Efficacy and Safety of Zanubrutinib, Rituximab, and Lenalidomide (ZR²) in Combination With Tislelizumab for Relapsed/Refractory Follicular Lymphoma

February 11, 2026 updated by: The First Affiliated Hospital with Nanjing Medical University

This is a prospective, open-label, single-arm, single-center, Phase II clinical study designed to evaluate the efficacy and safety of zanubrutinib, rituximab, and lenalidomide (ZR²) in combination with tislelizumab in patients with relapsed/refractory follicular lymphoma who have relapsed or are refractory after ≥1 prior systemic therapy.

After successful screening, enrolled patients will receive 6 treatment cycles (21 days per cycle). Disease response will be assessed by CT/PET-CT during treatment and after completion of induction. Patients who achieve CR/PR/SD will proceed to the maintenance phase; patients who do not achieve at least SD (i.e., fail to reach CR/PR/SD) during induction will discontinue the study. Patients with CR/PR/SD after induction will receive maintenance therapy with zanubrutinib plus tislelizumab until disease progression, unacceptable toxicity, or completion of 1 year of maintenance.

Efficacy and safety assessments will be performed per protocol. Tumor response will be assessed by site investigators according to the 2014 Lugano criteria, including determination of response status, date of response, and date of progression/relapse.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

33

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Eligible participants must meet all of the following criteria:

Provide written informed consent. Age ≥18 years . Histologically confirmed relapsed/refractory follicular lymphoma (R/R FL) . Received at least two prior lines of systemic therapy , including anti-CD20 monoclonal antibody therapy.

ECOG performance status 0-1 . Measurable disease , with longest diameter >1.5 cm . Estimated life expectancy (per investigator assessment) ≥18 weeks . Adverse events from prior anticancer therapy must have resolved to ≤ grade 1 (except alopecia and anorexia).

Adequate hepatic function:

Total bilirubin ≤1.5 × ULN ; for patients with documented Gilbert syndrome: total bilirubin ≤3 × ULN with predominantly indirect hyperbilirubinemia.

AST and ALT ≤3 × ULN .

Adequate hematologic function:

ANC ≥1.5 × 10⁹/L (≥1,500/µL) Platelets ≥75,000/µL , with no platelet transfusion within 14 days prior to first dosing on Cycle 1 Day 1 Hemoglobin ≥10.0 g/dL (6.2 mmol/L), with no blood transfusion within 21 days prior to first dosing on Cycle 1 Day 1 Adequate renal function: serum creatinine ≤1.5 × ULN , or creatinine clearance ≥50 mL/min calculated by the Cockcroft-Gault formula (see Appendix 14), for patients in whom serum creatinine may not adequately reflect renal function per investigator judgment.

For women of childbearing potential: negative serum pregnancy test within 7 days before study treatment; postmenopausal women (non-treatment-related amenorrhea ≥12 months) or surgically sterile women (no ovaries and/or uterus) are exempt. Women of childbearing potential must agree to abstinence (avoid heterosexual intercourse) or to use effective contraception.

For men: agree to abstinence (avoid heterosexual intercourse) or to use effective contraception.

Exclusion Criteria:

  • Participants meeting any of the following will be excluded:

    1. Unable to comply with protocol-required hospitalization and restrictions.
    2. Active infection or latent tuberculosis infection.
    3. History of severe hypersensitivity to drugs of the same class.
    4. Current central nervous system involvement.
    5. Pregnant or breastfeeding women.
    6. Uncontrolled comorbidities (e.g., cardiac disease, immune disorders); myocardial infarction, unstable arrhythmia, or unstable angina within the past 6 months.
    7. Illicit drug use or alcohol abuse within 12 months prior to screening, per investigator judgment.
    8. Any other disease, metabolic disorder, physical examination finding, or clinical laboratory abnormality that reasonably suggests a contraindication to the investigational products.
    9. The investigator should review vaccination status of potential participants and, prior to study initiation, follow local disease control and prevention guidelines for adult immunization with non-live vaccines aimed at preventing infectious diseases.
    10. Any psychiatric or cognitive disorder that may limit understanding/execution of informed consent or protocol compliance.
    11. Pregnant or breastfeeding women, or women/men (or male partners) planning pregnancy during the study period.

    12. Any other condition deemed by the investigator to make the participant unsuitable for the trial.

      • Cases to Be Excluded From Statistical Analysis (per protocol)

Participants already enrolled who meet any of the following will be treated as excluded cases in statistical analyses:

Post-enrollment discovery of non-fulfillment of eligibility criteria. Prior exposure to zanubrutinib or other BTK inhibitors. Intolerable toxicity after taking zanubrutinib or other BTK inhibitors. Received fewer than two consecutive administrations after enrollment such that objective efficacy cannot be assessed (adverse events may still be assessable).

Protocol violations. Prior hematopoietic stem cell transplantation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: PD-1+ZR2
Drug: tislelizumab + zanubrutinib + rituximab + lenalidomide

Patients with FL will receive a PD-1 + ZR² regimen (tislelizumab + zanubrutinib + rituximab + lenalidomide) for 6 cycles (3 weeks per cycle).

Induction Phase (Cycles 1-6; 21 days per cycle) Zanubrutinib (Z): 160 mg orally twice daily (BID). Rituximab (R): 375 mg administered intravenously on Day 1 of cycles 1-6; additionally administered on Day 1 of cycles 2-8/12 per protocol (21-day cycles).

Lenalidomide: 20 mg orally once daily on cycles 1-6. Tislelizumab: 200 mg intravenous infusion on Day 1 every 3 weeks. After 6 cycles of the four-drug combination, response will be assessed by CT/PET-CT. Patients achieving CR/PR/SD will proceed to maintenance; those not achieving at least SD will discontinue the study.

Maintenance Phase

Patients achieving CR/PR/SD during induction will receive:

Zanubrutinib: 160 mg orally BID; and Tislelizumab: 200 mg IV on Day 1 every 3 weeks until disease progression, unacceptable toxicity, or completion of 1 year of maintenance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete response rate (CRR)
Time Frame: Within 21 days after the completion of the 6th cycle of induction therapy (Each cycle is 21 days)
The proportion of evaluable participants who achieve complete response (CR) following 6 cycles of induction therapy. CR is defined in accordance with the 2014 Lugano Classification for Lymphoma: this requires the complete disappearance of all measurable/evaluable lymphoma lesions, resolution of all disease-related clinical symptoms, and normalization of imaging findings (e.g., no residual measurable disease on CT/MRI, and no metabolically active disease on FDG-PET/CT). The analysis population is restricted to participants who complete at least 4 cycles of induction therapy and have available post-treatment efficacy assessment data.
Within 21 days after the completion of the 6th cycle of induction therapy (Each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Treatment-Related Adverse Events (TRAE)
Time Frame: From the first dose of study intervention to 30 days after the last dose of study intervention
The proportion of participants experiencing any treatment-related adverse event, graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. This includes the incidence of grade 3-4 TRAEs and serious adverse events (SAEs; defined as events that are life-threatening, require hospitalization, result in persistent disability, or are fatal).
From the first dose of study intervention to 30 days after the last dose of study intervention
Objective response rate (ORR)
Time Frame: Within 21 days after the completion of the 6th cycle of induction therapy At the end of Cycle 1 (each cycle is 21 days)
The proportion of evaluable participants who achieve objective response (defined as complete response [CR] or partial response [PR]) following 6 cycles of induction therapy. Response assessment adheres to the 2014 Lugano Classification for Lymphoma: PR requires a ≥50% reduction in the sum of the longest diameters of measurable lesions, with no new lesions or progression of existing non-measurable disease. The analysis population includes participants who complete at least 4 induction cycles and have available post-treatment efficacy evaluation data.
Within 21 days after the completion of the 6th cycle of induction therapy At the end of Cycle 1 (each cycle is 21 days)
2-Year Progression-Free Survival (PFS)
Time Frame: Up to 2 years after Start treatment
The duration from randomization to the first occurrence of disease progression (per the 2014 Lugano Classification) or death from any cause. PFS will be estimated using the Kaplan-Meier method, and between-arm comparisons will be conducted via the log-rank test. Participants without progression or death at the end of follow-up will be censored at their last documented disease-evaluation date.
Up to 2 years after Start treatment
2-Year Overall Survival (OS)
Time Frame: Up to 2 years after start treatment
The duration from randomization to death from any cause. OS will be estimated using the Kaplan-Meier method, with between-arm comparisons performed using the log-rank test. Participants who remain alive at the 2-year follow-up endpoint will be censored at their last confirmed survival date.
Up to 2 years after start treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The First Affiliated Hospital with Nanjing Medical University

Investigators

  • Principal Investigator: Wei Xu, PHD, Hematological Department, Jiangsu Province Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

February 1, 2026

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2029

Study Registration Dates

First Submitted

January 20, 2026

First Submitted That Met QC Criteria

February 11, 2026

First Posted (Actual)

February 18, 2026

Study Record Updates

Last Update Posted (Actual)

February 18, 2026

Last Update Submitted That Met QC Criteria

February 11, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2025-SR-921

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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