Nemtabrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Recruiting at 71 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: BCL2 inhibitors, BTK inhibitors

Disqualifiers: Active infection, CNS involvement, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

735 Participants Needed

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 (CLL) or small lymphocytic lymphoma (SLL) that has recurred or resisted other treatments. Researchers aim to determine if combining nemtabrutinib (also known as MK-1026 or ARQ 531) with venetoclax is more effective at preventing cancer growth than the combination of venetoclax and rituximab. Individuals diagnosed with CLL/SLL who have tried at least one other treatment without success might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants early access to potentially effective treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude participants who are currently being treated with certain medications like p-glycoprotein substrates, CYP3A inducers, or inhibitors. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

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

Research has shown that nemtabrutinib has been tested in people with blood cancers and is generally well-tolerated. In studies, most patients did not experience severe side effects, though some reported mild issues like tiredness or nausea.

Venetoclax, another part of the treatment, has already received FDA approval for certain blood cancers, indicating a known safety profile. It is generally considered safe but can cause side effects like low blood cell counts or digestive problems.

Researchers are carefully studying the combination of nemtabrutinib and venetoclax to ensure safety. Both drugs have shown promise, but monitoring for potential side effects during the trial remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of nemtabrutinib and venetoclax for treating Chronic Lymphocytic Leukemia (CLL) because nemtabrutinib offers a novel mechanism of action by targeting Bruton's tyrosine kinase (BTK), which plays a critical role in the survival and proliferation of B-cells involved in CLL. This is different from traditional treatments like chemoimmunotherapy, which often target the cancer cells more broadly. Additionally, combining nemtabrutinib with venetoclax, which disrupts cancer cell survival by inhibiting the BCL-2 protein, could potentially enhance treatment efficacy by attacking the cancer cells from multiple angles. Unlike standard treatments that might have limitations in terms of resistance and side effects, this combination aims to improve outcomes and reduce disease progression with a more targeted approach.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research shows that combining the drugs nemtabrutinib and venetoclax, which participants in this trial may receive, holds promise for treating chronic lymphocytic leukemia (CLL). Studies have found that venetoclax effectively targets cancer cells in CLL, while nemtabrutinib is under investigation for its potential to assist when other treatments, like ibrutinib, fail. A recent study suggested that using nemtabrutinib with venetoclax might benefit patients who haven't responded well to other therapies. Another treatment arm in this trial involves venetoclax combined with rituximab, which has shown better results in patients previously treated with venetoclax-based treatments. Overall, these treatments might offer a better chance of controlling the disease. ^{1 2 3 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for people with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma who have tried at least one therapy before. They must be able to take oral meds, not be pregnant or breastfeeding, and use effective contraception if necessary. They should have a life expectancy of over 3 months and good organ function.

Inclusion Criteria

I have been diagnosed with CLL/SLL and need treatment.

My organ function is good, tested within the last week.

I am HBsAg positive but have been on HBV therapy for 4 weeks with undetectable HBV DNA.

Exclusion Criteria

I am still recovering from major surgery or have complications.

Has a known psychiatric or substance use disorder that would interfere with the participant's ability to cooperate with the requirements of the study

I am HIV-positive with a history of specific conditions or infections in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nemtabrutinib plus venetoclax or venetoclax plus rituximab for up to 2 years or until progressive disease

Up to 2 years

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 71 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Nemtabrutinib
• Rituximab
• Venetoclax

Trial Overview The study tests the combination of Nemtabrutinib plus Venetoclax against Venetoclax with Rituximab in treating CLL/SLL. It aims to see if the new combo improves how long patients live without their disease getting worse compared to the existing treatment option.

How Is the Trial Designed?

Group I: Nemtabrutinib + Venetoclax Experimental Treatment 2 Interventions

Participants will receive nemtrabrutinib oral tablets at specified doses daily starting at Cycle 1 Day 1 (C1D1) and venetoclax oral tablets at doses of 20 mg up to 400 mg daily starting at Cycle 2 Day 1 (C2D1) up to 2 years post C2D1 or until progressive disease (PD) or discontinuation. A cycle = 4 weeks.

Group II: Venetoclax + Rituximab Active Control 2 Interventions

Participants will receive venetoclax oral tablets at doses from 20 mg up to 400 mg daily starting at C1D1 on 4-week cycles up to 2 years and rituximab or biosimilar at 375 mg/m\^2 up to 500 mg/m2 intravenous infusion once per 28-day cycle starting at C2D1, for 6 total cycles. Treatment will continue until progressive disease (PD) or discontinuation.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead 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

Published Research Related to This Trial

In a study involving 127 patients with relapsed or refractory chronic lymphocytic leukaemia who had previously been treated with ibrutinib, 65% showed an overall response to venetoclax, indicating its effectiveness as a treatment option for those who did not respond to ibrutinib.

Venetoclax was found to have a favorable safety profile, with no treatment-related deaths reported, although common side effects included neutropenia and thrombocytopenia, which were observed in a significant number of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Jones, JA., Mato, AR., Wierda, WG., et al.[2021]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Three new oral small molecule inhibitors—ibrutinib, idelalisib, and venetoclax—have been approved for chronic lymphocytic leukemia (CLL) treatment in the last four years, showing excellent efficacy.

These inhibitors have different toxicity profiles, which is important for tailoring treatment, especially in older patients, and raises questions about how to best sequence their use in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches to Chronic Lymphocytic Leukemia Therapy in the Era of New Agents: The Conundrum of Many Options. Jain, N., Thompson, P., Ferrajoli, A., et al.[2020]

The HOVON 141/VISION trial is investigating the combination treatment of ibrutinib and venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia (RR-CLL), focusing on the possibility of stopping ibrutinib in patients who achieve undetectable minimal residual disease (uMRD) after 12 cycles of treatment.

The primary goal of the study is to assess progression-free survival 12 months after randomization, providing insights into the long-term efficacy and safety of discontinuing ibrutinib in patients who have reached deep remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance ≥30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations. Levin, MD., Kater, AP., Mattsson, M., et al.[2021]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

Venetoclax is an effective oral medication for treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), showing significant efficacy when combined with other therapies like obinutuzumab and azacitidine.

While venetoclax is associated with adverse events such as neutropenia and gastrointestinal disorders, the article emphasizes the importance of managing these side effects to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia. Waggoner, M., Katsetos, J., Thomas, E., et al.[2022]

A study analyzing 19,107 adverse event reports related to venetoclax (VEN) identified significant unexpected serious adverse events, including pleural effusion and atrial fibrillation, highlighting the need for careful monitoring of patients.

The median time for these adverse events to occur was 31 days after starting VEN treatment, with many events happening within the first month, indicating that early detection and management of side effects are crucial for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for venetoclax. Yang, Y., Shu, Y., Chen, G., et al.[2023]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04728893

NCT04728893 | Efficacy and Safety of Nemtabrutinib (MK- ... The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10855898/

Treatment of Double-Refractory Chronic Lymphocytic ... This review explores the resistance mechanisms for both ibrutinib and venetoclax. Moreover, we present innovative approaches evaluated for treating double- ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-09870

Efficacy and Safety of Nemtabrutinib (MK-1026) in ... The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies.

4. sciencedirect.com sciencedirect.com/science/article/pii/S000649712500864X

Doubling down: the new deal in the clinical management of ... PJ Hampel, KG Rabe, Y Wang, et al. Clinical outcomes with venetoclax-based treatment regimens in patients with chronic lymphocytic leukemia (CLL) ...

5. msdclinicaltrials.com msdclinicaltrials.com/trial/nct05947851/

A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + ... The purpose of this study is to assess the safety and tolerability and to confirm the dose of nemtabrutinib in combination with venetoclax in participants ...

6. mayo.edu mayo.edu/research/clinical-trials/cls-20529145

Efficacy and Safety of Nemtabrutinib (MK-1026) in ... The purpose of this study is to evaluate the safety and effectiveness of MK-1026 (formerly ARQ 531) in participants with hematologic malignancies.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03162536

NCT03162536 | A Study of Nemtabrutinib (MK-1026) in ... This study aims to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic (PK) of nemtabrutinib (formerly ARQ 531) tablets in selected ...