A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010)

Study Overview
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Brief Summary
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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 with R/R CLL/SLL. The primary study hypotheses are that the combination of nemtabrutinib plus venetoclax is superior to VR with respect to progression-free survival (PFS) per 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria as assessed by blinded independent central review (BICR).

Official Title
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A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Nemtabrutinib (MK-1026) Plus Venetoclax Versus Venetoclax Plus Rituximab in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least 1 Prior Therapy (BELLWAVE-010)

Conditions
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Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Chronic Lymphocytic, Small-Cell Lymphoma, Lymphoma, Small Lymphocytic, CLL, SLL

Intervention / Treatment
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* Drug: Nemtabrutinib
* Drug: Venetoclax
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and active disease clearly documented to initiate therapy. Deletion (Del) (17p) status, tumor protein 53 (TP53) mutation status, immunoglobulin heavy chain gene (IGHV) mutation status and Bruton's tyrosine kinase (BTK)-C481 mutation status results required before randomization for Part 2 participants only. Relapsed or refractory to at least 1 prior available therapy. Have 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 a life expectancy of at least 3 months. 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. Participants with adequate organ function with specimens collected within 7 days before the start of study intervention. If capable of producing sperm, participant agrees to eliminate Nemtabrutinib: 12 days, Venetoclax: 1 month (30 days), Rituximab (rituximab biosimilar): not applicable; abstains from penile-vaginal intercourse as their preferred and usual lifestyle; OR uses prescribed contraception. Participant assigned female sex at birth are eligible to participate if not pregnant or breastfeeding and are not a person of childbearing potential (POCBP) OR is a POCBP and uses a contraceptive method that is highly effective, has a negative highly sensitive pregnancy test, and abstains from breastfeeding. Exclusion Criteria: Has an active hepatitis B virus/ hepatitis C virus (HBV/HCV) infection. Has gastrointestinal (GI) dysfunction that may affect drug absorption. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL. Has an active infection requiring systemic therapy, such as intravenous (IV) antibiotics, during screening. HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease and/or 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 a known allergy/sensitivity to nemtabrutinib or contraindication to venetoclax/rituximab (or rituximab biosimilar), or any of the excipients. Has history of severe bleeding disorders (eg, hemophilia). Has received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before randomization. Has received prior B-cell lymphoma 2 inhibitor(s) (BCL2i) including venetoclax or Non-covalent Bruton's tyrosine kinase inhibitor (BTKi). 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. Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention. Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration. Has a known psychiatric or substance use disorder that would interfere with the participant's ability to cooperate with the requirements of the study. 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
Interventional Model Description: In Part 1, Dose Confirmation will be determined by modified toxicity probability interval (mTPI) design, where participants will be assigned to two treatment groups, Nemtabrutinib + Venetoclax in parallel with Nemtabrutinib + Venetoclax. Part 2 will be an Efficacy Expansion where all participants will be randomized 1:1 to Nemtabrutinib Part 1 Dose Selection plus Venetoclax or Venetoclax plus Rituximab (VR) (or Rituximab biosimilar) for the duration of the study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nemtabrutinib + Venetoclax<br>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. | Drug: Nemtabrutinib<br>* 5 and 20 mg tablets<br>* Other names: MK-1026;Drug: Venetoclax<br>* 10, 50, and 100 mg tablets<br>* Other names: GDC-0199;|
| Active Comparator: Venetoclax + Rituximab<br>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. | Drug: Venetoclax<br>* 10, 50, and 100 mg tablets<br>* Other names: GDC-0199;Biological: Rituximab<br>* 100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) | DLT evaluation period is defined as 8 weeks after the first dose of the combination treatment of nemtabrutinib plus venetoclax Cycle 2 Day 1 in Part 1 + 4 weeks follow up. Each cycle is 4 weeks. DLTs are: Grade ≥3 nonhematologic toxicity (except Grade 3 nausea, vomiting, diarrhea, rash, fatigue, and uncontrolled hypertension which will not be considered a DLT unless lasting ≥72 hours despite optimal supportive care); Grade 4 hematologic toxicity lasting >7 days (except Grade 3 lymphocytosis, Grade 4 platelet count decreased of any duration, or Grade 3 platelet count decreased if associated with bleeding); any Grade 3 or Grade 4 nonhematologic laboratory abnormality if values result in drug-induced liver injury, or medical intervention is required, or the abnormality leads to hospitalization, or the abnormality persists for >1 week (with exceptions); missing >25% of nemtabrutinib or venetoclax doses as a result of drug-related adverse events during the first 2 cycles; Grade 5 toxicity. | Up to approximately 12 Weeks | 
| Part 1: Number of participants experiencing adverse events (AEs) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants experiencing AEs will be reported for Part 1. | Up to approximately 28 months | 
| Part 1: Number of participants discontinuing study treatment due to AEs | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants discontinuing study treatment due to AEs will be reported for Part 1. | Up to approximately 25 months | 
| Part 2: PFS per the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as assessed by Blinded Independent Central Review (BICR) | PFS is defined as the time from randomization to the first documented disease progression per iwCLL criteria 2018 as accessed by BICR, or death due to any cause, whichever occurs first. PFS will be presented. | Up to approximately 71 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Undetectable minimal residual disease (MRD) rate in bone marrow as assessed by central laboratory | Undetectable MRD, defined as <1 leukemic cell per 10,000 cells (MRD <10-4) in bone marrow. The MRD rate will be presented. | Month 14 | 
| Part 2: Overall Survival (OS) | OS, defined as the time from randomization to death due to any cause. OS will be presented. | Up to approximately 108 months | 
| Part 2: Objective Response Rate (ORR) per iwCLL Criteria 2018 as assessed by BICR | OR, defined as complete response/remission (CR), complete response with incomplete count recovery (CRi), nodular partial remission (nPR), or partial remission (PR). CR is defined as meeting the following criteria: no lymph nodes >1.5 cm, spleen size <13 cm, liver normal; no constitutional symptoms, normal lymphocyte count, platelets ≥100 x 10^9/L; hemoglobin ≥11 g/dL; and normocellular marrow (no CLL cells or B lymphoid nodules). CRi is defined as meeting CR criteria but with hypocellular bone marrow. nPR is defined as having features of CR but with lymphoid nodules in the marrow. PR is defined as ≥50% decrease in ≥2 of the following: lymph nodes, liver and/or spleen size, lymphocytes PLUS ≥1 of the following met: platelets ≥100 x 10^9/L or ≥50% increase from screening, hemoglobin >11 g/dL or ≥50% increase from screening, CLL cells or B lymphoid nodules in marrow. ORR will be presented. | Up to approximately 108 months | 
| Part 2: Duration of Response (DOR) per iwCLL Criteria 2018 as assessed by BICR | DOR, 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. CR is defined as meeting the following criteria: no lymph nodes >1.5 cm, spleen size <13 cm, liver normal; no constitutional symptoms, normal lymphocyte count, platelets ≥100 x 10^9/L; hemoglobin ≥11 g/dL; and normocellular marrow (no CLL cells or B lymphoid nodules). CRi is defined as meeting CR criteria but with hypocellular bone marrow. nPR is defined as having features of CR but with lymphoid nodules in the marrow. PR is defined as ≥50% decrease in ≥2 of the following: lymph nodes, liver and/or spleen size, lymphocytes PLUS ≥1 of the following met: platelets ≥100 x 10^9/L or ≥50% increase from screening, hemoglobin >11 g/dL or ≥50% increase from screening, CLL cells or B lymphoid nodules in marrow. DOR will be presented. | Up to approximately 108 months | 
| Part 2: Number of participants experiencing AEs | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants experiencing AEs will be reported for Part 2. | Up to approximately 28 months | 
| Part 2: Number of participants discontinuing study treatment due to AEs | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants discontinuing study treatment due to AEs will be reported for Part 2. | Up to approximately 25 months |