Zanubrutinib, rituximab, lenalidomide plus tislelizumab for relapsed/refractory follicular lymphoma

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

This trial tests whether adding the PD‑1 blocker tislelizumab to zanubrutinib, rituximab, and lenalidomide helps adults with relapsed or refractory follicular lymphoma who have had at least two prior therapies.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 33 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: The First Affiliated Hospital with Nanjing Medical University (other)
• Drugs / interventions: zanubrutinib, rituximab, tislelizumab
• Locations: 1 site (Nanjing, Jiangsu)
• Trial ID: NCT07418190 on ClinicalTrials.gov

What this trial studies

This is an open‑label, single‑arm Phase II trial at a single center testing a four‑drug combination in patients with relapsed or refractory follicular lymphoma. Enrolled patients receive six 21‑day induction cycles, with tumor response measured by CT/PET‑CT during and after induction. Patients achieving complete response, partial response, or stable disease proceed to maintenance treatment with zanubrutinib plus tislelizumab until progression, unacceptable toxicity, or one year of maintenance. Key eligibility includes age ≥18, histologic confirmation of relapsed/refractory follicular lymphoma, at least two prior systemic therapies including an anti‑CD20 antibody, ECOG 0–1, and adequate organ function.

Who should consider this trial

Good fit: Ideal candidates are adults (≥18) with histologically confirmed relapsed/refractory follicular lymphoma who have received at least two prior systemic therapies including an anti‑CD20 antibody, have ECOG 0–1, and meet required organ‑function criteria.

Not a fit: Patients with poor organ function, ECOG performance status >1, those unable to tolerate immunomodulatory or targeted agents, or those who progress rapidly during induction are unlikely to benefit.

Why it matters

Potential benefit: If successful, this combination could increase response rates and lengthen remissions for people with relapsed or refractory follicular lymphoma.

How similar studies have performed: Related combinations of BTK inhibitors, lenalidomide, and anti‑CD20 antibodies have shown promising activity in indolent B‑cell lymphomas, but adding PD‑1 blockade like tislelizumab in this setting is less well established.

Eligibility criteria

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.

Where this trial is running

Nanjing, Jiangsu

• Jiangsu Province Hospital — Nanjing, Jiangsu, China (RECRUITING)

Study contacts

• Principal investigator: Wei Xu, PhD — Hematological Department, Jiangsu Province Hospital
• Study coordinator: Jinhua Liang

Conditions: Relapsed/Refractory Follicular Lymphoma