criteria:

* 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

  * 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
* Platelets ≥ 25 000/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
* Creatinine ≤ 1.5 × upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or CrCl) ≥ 30 mL/min for participant with creatinine levels \> 1.5 × institutional ULN

  * Creatinine clearance (CrCl) should be calculated per institutional standard
* Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 × ULN
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase \[SGPT\]) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases)
* International normalized ratio (INR) OR prothrombin time (PT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
* Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Cardiac (echocardiogram \[Echo\] or multi-gated acquisition scan \[MUGA\]) ejection fraction ≥ 40%

Exclusion Criteria:

* Diagnosis of Richter Transformation
* Clinically significant (symptomatic) central nervous system (CNS) involvement at time of study enrollment. Previously treated CNS disease is allowed if the participant is asymptomatic. Incidental findings including positive cerebral spinal fluid (CSF) studies are not exclusionary
* 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
* History of severe bleeding disorder defined as an ongoing congenital or acquired condition that leads to an increased likelihood of bleeding
* History of a second malignancy

  * NOTE: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder
* A participant of childbearing potential (POCBP) who has a positive urine pregnancy test within 72 hours prior to study enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

  * Note: In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for participant to start receiving study medication
* Need or anticipation of need for additional bridging therapy in addition to nemtabrutinib

  * Palliative radiation therapy for less than 2 weeks or the use of prednisone 30mg (or the prednisone equivalent) for a maximum of 5 days is allowed and is not exclusionary
* Currently being treated with the following drugs:

  * P-gp substrates with a narrow therapeutic index
  * CYP3A strong inducers
  * CYP3A strong inhibitors
  * NOTE: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment
* Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of inactivated vaccines are allowed
* Is currently enrolled on another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* Has not adequately recovered after 4 weeks from major surgery or has ongoing surgical complications

  * Note: Biopsy and placement of central venous access devices are not considered major surgery
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Any condition or history that the study investigator deems not in the best interest of the patient to participate

Where this trial is running

Seattle, Washington

• Fred Hutch/University of Washington Cancer Consortium — Seattle, Washington, United States (RECRUITING)

Study contacts

• Principal investigator: Mazyar Shadman, MD, MPH — Fred Hutch/University of Washington Cancer Consortium
• Study coordinator: Fred Hutch Immunotherapy Intake

Conditions: Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma