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)
- Trial ID
- 2022-501697-19-00
- Protocol
- MK-1026-011
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized study is to compare **nemtabrutinib** to ibrutinib or acalabrutinib in participants with untreated **Chronic Lymphocytic Leukemia** (CLL) or **Small Lymphocytic Lymphoma** (SLL). The comparison focuses on the **Overall Response Rate** (ORR) and **Progression-Free Survival** (PFS) as per the 2018 criteria of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), assessed by Blinded Independent Central Review (BICR). These endpoints are clinically relevant as they provide insights into the efficacy of nemtabrutinib in achieving and maintaining a therapeutic response compared to existing treatments.
Secondary objectives include:
- Comparing nemtabrutinib to ibrutinib or acalabrutinib with respect to **Overall Survival** (OS).
- Evaluating the **Duration of Response** (DOR) per iwCLL criteria 2018 as assessed by BICR.
- Assessing the safety and tolerability of nemtabrutinib.
Participants
The clinical trial involves a total of **943 participants** diagnosed with **Small Lymphocytic Lymphoma (SLL)** or untreated **Chronic Lymphocytic Leukemia (CLL)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on a confirmed diagnosis of CLL/SLL and the presence of active disease necessitating therapy initiation. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are fully active or capable of self-care. Participants must be able to swallow and retain oral medication. The study also considers individuals with controlled hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), provided they meet all eligibility criteria. The trial population includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of **nemtabrutinib** compared to a comparator, which is the investigator's choice of **ibrutinib** or **acalabrutinib**, in participants with untreated **chronic lymphocytic leukemia**/**small lymphocytic lymphoma** (CLL/SLL). The trial aims to assess the **objective response rate** (ORR) and **progression-free survival** (PFS) per the 2018 iwCLL criteria, as evaluated by a blinded independent central review (BICR). The study is expected to last until December 20, 2032, with recruitment starting on December 19, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of CLL/SLL, active disease requiring therapy, and an ECOG performance status of 0 to 2. The ability to swallow and retain oral medication is also required. Follow-up visits will be conducted to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the trial for each participant, assessing the overall survival and duration of response.
The expected length of participant involvement is up to 108 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of adverse events or the participant's decision to withdraw consent. The trial will ensure that all participants receive oral medication, with **nemtabrutinib** administered in tablet form, and the comparators also provided in their respective pharmaceutical forms. The study is not a low-intervention trial and is classified as a Phase III trial, focusing on confirming the safety and efficacy of the treatments in the target population.
Treatment
The clinical trial involves the administration of **Nemtabrutinib**, an experimental medication, in the form of a **tablet**. The active substance, nemtabrutinib, is of chemical origin and is provided by Merck & Co. Inc. The maximum daily dose of nemtabrutinib is 65 mg, with a total maximum dose of 213.7 g over the treatment period. The medication is administered orally, and the treatment period extends up to 108 days. Participant compliance with the dosing schedule is monitored throughout the trial.
In addition to nemtabrutinib, the trial includes comparator treatments, which are **Acalabrutinib** and **Ibrutinib**. Acalabrutinib is also of chemical origin and is administered orally. The maximum daily dose for acalabrutinib is 200 mg, with a total maximum dose of 657 g over the treatment period. The pharmaceutical form of acalabrutinib is denoted as PHF00006MIG. Similarly, ibrutinib, another comparator, is administered orally with a maximum daily dose of 420 mg and a total maximum dose of 1.38 g over the treatment period. The pharmaceutical form of ibrutinib is also PHF00006MIG. Both acalabrutinib and ibrutinib are used as standard-of-care therapies in the trial, providing a basis for comparison against the experimental treatment, nemtabrutinib.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** and **Progression-Free Survival (PFS)**, both evaluated according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and assessed by Blinded Independent Central Review (BICR). Secondary endpoints encompass **Overall Survival (OS)**, **Duration of Response (DOR)** per iwCLL criteria as assessed by BICR, the number of participants experiencing one or more adverse events (AEs), and the number of participants who discontinue study treatment due to an AE.
The trial is designed to compare the efficacy of **Nemtabrutinib** against the investigator's choice of **Ibrutinib** or **Acalabrutinib** in participants with untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). The efficacy parameters will be measured and collected at various timepoints throughout the study, with assessments conducted by BICR to ensure objectivity and consistency. The trial aims to provide a comprehensive evaluation of the treatment's impact on disease progression and patient outcomes, contributing valuable data to the understanding of therapeutic options for CLL/SLL.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Confirmed diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (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
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Yet Recruiting | 19 Dec 2023 | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Nemtabrutinib | Test | TABLET | ORAL USE | 65 | 108 | PRD7571582 |
ACALABRUTINIB | Comparator | PHF00006MIG | ORAL USE | 200 | 108 | SCP46660836 |
Nemtabrutinib | Test | TABLET | ORAL USE | 65 | 108 | PRD7571581 |
IBRUTINIB | Comparator | PHF00006MIG | ORAL USE | 420 | 108 | SCP674865 |