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

NCT07418190 | Recruiting Phase 2

• 1 other identifier: 2025-SR-921
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Relapsed/Refractory Follicular Lymphoma

Outcome Measures

Primary Outcomes (1)

• Complete response rate (CRR)

  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 Outcomes (4)

• Objective response rate (ORR)

  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)

  Up to 2 years after Start treatment

• 2-Year Overall Survival (OS)

  Up to 2 years after start treatment

• Incidence of Treatment-Related Adverse Events (TRAE)

  From the first dose of study intervention to 30 days after the last dose of study intervention

Study Arms (1)

PD-1+ZR2

EXPERIMENTAL

Drug: tislelizumab + zanubrutinib + rituximab + lenalidomide

Interventions

tislelizumab + zanubrutinib + rituximab + lenalidomide DRUG

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.

PD-1+ZR2

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Participants meeting any of the following will be excluded:
• Unable to comply with protocol-required hospitalization and restrictions.
• Active infection or latent tuberculosis infection.
• History of severe hypersensitivity to drugs of the same class.
• Current central nervous system involvement.
• Pregnant or breastfeeding women.
• Uncontrolled comorbidities (e.g., cardiac disease, immune disorders); myocardial infarction, unstable arrhythmia, or unstable angina within the past 6 months.
• Illicit drug use or alcohol abuse within 12 months prior to screening, per investigator judgment.
• Any other disease, metabolic disorder, physical examination finding, or clinical laboratory abnormality that reasonably suggests a contraindication to the investigational products.
• 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.
• Any psychiatric or cognitive disorder that may limit understanding/execution of informed consent or protocol compliance.
• Pregnant or breastfeeding women, or women/men (or male partners) planning pregnancy during the study period.
• 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:

Sponsors & Collaborators

• The First Affiliated Hospital with Nanjing Medical University: lead

Study Sites (1)

Jiangsu Province Hospital

Nanjing, Jiangsu, 210000, China

RECRUITING

MeSH Terms

Conditions

Lymphoma, Follicular

Interventions

tislelizumab; zanubrutinib; Rituximab; Lenalidomide

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Wei Xu, PhD

  Hematological Department, Jiangsu Province Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jinhua Liang

CONTACT

15952032421; 1151525490@qq.com

Wei Xu, PhD

CONTACT

xuwei10000@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A prospective, open-label, single-arm, single-center Phase II study in R/R FL after ≥1 prior systemic therapy. Patients receive 6 induction cycles (21 days per cycle), followed by response-based maintenance with zanubrutinib plus tislelizumab for up to 1 year or until progression/unacceptable toxicity.

Study Record Dates

• First Submitted: January 20, 2026
• First Posted: February 18, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2029
• Last Updated: February 18, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)