Nemtabrutinib + Lisocabtagene Maraleucel for CLL/SLL

Overseen By Fred Hutch Immunotherapy Intake

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: CYP3A inducers, inhibitors

Disqualifiers: Richter Transformation, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: Up to 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) that has returned or is unresponsive to other treatments. The study tests whether adding nemtabrutinib, a drug that blocks cancer cell growth, to the immune therapy lisocabtagene maraleucel can be effective. This immune therapy modifies a person's immune cells to better attack cancer cells. The trial seeks participants with CLL/SLL who have measurable disease and are suitable for the immune therapy. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop taking my current medications to join the trial?

The trial requires a washout period (time without taking certain medications) for drugs that are P-gp substrates with a narrow therapeutic index, CYP3A strong inducers, or CYP3A strong inhibitors. This means you may need to stop taking these specific medications before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that lisocabtagene maraleucel, or liso-cel, has a manageable safety profile for patients with relapsed or hard-to-treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients tolerated the treatment well, and no new safety concerns emerged.

Research on nemtabrutinib also indicates a manageable safety profile. Earlier studies showed that patients with relapsed CLL who took nemtabrutinib experienced promising results with controllable side effects.

Both treatments have been tested in other studies, demonstrating safe use in people. However, individual experiences may vary, so discussing any concerns with the medical team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Nemtabrutinib and Lisocabtagene Maraleucel for CLL/SLL because it offers a novel approach by combining a targeted therapy with a cell-based therapy. Nemtabrutinib is a Bruton's tyrosine kinase (BTK) inhibitor, which interferes with signals that help cancer cells survive, while Lisocabtagene Maraleucel is a CAR T-cell therapy that engineers a patient's own immune cells to target and destroy cancer cells. This dual-action strategy aims to improve treatment effectiveness by both directly targeting cancer cells and boosting the immune system's ability to fight the disease, which could potentially lead to better outcomes than current therapies like chemotherapy or single-agent BTK inhibitors.

What evidence suggests that the combination of nemtabrutinib and lisocabtagene maraleucel might be an effective treatment for relapsed/refractory CLL/SLL?

Studies have shown that lisocabtagene maraleucel (liso-cel) effectively treats chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) when they return or resist other treatments. Many patients experienced a complete response, with their cancer shrinking or disappearing. On average, these positive effects lasted over 35 months. Research has also indicated that nemtabrutinib, a Bruton tyrosine kinase (BTK) inhibitor, showed promising results in early studies. This trial will evaluate the combination of lisocabtagene maraleucel and nemtabrutinib, which might offer a strong approach to fighting CLL and SLL. ^{1 2 3 6 7}

Who Is on the Research Team?

Mazyar Shadman, MD, MPH

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for people with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that has either returned after getting better or hasn't responded to other treatments. Specific eligibility criteria are not provided, but typically participants would need to meet certain health standards and have a history of CLL/SLL.

Inclusion Criteria

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)

Absolute neutrophil count (ANC) ≥ 500/µL

Hemoglobin ≥ 8 g/dL

Exclusion Criteria

Is currently enrolled on another therapeutic clinical trial

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

Known allergy/sensitivity to nemtabrutinib or any of the excipients

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive nemtabrutinib orally daily on days 1-28 of each cycle, with cycles repeating every 28 days for up to 1 year after lisocabtagene maraleucel infusion. Patients also undergo leukapheresis, lymphodepleting therapy, and receive lisocabtagene maraleucel IV.

Up to 1 year

Multiple visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, including PET/CT scans, bone marrow biopsy, and blood sample collection.

5 years

Periodic visits for monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Lisocabtagene Maraleucel
• Nemtabrutinib

Trial Overview The study is testing the effectiveness of combining nemtabrutinib, an enzyme inhibitor, with lisocabtagene maraleucel, a CAR T-cell therapy where modified immune cells attack cancer cells. This phase II trial aims to see if this combination works better for relapsed/refractory CLL/SLL patients.

How Is the Trial Designed?

Group I: Treatment (nemtabrutinib, lisocabtagene maraleucel) Experimental Treatment 2 Interventions

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.

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4633/529893/Lisocabtagene-Maraleucel-liso-cel-in-Patients-pts

Lisocabtagene Maraleucel (liso-cel) in Patients (pts) with ... Median duration of response (DOR) was 35.3 mo (95% CI, 12.4-not reached [NR]), and median OS was 30.3 mo (95% CI, 15.0-NR) (Siddiqi T, et al.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37295445/

a multicentre, open-label, single-arm, phase 1-2 study - PubMed We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or ...

3. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(23)01052-8/fulltext

Lisocabtagene maraleucel in chronic lymphocytic ... The study met its primary endpoint, with liso-cel achieving a rate of complete response or remission (including with incomplete marrow recovery) ...

4. asco.org asco.org/abstracts-presentations/ABSTRACT409614

Lisocabtagene maraleucel (liso-cel) in R/R chronic ... Key secondary endpoints were ORR (H0: ≤ 40%) and rate of undetectable minimal residual disease (uMRD; 10−4) in blood (H0: ≤ 5%). Results: Of 137 leukapheresed ...

5. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper200339.html

Paper: Lisocabtagene Maraleucel (liso-cel) Combined with ... Results: A total of 65 pts underwent leukapheresis; 56 received ibr + liso-cel (DL1, n = 5; DL2, n = 51). At data cutoff (01/12/2024), 28 of 56 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06205290

NCT06205290 | A Study to Compare the Efficacy and ... The purpose of this study is to compare the efficacy and safety of liso-cel vs Investigator's Choice options (idelalisib + rituximab or bendamustine + rituximab) ...

7. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(23)01097-2/fulltext

CLL-094 Lisocabtagene Maraleucel (liso-cel) in R ... Liso-cel demonstrated durable CR/CRi, high uMRD rates, and manageable safety profile in patients with heavily pretreated, high-risk R/R CLL/SLL. Funding.