A Study of Nemtabrutinib vs Chemoimmunotherapy for Participants With Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Without TP53 Aberrations (MK-1026-008, BELLWAVE-008)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of nemtabrutinib compared to investigator's choice of fludarabine plus cyclophosphamide plus rituximab (FCR) or bendamustine plus rituximab (BR) in participants with previously untreated CLL/SLL without 17p deletion and/or tumor protein (TP) 53 mutation. The primary hypothesis is that nemtabrutinib is superior to FCR/BR with respect to progression-free survival (PFS).

Official Title
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A Phase 3, Randomized Study to Compare the Efficacy and Safety of Nemtabrutinib Versus Chemoimmunotherapy for Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Without TP53 Aberrations

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Nemtabrutinib
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Bendamustine
* Biological: Rituximab
* Biological: Truxima
* Biological: Ruxience
* Biological: Riabni


Participation Criteria
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Eligibility Criteria
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The main inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: Confirmed diagnosis of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) and active disease clearly documented to have a need to initiate therapy Has previously untreated CLL/SLL participants without tumor protein 53 (TP53) aberrations and documented 11q status and immunoglobulin heavy chain gene (IGHV) mutational status The ability to swallow and retain oral medication Exclusion Criteria: Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy) Known additional malignancy that is progressing or has required active treatment within the past 3 years, except basal cell carcinoma of skin, squamous cell carcinoma of skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potential curative therapy History of severe bleeding disorders Not adequately recovered from major surgery or has 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nemtabrutinib<br>Administered daily via oral tablet. | Drug: Nemtabrutinib<br>* 65 mg administered orally daily until disease progression, unacceptable toxicity, or discontinuation criteria met<br>* Other names: MK-1026;|
| Active Comparator: FCR or BR<br>Investigator's choice of fludarabine plus cyclophosphamide plus rituximab (FCR) OR bendamustine plus rituximab (BR). Participants will receive either rituximab or specified approved rituximab biosimilar. | Drug: Fludarabine<br>* 25 mg/m^2 administered via intravenous (IV) infusion on Days 1, 2, and 3 of each 28-day cycle up to 6 cycles<br>Drug: Cyclophosphamide<br>* 250 mg/m^2 administered via IV infusion on Days 1, 2, and 3 of each 28-day cycle up to 6 cycles<br>Drug: Bendamustine<br>* Administered via IV infusion on Days 1 and 2 of each 28-day cycle up to 6 cycles. The first dose is given as 70 to 90 mg/m^2. Subsequent doses may be escalated up to 90 mg/m^2, if applicable and as per local guidelines<br>Biological: Rituximab<br>* Administered as an IV infusion on Day 1 of each 28-day cycle. The initial dose is 375 mg/m^2 (cycle 1) followed by 500 mg/m^2 for remaining cycles<br>* Other names: RITUXAN®;Biological: Truxima<br>* Administered as an IV infusion on Day 1 of each 28-day cycle. The initial dose is 375 mg/m^2 (cycle 1) followed by 500 mg/m^2 for remaining cycles<br>* Other names: Rituximab biosimilar;Biological: Ruxience<br>* Administered as an IV infusion on Day 1 of each 28-day cycle. The initial dose is 375 mg/m^2 (cycle 1) followed by 500 mg/m^2 for remaining cycles<br>* Other names: Rituximab biosimilar;Biological: Riabni<br>* Administered as an IV infusion on Day 1 of each 28-day cycle. The initial dose is 375 mg/m^2 (cycle 1) followed by 500 mg/m^2 for remaining cycles<br>* Other names: Rituximab biosimilar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018 as Assessed by Blinded Independent Central Review (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 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by blinded independent central review (BICR). | Up to approximately 49 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 approximately 94 months | 
| Objective Response Rate (ORR) per iwCLL Criteria 2018 as Assessed by 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 approximately 36 months | 
| Duration of Response (DOR) per iwCLL Criteria 2018 as Assessed by BICR | For participants who demonstrate a CR, CRi, nPR, or PR per iwCLL criteria 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 approximately 94 months | 
| Number of Participants Who Experience an Adverse Event (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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to approximately 94 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to approximately 94 months |