Phase 3 Randomized Study of Zanubrutinib and Rituximab Versus Bendamustine and Rituximab in Untreated Mantle Cell Lymphoma Ineligible for Stem Cell Transplant
- Trial ID
- 2023-509908-15-00
- Protocol
- BGB-3111-306
- Sponsor
- BeOne Medicines AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of Zanubrutinib plus Rituximab versus Bendamustine plus Rituximab in patients with previously untreated **Mantle Cell Lymphoma** who are ineligible for stem cell transplantation. This is measured by progression-free survival (PFS) as determined by independent central review. The clinical relevance of this objective lies in its potential to establish a more effective treatment regimen for this patient population, potentially improving their prognosis and quality of life.
Secondary objectives include:
- Evaluating efficacy through various parameters such as overall response rate (ORR), duration of response (DOR), overall survival (OS), rate of complete response (CR) or complete metabolic response, and time to response, all determined by both independent central review and investigator assessment.
- Assessing patient-reported outcomes to gain insights into the treatment's impact on patients' quality of life.
- Evaluating the safety and tolerability of the treatment regimens, which is crucial for understanding the risk-benefit profile of the therapies involved.
Participants
The clinical trial involves a total of **251 participants** diagnosed with **Mantle Cell Lymphoma**. The study population includes both male and female subjects, with an age range of 60 years and older. Participants were selected based on specific criteria, including age and comorbidities that preclude autologous stem cell transplantation. The trial does not involve a vulnerable population. Participants are required to have a histologically confirmed diagnosis of Mantle Cell Lymphoma, with no prior systemic treatments for the condition. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include adequate organ function and a life expectancy of at least three months. The trial ensures that participants can provide informed consent and comply with study requirements.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, open-label, multicenter study designed to compare the efficacy of **zanubrutinib** plus **rituximab** versus **bendamustine** plus rituximab in patients with previously untreated **mantle cell lymphoma** who are ineligible for stem cell transplantation. The primary objective is to evaluate progression-free survival (PFS) as determined by independent central review. The trial is expected to run from July 2019 to April 2026, with the estimated duration of participant involvement being up to 48 months, depending on the treatment arm and individual response to therapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, comorbidities, and organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response, safety, and any adverse events. These visits will include physical examinations, laboratory tests, and imaging studies as required. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
The trial employs a controlled design, with participants being randomly assigned to one of the two treatment arms. The study is not blinded, allowing both investigators and participants to be aware of the treatment allocation. The inclusion criteria specify that participants must have a histologically confirmed diagnosis of mantle cell lymphoma, measurable disease, and adequate organ function. Exclusion criteria are not explicitly detailed in the provided data. The trial's primary endpoint is PFS, while secondary endpoints include overall response rate, duration of response, overall survival, and safety parameters.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Bendamustine hydrochloride** is utilized in two formulations: Bendamustin Hikma and Bendamustin Kabi, both at a concentration of 2.5 mg/ml. These are provided as a powder for concentrate to prepare a **solution for infusion**. The route of administration is via **intravenous infusion**. The maximum daily dose is 90 mg/m², with a treatment period extending up to 24 months. The pharmaceutical form is consistent across both products, and they are chemically derived substances.
**Rituximab** is another key component of the trial, available in two concentrations: MabThera 500 mg and MabThera 100 mg, both as a concentrate for solution for infusion. The administration is through **intravenous use**, with a maximum daily dose of 375 mg/m². The treatment duration is set at 24 months. Rituximab is a protein-based substance, specifically categorized as a protein - other, and is used as a test product in the study.
**Zanubrutinib**, identified by the sponsor product code BGB-3111, is administered in capsule form. The route of administration is **oral**, with a maximum daily dose of 320 mg. The treatment period for Zanubrutinib extends up to 48 months. This substance is chemically derived and serves as a test product in the trial.
Throughout the study, participant compliance with dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of these treatments in patients with previously untreated mantle cell lymphoma who are ineligible for stem cell transplantation, with a primary focus on progression-free survival as determined by independent central review.
Efficacy
Efficacy in this clinical trial will be assessed primarily through **progression-free survival (PFS)**, as determined by independent central review using the Lugano Classification for Non-Hodgkin Lymphoma (NHL). PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurs first. Secondary endpoints include PFS as determined by investigator assessment, overall response rate, duration of response, overall survival, rate of complete response or complete metabolic response, time to response, and patient-reported outcomes. These secondary endpoints will also be evaluated using the Lugano Classification for NHL and will involve both independent central review and investigator assessment.
Patient-reported outcomes will be measured using the EQ-5D-5L and EORTC QLQ-C30 questionnaires. Safety parameters, including adverse events (AEs), serious adverse events (SAEs), clinical laboratory tests, physical exams, and vital signs, will also be monitored. The trial will compare the efficacy of Zanubrutinib plus Rituximab versus Bendamustine plus Rituximab in patients with previously untreated Mantle Cell Lymphoma who are ineligible for stem cell transplantation. The study is designed to provide comprehensive data on the efficacy and safety of the treatment regimens over the course of the trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥ 70 years of age at the time of informed consent, OR ≥ 60 and < 70 years of age with comorbidities precluding autologous stem cell transplantation including at least one of the following: a. Cardiac ejection fraction (LVEF) ≤ 45% b. Diffusing capacity for carbon monoxide (DLCO) ≤ 60% predicted c. Creatinine clearance < 70 but ≥ 30 mL/min (if estimated by the Cockcroft-Gault equation, must be confirmed by nuclear medicine scan or 24-hour urine collection) d. Eastern Cooperative Oncology Group (ECOG) performance status of 2, which poses an unacceptable risk of toxicity for high-dose therapy and stem cell transplantation e. Cumulative Illness Rating Scale (CIRS) total score > 6 (Appendix 9)
- Histologically confirmed diagnosis of MCL based on the World Health Organization 2016 classification of tumors of hematopoietic and lymphoid tissue (Swerdlow et al, 2016), including demonstration of positive cyclin D1 and/or t(11;14) a. For patients enrolled in France only, MCL disease must be classified as Ann Arbor Stage II, III, or IV
- No prior systemic treatments for MCL
- Presence of measurable disease, defined as ≥ 1 nodal lesion that is > 1.5 cm in longest diameter, or ≥ 1 extranodal lesion that is > 1 cm in longest diameter
- Availability of archival tissue confirming diagnosis of MCL, or willing to undergo fresh tumor biopsy
- ECOG performance status of 0, 1, or 2
- Life expectancy of ≥ 3 months
- Adequate organ function defined as: a. Absolute neutrophil count (ANC) > 750/mm3 (without growth factor support within 7 days) For patients enrolled in the United Kingdom (UK) and Germany only, ANC must be > 1000/mm3 b. Platelets > 75,000/mm3 (or ≥ 50,000/mm3 for patients with bone marrow involvement of lymphoma); without growth factor support or transfusion within 7 days c. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 3.0 × upper limit of normal (ULN) d. Serum total bilirubin ≤ 1.5 × ULN (unless documented Gilbert’s syndrome) For patients with Gilbert’s syndrome enrolled in the UK only, direct bilirubin must be ≤ 1 x ULN e. For patients enrolled in the UK only, international normalized ratio (INR) < 1.5 for patients not receiving therapeutic anticoagulation; INR 2.0 to 3.0 for patients receiving therapeutic anticoagulation
- Female patients of childbearing potential must practice highly effective methods of contraception (Section 5.3) initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib or bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
- Male patients are eligible if abstinent, vasectomized or if they agree to the use of barrier contraception in combination with other methods described in Section 5.3 during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
- Ability to provide written informed consent and ability to understand and comply with the requirements of the study
- For all patients irrespective of their age, creatinine clearance of ≥ 30 mL/min determined by either: a. Estimation using the Cockcroft-Gault equation or b. Measurement by nuclear medicine scan or 24 hour urine collection
Exclusion Criteria
- Known central nervous system involvement by lymphoma
- Prior hematopoietic stem cell transplantation
- Prior exposure to a BTK inhibitor, rituximab, or bendamustine
- Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
- Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer
- Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before Screening b. Unstable angina within 3 months before Screening c. New York Heart Association class III or IV congestive heart failure (see Appendix 6) d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) e. QTcF > 480 msecs based on Fridericia’s formula f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg at Screening
- History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
- History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
- Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
- Active fungal, bacterial and/or viral infection requiring systemic therapy
- Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of safety or efficacy results
- Known infection with human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B or C infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU/mL), and if they are willing to undergo monitoring for HBV reactivation. b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
- Major surgery within 4 weeks of the first dose of study drug
- Pregnant or lactating women
- Vaccination with a live vaccine within 35 days prior to the first dose of study drug
- Ongoing alcohol or drug addiction
- Hypersensitivity to zanubrutinib, bendamustine, or rituximab or any of the other ingredients of the study drugs
- Requires ongoing treatment with a strong CYP3A inhibitor or inducer (see Appendix 3)
- Concurrent participation in another therapeutic clinical trial.
- Patients enrolled in Germany only, who are severely immunocompromised.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Jul 2019 | 8 |
 Belgium | Not Recruiting | 01 Jul 2019 | 13 |
 France | Not Recruiting | 01 Jul 2019 | 44 |
 Germany | Not Recruiting | 01 Jul 2019 | 9 |
 Ireland | Not Recruiting | 01 Jul 2019 | 12 |
 Italy | Not Recruiting | 01 Jul 2019 | 56 |
 The Netherlands | Not Recruiting | 01 Jul 2019 | — |
 Poland | Not Recruiting | 01 Jul 2019 | 61 |
 Portugal | Not Recruiting | 01 Jul 2019 | 11 |
 Romania | Not Recruiting | 01 Jul 2019 | 2 |
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 |
|---|---|---|---|---|---|---|
MabThera 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375.00 | 24 | PRD398760 |
Zanubrutinib | Test | CAPSULE | ORAL | 320.00 | 48 | PRD4470763 |
Bendamustin Hikma 2,5 mg/ml Pulver für ein Konzentrat zur Herstellung einer Infusionslösung | Comparator | PULVER FÜR EIN KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENIOUS INFUSION | 90.00 | 24 | PRD8734547 |
Bendamustin Kabi 2,5 mg/ml Pulver für ein Konzentrat zur Herstellung einer Infusionslösung | Comparator | PULVER FÜR EIN KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS | 90.00 | 24 | PRD5424039 |
MabThera 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375.00 | 24 | PRD398759 |