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).

Trial statusRecruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorMerck Sharp & Dohme LLC

About this trial

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).

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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, and immunoglobulin heavy chain gene (IGHV) 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

Disqualifiers

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 2 years

Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL

Trial design

Design model

Parallel

Treatments tested in this trial

  • Nemtabrutinib

    Drug

    5, 20, and 45 tablets

  • Venetoclax

    Drug

    10, 50, and 100 mg tablets

  • Rituximab

    Biological/Vaccine

    100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion

Treatment groups

735 Participants
are divided into 2 treatment groups
Group A: Nemtabrutinib + VenetoclaxExperimental treatment 2 interventions
Group B: Venetoclax + RituximabActive comparator 2 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
Up to approximately 12 Weeks
2

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.

Time frame
Up to approximately 28 months
3

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.

Time frame
Up to approximately 25 months
4

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.

Time frame
Up to approximately 71 months

Secondary outcomes

1

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.

Time frame
Up to approximately 46 months
2

Part 2: Overall Survival (OS)

OS, defined as the time from randomization to death due to any cause. OS will be presented.

Time frame
Up to approximately 108 months
3

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.

Time frame
Up to approximately 71 months
4

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.

Time frame
Up to approximately 108 months

Other outcomes

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