Combination of Zanubrutinib, Rituximab and Venetoclax in Patients With Previously Untreated Follicular Lymphoma (ZARAV)

Safety and Efficacy of Zanubrutinib in Combination With Rituximab and Venetoclax in Previously Untreated Follicular Lymphoma: An Open Label, Phase 2 Study

This is a single center, open label, single arm phase II clinical trial. The objective of this study is to assess the feasibility and efficacy of zanubrutinib combined with venetoclax and Rituximab in patients with previously untreated follicular lymphoma (FL) .

Study Overview

• Status: Recruiting
• Conditions: Ann Arbor Stage II Follicular Lymphoma; Ann Arbor Stage III Follicular Lymphoma; Ann Arbor Stage IV Follicular Lymphoma; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma
• Intervention / Treatment: Drug: Venetoclax; Drug: Zanubrutinib; Biological: Rituximab

Detailed Description

Follicular lymphoma (FL)is the most common inert non Hodgkin's lymphoma (iNHL). Their natural courses are slow but highly variable. The standard first-line treatment of advanced FL is based on rituximab. Whether combined with chemotherapy or not, it can induce lasting remission, but it is usually incurable. Although the first-line immunochemotherapy regimen has high efficacy, it also has high toxicity. Cytotoxic chemotherapy is related to many side effects, including bone marrow suppression and immunosuppression, gastrointestinal and cardiac toxicity, neurotoxicity and the occurrence of secondary tumors. About 20% of FL patients relapse within 2 years after first-line chemotherapy. The overall prognosis of these patients is poor. This clinical trial aims to evaluate the feasibility and efficacy of free-chemotherapy regimen (zanubrutinib combined with venetoclax and Rituximab) in patients with previously untreated follicular lymphoma.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: YANG LIU, MD; Phone Number: 010-66937463; Email: liuyang301blood@163.com

Study Locations

• China
  • Beijing, China, 100853
    • Recruiting
    • Biotherapeutic Department and Hematology Department of Chinese PLA General Hospital
    • Contact: Weidong Han; Phone Number: 86-10-13651392893; Email: hanwdrsw@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• A diagnosis of follicular lymphoma (grades 1, 2, or 3a), untreated
• Stage II, III, or IV disease
• Able and willing to provide written informed consent and to comply with the study protocol
• at least one measurable disease
• Must be in need of therapy as evidenced by at least one of the following criteria:

• Presence of at least one B symptom:

  • Fever (> 38 Celsius [C]) not due to infectious etiology
  • Night sweats
  • Weight loss > 10% in the past 6 months
• Fatigue due to lymphoma
• Splenomegaly (> 13 cm)
• Compression syndrome (ureteral, orbital, gastrointestinal)

• Any of the following cytopenias, due to lymphoma:

  • Hemoglobin ≤ 10 g/dL
  • Platelets ≤ 100 x 10^9/L
  • Absolute neutrophil count (ANC) < 1.5 x 10^9/L
• Pleural or peritoneal effusion
• Lactate dehydrogenase (LDH) > upper limit of normal (ULN) or beta (B)2 microglobulin > ULN
• Other lymphoma-mediated symptoms as determined by the treating physician

Exclusion Criteria:

• ECOG≤ 2
• Absolute neutrophil count (ANC) > 1.0 x 10^9/L
• Platelet count > 50 x 10^9/L
• Prothrombin time (PT)/international normal ratio (INR) < 1.5 x (upper limit of normal) ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonists, then INR ≤ 3.0)
• Serum aspartate transaminase (AST) and alanine transaminase (ALT) < 3 x upper limit of normal (ULN)
• Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula
• Bilirubin < 1.5 x ULN unless bilirubin is due to Gilbert's syndrome, documented liver involvement with lymphoma, or of non-hepatic origin, in which case bilirubin should not exceed 3 g/dL
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [B-hCG]) pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study

Exclusion Criteria:

• Known active central nervous system lymphoma or leptomeningeal disease
• Follicular lymphoma with evidence of diffuse large B-cell transformation
• Grade 3b follicular lymphoma
• Any prior history of other malignancy besides follicular lymphoma
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
• Patients who have undergone major surgery within 14 days
• The researchers believe that it is not advisable for the participant to take part in this trial.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (zanubrutinib, venetoclax, rituximab); stage I (cycles 1-3, every 4 weeks): zanubrutinib PO 160mg, BID; rituximab IV on day 1. stage II (cycles 4-9, every 4 weeks): if complete response : zanubrutinib PO 160mg, BID; rituximab IV on day 1. if no complete response : zanubrutinib PO160mg, BID; rituximab IV on day 1 and Venetoclax PO (100mg D1, 200mg D2, and 400mg D3 of cycle 4; 400mg QD).

Drug: Venetoclax; BCL-2 inhibitor; Drug: Zanubrutinib; BTK inhibitor; Biological: Rituximab; Monoclonal antibody to CD20

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR rate	Determined by PET/CT based on Cheson, Lugano classification 2014 as assessed by the investigator. The number and percentage of subjects with a CR will be tabulated.	Within 6 months of therapy completion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	CR + partial response (PR), determined by PET/CT based on Cheson, Lugano classification 2014 as assessed by the investigator. The number and percentage of subjects with an ORR will be tabulated.	Within 6 months of therapy completion
Progression-free survival	PFS is defined as the duration from date of treatment initiation to date of disease progression or death from any cause	up to two years
Overall survival	PFS is defined as the duration from date of treatment initiation to date of death from any cause	up to two years
Incidence of Treatment-Emergent Adverse Events	Incidence of subjects occuring treatment related adverse events.	Up to 90 days after the last dose of study drugs

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: June 18, 2024
• First Submitted That Met QC Criteria: June 18, 2024
• First Posted (Actual): June 24, 2024

Study Record Updates

• Last Update Posted (Actual): July 18, 2024
• Last Update Submitted That Met QC Criteria: July 16, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Follicular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Venetoclax; Rituximab; Zanubrutinib
• Other Study ID Numbers: CHN-PLAGH-BT-086

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