Zanubrutinib, Obinutuzumab Combined With Lenalidomide (ZGR) for the Treatment of Untreated Follicular Lymphoma

Official title

A Prospective, Open-label, Single-arm Multicenter Clinical Study of Zanubrutinib, Obinutuzumab, and Lenalidomide (ZGR) in the Treatment of Untreated Follicular Lymphoma

Overview

This study is planned to prospectively evaluates the efficacy and safety of the zanubrutinib, obinutuzumab, and lenalidomide (ZGR) combination regimen in treatment-naïve follicular lymphoma (FL) patients in a Chinese population.

Detailed description

Regarding chemotherapy-free first-line treatment regimens, current targeted therapies primarily focus on lenalidomide combined with anti-CD20 antibodies. Chemotherapy-free regimens such as rituximab plus lenalidomide (R²) or obinutuzumab plus lenalidomide (O-Len) have been recommended for clinical use. Encouraged by the promising efficacy of dual-targeted therapies, the potential of triple-combination therapy-comprising a BTK inhibitor (BTKi), an anti-CD20 monoclonal antibody, and lenalidomide-has garnered increasing attention in untreated hematologic malignancies. Most existing studies have concentrated on BTKi combined with rituximab and lenalidomide (e.g., ibrutinib + R²).

Given current clinical needs and available evidence, this study aims to explore a novel chemotherapy-free triple regimen: zanubrutinib combined with obinutuzumab and lenalidomide (ZGR) in treatment-naïve follicular lymphoma (FL) patients. This combination is expected to provide a new treatment paradigm for untreated FL, offering high antitumor efficacy while minimizing toxicity, thereby improving patients' quality of life.

Interventions

• Drug Induction Therapy: Zanubrutinib, obinutuzumab, lenalidomide
  All enrolled patients received: Zanubrutinib: 160 mg twice daily, orally, on Days 1-28; Obinutuzumab: 1000 mg, intravenous infusion: Days 1, 8, and 15 of Cycle 1,on Day 1 of Cycles 2-6; Lenalidomide: 25 mg once daily, orally, on Days 1-21 of each 28-day cycle.
• Drug Maintenance therapy: Zanubrutinib, lenalidomide
  Maintenance therapy consists of zanubrutinib plus lenalidomide: Zanubrutinib: 160 mg twice daily, orally, on Days 1-28.Lenalidomide: 25 mg every other day, orally, on Days 1-21 of each 28-day cycle

Primary outcome measures

• Objective response rate，ORR [Time frame: up to the end of 6 cycles of treatment(each cycle is 28 days)]]

Secondary outcome measures (9)

• Complete response rate，CRR [Time frame: up to the end of 6 cycles of treatment(each cycle is 28 days)]
• Best overall response rate (ORR) and complete response rate (CRR) during treatment [Time frame: Up to the end of 6 cycles of treatment(each cycle is 28 days)]
• CRR and ORR at end of treatment [Time frame: at the end of Cycle 24 (each cycle is 28 days)]
• Progression-free survival (PFS) [Time frame: up to 5 years]
• Duration of response (DOR) [Time frame: up to 5 years]
• Time to response (TTR) [Time frame: at the end of Cycle 24 (each cycle is 28 days)]
• 2-year overall survival (OS) rate [Time frame: up to 2 years]
• Proportion of patients with progression of disease within 24 months (POD24) [Time frame: Up to the end of 2 years (each cycle is 28 days)]
• The safety [Time frame: up to 5 years]

Eligibility criteria

Inclusion criteria

• Gender: No restrictions; age ≥18 years.
• Diagnosis: Histologically confirmed CD20-positive follicular lymphoma (FL), Grade 1, 2, or 3A, per 2016 WHO classification. All patients must provide sufficient archived or fresh tumor tissue samples for immunohistochemical (IHC) analysis.
• Disease Stage \& Treatment Need:
• Stage III or IV disease, or Stage II with bulky disease, meeting at least one of the following criteria:
• a) Bulky disease: Lymph node or extranodal (excluding spleen) mass with maximum diameter ≥7 cm.
• b) Local symptoms or organ dysfunction due to progressive lymphadenopathy or extranodal tumor mass.
• c) B symptoms (fever, night sweats, or unintentional weight loss >10% of body weight within ≤6 months).
• d) Symptomatic extranodal involvement (e.g., pleural/peritoneal effusion).
• e) Cytopenias due to bone marrow infiltration (hemoglobin <10 g/dL, absolute neutrophil count \[ANC\] <1.0×10⁹/L, platelets <100×10⁹/L).
• f) Involvement of ≥3 lymph nodes, each ≥3 cm in diameter.
• g) Symptomatic splenomegaly.
• Prior Therapy: No prior systemic therapy for FL.
• ECOG Performance Status: ≤2.
• Measurable Disease: At least one measurable lesion (>2 cm in longest diameter by CT/MRI).
• Life Expectancy: ≥6 months.
• Adequate Organ Function:
• a) ANC ≥1.0×10⁹/L (without growth factor support).
• b) Platelets ≥50×10⁹/L (untransfused within 7 days).
• c) Total bilirubin (TBIL) ≤1.5×ULN.
• d) ALT/AST ≤3×ULN.
• e) Creatinine clearance ≥30 mL/min (calculated by modified Cockcroft-Gault formula).
• Contraception: Men and women of childbearing potential must agree to use highly effective contraception during the study and for 4 weeks after treatment discontinuation.
• Informed Consent: Patients must voluntarily participate and sign informed consent forms (ICF).

Exclusion criteria

• Patients meeting any of the following criteria will be excluded from this study:
• Histologic evidence of central nervous system (CNS) lymphoma, leptomeningeal lymphoma, or transformation to high-grade lymphoma (e.g., diffuse large B-cell lymphoma, DLBCL).
• Grade 3B follicular lymphoma (FL) or transformed FL.
• Ann Arbor Stage I FL.
• Prior history of malignancy, unless the patient has been disease-free for ≥5 years and the treating physician deems the risk of recurrence low (exceptions: non-melanoma skin cancer, cured localized prostate cancer, carcinoma in situ of the cervix, or squamous intraepithelial lesions on PAP smear).
• Use of any investigational drugs, antibiotics, or participation in another interventional clinical trial within 4 weeks prior to enrollment.
• Major surgery (excluding lymph node biopsy) within 14 days before enrollment or anticipated need for major surgery during the study.
• Prior treatment with zanubrutinib, obinutuzumab, or lenalidomide.
• Immunodeficiency or autoimmune disease history, or chronic systemic steroid therapy (>10 mg/day prednisone equivalent) or immunosuppressive therapy within 7 days before enrollment.
• Severe hepatic dysfunction (including severe jaundice, hepatic encephalopathy, refractory ascites, or hepatorenal syndrome), cachexia, or multi-organ failure with renal impairment.
• Clinically significant cardiovascular abnormalities:
• NYHA Class III/IV heart failure
• Myocardial infarction within 6 months before enrollment, Malignant arrhythmias (including QTc ≥480 ms), Uncontrolled hypertension (Systolic blood pressure (SBP) ≥150 mmHg and diastolic blood pressure (DBP) ≥100 mmHg), Unstable angina.

Active infections:

• HIV, active hepatitis B/C infection (HBV DNA ≥2000 IU/mL or HCV RNA detectable)
• Uncontrolled systemic infections.
• Bleeding disorders or coagulation abnormalities, or thrombotic events within 3 months.
• Severe hypersensitivity to the active ingredients or excipients of the study drugs.
• Pregnancy, lactation, or unwillingness to use effective contraception in women of childbearing potential.
• Other conditions deemed unsuitable by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• Institute of Hematology and Blood Diseases Hospital ,Chinese Academy of Medical Sciences, — Tianjin
• Institute of Hematology and Blood Diseases Hospital ,Chinese Academy of Medical Sciences — Tianjin

Identifiers

NCT: NCT07299149 · IIT2025107

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗