A Study of Nemtabrutinib (MK-1026) Versus Comparator (Investigator's Choice of Ibrutinib or Acalabrutinib) in First Line (1L) Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) (MK-1026-011/BELLWAVE-011)

Study Overview
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Brief Summary
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The goal of this study is to evaluate nemtabrutinib compared with investigator's choice of ibrutinib or acalabrutinib in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who have not received any prior therapy. The primary hypotheses are that (1) nemtabrutinib is non-inferior to ibrutinib or acalabrutinib with respect to objective response rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018 by blinded independent central review (BICR) and (2) nemtabrutinib is superior to ibrutinib or acalabrutinib with respect to progression free survival (PFS) per iwCLL Criteria 2018 by BICR.

Official Title
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A Phase 3, Randomized Study to Compare Nemtabrutinib Versus Comparator (Investigator's Choice of Ibrutinib or Acalabrutinib) in Participants With Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BELLWAVE-011)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Nemtabrutinib
* Drug: Ibrutinib
* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The main inclusion criteria include but are not limited to the following: Confirmed diagnosis of CLL/SLL and active disease clearly documented to have a need to initiate therapy. Has at least 1 marker of disease burden. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before randomization. Has the ability to swallow and retain oral medication. 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 deoxyribonucleic acid (DNA) viral load before randomization. Participants with history of hepatitis C virus (HCV) infection are eligible if HCV ribonucleic acid (RNA) viral load is undetectable at screening. Participants with human immunodeficiency virus (HIV) who meet ALL eligibility criteria. Exclusion Criteria: The main exclusion criteria include but are not limited to the following: Has an active hepatitis B virus/ hepatitis C virus (HBV/HCV) infection. Has gastrointestinal (GI) dysfunction that may affect drug absorption. Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL. Has had acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in the past 12 months before screening. Has QT interval corrected (QTc) prolongation or other significant electrocardiogram (ECG) abnormalities. Has hypersensitivity to nemtabrutinib or contraindication to ibrutinib or acalabrutinib, or any of the excipients. Has history of severe bleeding disorder. Has history of second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Has received any systemic anticancer therapy for CLL/SLL. Is currently being treated with p-glycoprotein (P-gp) substrates with a narrow therapeutic index, cytochrome P450 3A (CYP3A) strong or moderate inducers or CYP3A strong inhibitors. Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration. Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication. Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed. Has active infection requiring systemic therapy. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nemtabrutinib<br>Participants will receive nemtabrutinib at specified dose until disease progression, unacceptable toxicity or until discontinuation criteria are met. | Drug: Nemtabrutinib<br>* Administered orally<br>* Other names: ARQ 531;|
| Active Comparator: Ibrutinib/Acalabrutinib<br>Participants will receive investigator's choice of ibrutinib or acalabrutinib at specified dose until disease progression, unacceptable toxicity or until discontinuation criteria are met. | Drug: Ibrutinib<br>* Administered orally<br>Drug: Acalabrutinib<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) per Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018 as assessed by Blinded Independent Central Review (BICR) | ORR is defined as the percentage of participants with complete response (CR), complete response with an incomplete recovery of the participant's bone marrow (CRi), nodular partial response (nPR), or partial response (PR), per iwCLL Criteria 2018 as assessed by BICR. | Up to  33 months | 
| Progression-Free Survival (PFS) per iwCLL Criteria 2018 as assessed by BICR | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PD is evaluated per iwCLL Criteria 2018 as assessed by BICR. | Up to  104 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to  104 months | 
| Duration of Response (DOR) per iwCLL Criteria 2018 as assessed by BICR | For participants who demonstrate a complete response (CR), complete response with an incomplete recovery of the participant's bone marrow (CRi), nodular partial response (nPR), or partial response (PR) per iwCLL Criteria 2018 as assessed by BICR, DOR is defined as the time from the first documented evidence of CR, CRi, nPR, or PR that led to response until disease progression or death due to any cause, whichever occurs first. | Up to  104 months | 
| Number of Participants Who Experience One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to  104 months | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to  104 months |