A Phase 3 Randomized, Open-Label, Multicenter Study of Zanubrutinib (BGB 3111) Plus Anti-CD20 Antibodies Versus Lenalidomide Plus Rituximab in Patients With Relapsed/Refractory Follicular or Marginal Zone Lymphoma
- Trial ID
- 2022-502548-12-00
- Protocol
- BGB-3111-308
- Sponsor
- BeOne Medicines AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of **zanubrutinib** plus obinutuzumab (ZO) compared to lenalidomide plus rituximab (R2) in patients with relapsed/refractory follicular lymphoma (R/R FL), and to compare the efficacy of zanubrutinib plus rituximab (ZR) versus R2 in patients with relapsed/refractory marginal zone lymphoma (R/R MZL). This is clinically relevant as it aims to determine the most effective treatment regimen for these specific lymphoma subtypes, potentially improving patient outcomes.
Secondary objectives include:
- Comparing the efficacy of ZO versus R2 in patients with R/R FL and ZR versus R2 in patients with R/R MZL.
- Assessing the Health-related Quality of Life (HRQoL) of ZO versus R2 in patients with R/R FL and ZR versus R2 in patients with R/R MZL.
- Evaluating the safety and tolerability of ZO versus R2 in patients with R/R FL and ZR versus R2 in patients with R/R MZL.
Participants
The clinical trial involves a total of **495 participants** diagnosed with **marginal zone lymphoma** or **follicular lymphoma**. The study population includes both male and female subjects, aged 18 years and older, with an **ECOG performance status** ranging from 0 to 2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants were selected based on their documented failure to achieve at least a partial response during the most recent systemic therapy or documented progressive disease after the most recent systemic therapy. The trial does not include a vulnerable population. Participants are required to have adequate bone marrow and organ function, and a life expectancy of at least six months. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with study requirements, including contraceptive measures for those of childbearing potential. The trial does not provide specific information on lifestyle habits such as diet or physical activity. The sponsor has not provided additional details regarding lifestyle considerations or specific exclusion criteria beyond the general health status and treatment history requirements.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, open-label, multicenter study designed to evaluate the efficacy of **zanubrutinib** in combination with anti-CD20 antibodies compared to **lenalidomide** plus **rituximab** in patients with relapsed or refractory **follicular lymphoma** or **marginal zone lymphoma**. The trial aims to assess progression-free survival as the primary endpoint, with secondary endpoints including overall response rate, overall survival, and patient-reported outcomes. The study is expected to run until June 2029, with recruitment starting in September 2023.
Participants will be randomly assigned to one of the treatment arms. The trial involves multiple study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.
The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of 336 days for those receiving **lenalidomide**. Participants may be withdrawn from the study early due to adverse events, disease progression, or withdrawal of consent. The study is designed to ensure rigorous monitoring and adherence to ethical standards, with all procedures conducted in accordance with regulatory guidelines.
Treatment
The clinical trial involves the administration of **Zanubrutinib**, a chemical compound provided in the form of capsules. The pharmaceutical form is a capsule, and the medication is administered orally. The maximum daily dose is 320 mg, with a total maximum dose of 681,600 mg over a treatment period of 71 days. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.
**Rituximab** is used as a comparator treatment in the study. It is provided as a concentrate for solution for infusion and is administered via infusion. The maximum daily dose is 375 mg/m², with a total maximum dose of 3,000 mg/m² over a treatment period of 5 to 6 cycles, depending on the cohort. The administration schedule is designed to align with standard infusion protocols, and participant compliance is monitored throughout the study.
**Lenalidomide** is another comparator treatment in the trial, provided in the form of hard capsules. It is administered orally with a maximum daily dose of 25 mg and a total maximum dose of 6,300 mg over a treatment period of 336 days. The dosing schedule is structured to ensure consistent administration, and adherence is monitored to maintain the integrity of the trial data.
**Obinutuzumab** is included as a test treatment in the study. It is provided as a concentrate for solution for infusion and administered via intravenous infusion. The maximum daily dose is 1,000 mg, with a total maximum dose of 8,000 mg over a treatment period of 6 cycles. The infusion schedule is carefully managed to optimize therapeutic outcomes, and participant compliance is closely monitored.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for the **Relapsed/Refractory Follicular Lymphoma (R/R FL)** cohort is progression-free survival (PFS), which will be evaluated by a Blinded Independent Review Committee (BIRC) using the 2014 modification of the International Working Group on non-Hodgkin lymphoma (NHL) Criteria, specifically the PET/CT-based Lugano 2014 criteria. For the **Relapsed/Refractory Marginal Zone Lymphoma (R/R MZL)** cohort, PFS will also be assessed by BIRC in accordance with the CT-based Lugano 2014 criteria.
Secondary endpoints include overall response rate (ORR) and overall survival (OS) for both cohorts. Additional measures for the R/R FL cohort include PFS by investigator, ORR by investigator, duration of response (DOR), complete response rate (CRR), time to response (TTR), and time to next anti-lymphoma treatment (TTNT), all evaluated using PET/CT-based Lugano 2014 criteria. For the R/R MZL cohort, similar secondary endpoints will be assessed using both PET/CT-based and CT-based Lugano 2014 criteria.
Patient-reported outcomes (PROs) will be collected using validated questionnaires, including the European Organization for Research on Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI 18), and the European Quality of Life 5Dimension 5Level Questionnaire (EQ 5D 5L). Additionally, the incidence rate of adverse events, laboratory abnormalities, and vital signs will be monitored throughout the trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age of ≥ 18 years at the time of informed consent.
- Able to provide written informed consent and understand and comply with study requirements.
- Women of childbearing potential (WOCBP [1]; Section 6.3) must: a. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for up to 1 month after the last dose of zanubrutinib, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer. b. Have 2 negative pregnancy tests (minimum sensitivity 25 mIU/mL) as verified by the investigator prior to starting study treatment (between Days -14 and -10 before the first dose of study treatment, and the other test is performed ≤ 24 hours before the start of lenalidomide). She must agree to ongoing pregnancy testing during the study, and after end of study treatment. This applies even if the patient practices true abstinence from heterosexual contact. c. Either commit to true abstinence [2] from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with 2 forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption during screening for all WOCBP, and during the study treatment for WOCBP in Arm B and Arm D (including dose interruptions), and for at least 28 days after the last dose of lenalidomide.
- Male patients are eligible if: a. Abstinent, vasectomized, or if they agree to use barrier contraception (condom) with other methods (Section 6.4; even vasectomized male patients receiving lenalidomide must practice true abstinence) or agree to use a condom during sexual contact with a pregnant woman or a WOCBP)] during the study treatment period and for up to 1 week after the last dose of zanubrutinib, for ≥ 28 days after the last dose of lenalidomide, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer. b. Agree to not donate semen or sperm during study treatment and for up to 1 week after the last dose of zanubrutinib, for at least 28 days after the last dose of lenalidomide, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer.
- All patients must: a. Have an understanding that the study treatment could have a potential teratogenic risk. b. Agree to abstain from donating blood while taking study treatment and for 4 weeks after discontinuation of study treatment therapy. c. Agree not to share study medication with another person. d. Agree to be counseled about pregnancy precautions and risk of fetal exposure. e. Female patients must agree to abstain from breastfeeding during study participation and for ≥ 14 days after the last dose of zanubrutinib, for ≥ 28 days after the last dose of lenalidomide, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer.
- Histologically confirmed Grade 1-3a FL or MZL according to World Health Organization 2016 classification. All three subtypes of MZL (extranodal, nodal, and splenic) are eligible. NOTE: A formalin-fixed, paraffin-embedded specimen must be available for central review. If an archival specimen is not available, or if there is suspicion of transformation, a re-biopsy is required before randomization.
- Previously treated with at least one line of systemic therapy (for Grade 1-3a FL or MZL) including anti-CD20 monoclonal antibody (≥ 4 doses as consecutive monotherapy or ≥ 2 doses as consecutive combination therapy). Must have a documented failure to achieve at least PR during the most recent systemic therapy or documented progressive disease after the most recent systemic therapy. Systemic therapy does not include Helicobacter pylori eradication or local involved field radiotherapy.
- Need for systemic therapy for FL or MZL if, based on the investigators’ assessment, the patient has ≥ 1 of the following symptoms: a. Local symptoms from progressive disease and/ or bulky disease. b. Compromise of normal organ function from progressive disease. c. B-symptoms including fevers, weight loss, and night sweats. d. Symptomatic extranodal disease such as effusions. e. Severe cytopenias from BM infiltration, (leukocytes < 1.0 x 109/L and/or platelets < 100 x 109/L), autoimmune hemolytic anemia or thrombocytopenia, or hypersplenism. f. An increase in disease tempo. g. Gastrointestinal bleeding (related to lymphoma).
- Measurable disease by CT or magnetic resonance imaging (MRI). Measurable disease as defined by ≥ 1 nodal lesion that is > 1.5 cm in longest diameter and/or ≥ 1 extranodal lesion that is > 1.0 cm in longest diameter, and lesion(s) measurable in 2 perpendicular diameters, as defined by the Lugano classification (Cheson et al 2014). Site of measurable disease cannot be previously irradiated.
- ECOG performance status of 0 to 2.
- Life expectancy ≥ 6 months.
- Adequate BM function, defined as: a. Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 (1.0 x 109/L), except for the patients with BM involvement or hypersplenism by FL or MZL, or for patients with benign neutropenia associated with ethnicity (Kanapuru et al 2023,), in which case ANC must be ≥ 750 cells/mm3. NOTE: The screening hematology values confirming the patient meets the ANC requirement must be dated at least 14 days following the most recent administration of peg-filgrastim (or other pegylated myeloid growth factors) and at least 7 days following the most recent administration of filgrastim or other myeloid growth factors. b. Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without growth factor support or platelet transfusion within 7 days) except for patients with BM involvement or hypersplenism by FL or MZL, in which case platelet count must be ≥ 50,000 cells/mm3 (50 x 109/L) (without growth factor support or platelet transfusion within 7 days). c. Hemoglobin ≥ 8.0 g/dL (80.0 g/L; 5 mmol/L; without growth factor support or red blood cell transfusion within 7 days).
- Adequate organ function, defined as: a. CrCl of ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation, MDRD or CKD-EPI equations, see Appendix 7). b. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase and alanine aminotransferase/serum glutamic pyruvic transaminase ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN if liver involvement by FL or MZL. c. Serum total bilirubin ≤ 2.0 x ULN or ≤ 5 x ULN due to Gilbert’s syndrome or documented liver or pancreatic involvement by FL or MZL.
- Must have a documented failure to achieve at least PR during the most recent systemic therapy or documented progressive disease after the most recent systemic therapy. Systemic therapy does not include H. pylori eradication or local involved field radiotherapy.
Exclusion Criteria
- Transformation to aggressive lymphoma, such as diffuse large B-cell lymphoma or Grade 3b FL. If transformation is suspected, a biopsy of the suspected area is required to exclude transformation. NOTE: Patients with a prior history of transformation may be enrolled if 1) they have received at least one prior line of treatment for FL or MZL AND 2) interval between end of treatment for transformation and enrollment is more than 2 years AND 3) current relapse as Grade 1-3a FL or MZL confirmed.
- Requiring ongoing need for corticosteroid treatment, except for adrenal replacement. NOTE: Systemic corticosteroids must be fully tapered off/stopped ≥ 5 days before the first dose of study treatment.
- Clinically significant cardiovascular disease including the following: a. Myocardial infarction ≤ 6 months before screening. b. Unstable angina ≤ 3 months before screening. c. New York Heart Association class 3 or 4 congestive heart failure (see Appendix 4). d. History of clinically significant arrhythmia (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes). e. QTcF (Fridericia’s correction) > 480 msec. f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. g. Uncontrolled hypertension as indicated by ≥ 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and/or diastolic blood pressure > 105 mm Hg at screening.
- Prior malignancy within the past 2 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized prostate cancer (Gleason score of ≤ 6).
- 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 ≤ 180 days before the first dose of study treatment.
- Severe or debilitating pulmonary disease.
- Inability to swallow capsules or gastrointestinal disfunction such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery, inflammatory bowel disease, or bowel obstruction.
- Active fungal, bacterial, and/or viral infection that requires systemic therapy. Note: Patients with infections that are managed by oral antibiotics and who are otherwise clinically stable are not excluded from study participation
- Confirmed central nervous system involvement by FL or MZL.
- Underlying medical conditions that, in the investigator’s opinion, will render the administration of study treatment hazardous or obscure the interpretation of safety.
- Severely immunocompromised state.
- History or active infection with human immunodeficiency virus (seropositive patients with sustained undetectable viral load may be enrolled).
- Serologic status reflecting active viral HBV or HCV infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but without HBsAg, are eligible if HBV DNA is undetectable (NOTE: the limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL), and if they are willing to undergo monthly monitoring for HBV reactivation. b. Presence of HCV antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (NOTE: the limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL) and if they are willing to undergo monthly monitoring for HCV reactivation.
- Major surgery ≤ 4 weeks before the first dose of study treatment or planned during study.
- Prior treatment with a BTK inhibitor (including zanubrutinib)
- Prior treatment with lenalidomide (or drugs from the same class, ie, immunomodulatory drugs or cereblon E3 ligase modulatory drugs), including but not limited to combination with rituximab, and without response (response is defined as best overall response that is PR or CR) or with short remission (short remission defined as: a response was achieved but the DOR was < 24 months).
- Last dose of prior therapy for FL or MZL, including herbal medicine with anti neoplastic intent ≤ 21 days before the first dose of study treatment with additional exclusion requirements: a. Treatment with monoclonal antibody-based therapy (including bispecifics antibody) ≤ 28 days before the first dose of study treatment. b. Chimeric antigen receptor T-cell therapy ≤ 180 days before the first dose of study treatment. c. Allogeneic hematopoietic cell transplantation ≤ 1 year before the first dose of study treatment. d. Autologous hematopoietic stem cell transplantation ≤ 3 months before the first dose of study treatment
- Any chemotherapy or radiation treatment for non-FL or MZL indications ≤ 21 days before the first dose of study treatment.
- Ongoing toxicity of ≥ Grade 2 from prior anticancer therapy (except for alopecia, ANC, and platelets. For ANC and platelets, please follow inclusion criterion #9).
- Pregnant, planning to become pregnant, or lactating women.
- Vaccination with a live vaccine ≤ 35 days before the first dose of study treatment.
- Hypersensitivity to zanubrutinib, lenalidomide, obinutuzumab or rituximab, murine products, thalidomide, or any of the other ingredients/excipients of the study drugs, with exception of minor (Grade 1-2), immediate infusion-related reactions to anti-CD20 antibodies.
- Requiring ongoing therapy with strong or moderate cytochrome P450 3A (CYP3A) inducers.
- Use of strong/moderate CYP3A inhibitors (see Appendix 5) within 7 days or 5 half-lives prior to the first dose of zanubrutinib; usage of strong/moderate CYP3A inducers (see Appendix 4) within 14 days prior to the first dose of zanubrutinib.
- Patients who are at a risk for a thromboembolic event and are not willing to take venous thromboembolism (VTE) prophylaxis.
- Neuropathy of Grade > 1.
- Plan to receive another investigational drug on study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Sept 2023 | 17 |
 Belgium | Not Recruiting | 01 Sept 2023 | 8 |
 Bulgaria | Not Recruiting | 01 Sept 2023 | 9 |
 Czechia | Not Recruiting | 01 Sept 2023 | 11 |
 France | Not Recruiting | 01 Sept 2023 | 32 |
 Germany | Not Recruiting | 01 Sept 2023 | 1 |
 Greece | Not Recruiting | 01 Sept 2023 | 6 |
 Ireland | Not Recruiting | 01 Sept 2023 | 9 |
 Italy | Not Recruiting | 01 Sept 2023 | 41 |
 The Netherlands | Not Recruiting | 01 Sept 2023 | — |
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 |
|---|---|---|---|---|---|---|
OBINUTUZUMAB | Test | — | IV INFUSION | 1000 | 6 | SUB32751 |
LENALIDOMIDE | Comparator | — | ORAL | 25 | 336 | SUB25389 |
LENALIDOMIDE | Comparator | — | ORAL | 25 | 336 | SUB25389 |
RITUXIMAB | Comparator | — | INFUSION | 375 | 5 | SUB12570MIG |
RITUXIMAB | Comparator | — | INFUSION | 375 | 6 | SUB12570MIG |
Zanubrutinib | Test | CAPSULE | ORAL | 320 | 71 | PRD4470763 |