Zanubrutinib With Obinutuzumab in Untreated Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT06544785 | Recruiting Phase 2 DMC

• 1 other identifier: GELLC-10-ZANUBIO
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this phase II randomized open label study is to compare the rate of complete remission (CR) with undetectable minimal residual disease (uMRD) obtained with zanubrutinib in combination with obinutuzumab with two different schedules of administration of obinutuzumab (starting obinutuzumab at cycle 2 or 12 months) in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). There is scarce information about which is the most appropriate schedule of combining the BTKi and the anti-CD20 monoclonal antibody, and whether treatment can be safely stopped in those patients attaining deep responses (CR with uMRD) remains to be determined. Response will be assessed after 20 cycles of treatment for the primary objective of the study. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Keywords

zanubrutinib; obinutuzumab; untreated CLL/SLL

Outcome Measures

Primary Outcomes (1)

• Rate of Complete Remission (CR) with undetectable Measurable Residual Disease (uMRD).

  To compare the rates of complete remission (CR) with undetectable minimal residual disease (uMRD, assessed by flow cytometry in bone marrow with a value \<10-4 \[0.01%\] tumour cells for being considered as negative) between both arms A and B. Response will be assessed after 20 cycles of treatment for the primary outcome measure. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first. Patients who achieve an uMRD in bone marrow beyond C20, will also be allowed to stop the treatment. The IWCLL guidelines (Hallek, 2018) will be used to measure response in CLL subjects.

  7.5 Years

Secondary Outcomes (6)

• Overall response rate (ORR)

  7.5 Years

• Measurable Residual Disease (MRD) analysis

  7.5 Years

• Progression-Free Survival (PFS)

  7.5 Years

• Overall Survival (OS)

  7.5 Years

• Immunological recovery

  7.5 Years

Study Arms (2)

Arm Zanubrutinib+early Obinutuzumab

EXPERIMENTAL

Patients will be treated with the combination of zanubrutinib 320 mg P.O qDay and obinutuzumab, starting obinutuzumab at cycle 2 to reduce infusion-related reactions. Intravenous obinutuzumab will be given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3-7. Response will be assessed after 20 cycles of treatment for the primary objective of the study. Patients that in the evaluation of cycle 20 who achieve uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity or trial completion, whichever comes first. Patients who achieve an uMRD in bone marrow beyond C20, will also be allowed to stop the treatment, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first.

Drug: Zanubrutinib Oral Product; Drug: Obinutuzumab

Arm Zanubutinib+late Obinutuzumab

EXPERIMENTAL

Patients will start treatment with zanubrutinib 320 mg P.O qDay in monotherapy. After 12 cycles of zanubrutinib patients will be treated with the combination of zanubrutinib and obitnutuzumab. Intravenous obinutuzumab will be given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 13 and on day 1 (1000 mg) of cycles 14-18. Response will be assessed after 20 cycles of treatment for the primary objective of the study. Patients that in the evaluation of cycle 20 who achieve uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity or trial completion, whichever comes first. Patients who achieve an uMRD in bone marrow beyond C20, will also be allowed to stop the treatment, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first.

Drug: Zanubrutinib Oral Product; Drug: Obinutuzumab

Interventions

Zanubrutinib Oral Product DRUG

Zanubrutinib drug product is supplied as 80 mg strengths in capsules for oral administration. In both arms A and B, zanubrutinib 320 mg will be taken qDay with or without food. Patients will take zanubrutinib with water at approximately the same time every day.

Also known as: Zanubrutinib

Arm Zanubrutinib+early Obinutuzumab; Arm Zanubutinib+late Obinutuzumab

Obinutuzumab DRUG

Each dose of obinutuzumab is 1000 mg administered intravenously, per institutional standards, with the exception of the first infusion in Cycle 2 (arm A) or Cycle 13 (arm B). It is recommended that the initial 1000 mg dose be administered over Day 1 (100 mg) and Day 2 (900 mg). For subjects who tolerate the initial 100 mg dose well and required no dose interruption or modification of the infusion rate, the treating physician may opt to administer the remaining 900 mg on Day 1. Arm A: patients will receive obinutuzumab on days 1 (100 mg), 2 (or day 1 continued, 900 mg), 8 and 15 (1000 mg) of the cycle 2 of zanubrutinib treatment, and on the day 1 of cycles 3-7 (1000 mg). Arm B: patients will receive obinutuzumab on days 1 (100 mg), 2 ( (or day 1 continued, 900 mg), 8 and 15 (1000 mg) of the cycle 13 of zanubrutinib treatment, and on the day 1 of cycles 14-18 (1000 mg).

Arm Zanubrutinib+early Obinutuzumab; Arm Zanubutinib+late Obinutuzumab

Eligibility Criteria

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

You may qualify if:

• Adult patients with previously untreated CLL defined following IWCLL criteria (Hallek, 2018).
• Must understand and voluntarily sign an informed consent form.
• Age ≥ 18 years at the time of signing the informed consent form and must be able to adhere to the study visit schedule and other protocol requirements.
• Must have a documented diagnosis of CLL or SLL \[IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018)\] meeting at least one of the following criteria:
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
• Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
• Massive nodes (i.e. ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
• Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or lymphocyte doubling time (LDT) of less than 6 months.
• A minimum of any one of the following disease-related symptoms: unintentional weight loss ≥ 10% within the previous 6 months, significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities), fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection, or night sweats for more than 1 month without evidence of infection.
• Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids.
• Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine).
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
• Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib and 18 months after last dose of obinutuzumab.
• Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other applicable highly effective methods described below during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib and 18 months after last dose of obinutuzumab.
• A woman is considered of childbearing potential, ie, fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Contraception methods include the following:

You may not qualify if:

• Prior treatment for CLL.
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative could be eligible if they have an undetectable HBV DNA (negative polymerase chain reaction (PCR) \<20 IU). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.
• Per published guidelines (NCCN 2012) or institutional guidelines, patients should be closely monitored for hepatitis B reactivation. Obtaining repeated hepatitis B PCR every 3 months during treatment and for the 12 months after last dose of study drug according to usual clinical practice in order to monitor for reactivation of hepatitis B is recommended.
• Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤30 mL/min/1.73m2.
• Absolute neutrophil count (ANC) \< 1.0 X 109/L.
• Platelet count \< 75 X 109/L, except for patients with bone marrow involvement by CLL in which case the platelet count must be ≥ 30 X 109/L.
• Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) \>2.5 x upper limit of normal (ULN).
• Serum total bilirubin \> 1.5 x ULN, except in cases of Gilbert's syndrome.
• Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) \> 2x ULN.
• Active bleeding, history of bleeding diathesis (eg, haemophilia or von Willebrand disease).
• Unable to swallow capsules, or has disease significantly affecting gastrointestinal function that would limit absorption of oral medication.
• Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 3 months prior to enrollment. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening can enrol on study.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
• Systemic infection that has not resolved prior to initiating study treatment in spite of adequate anti-infective therapy.
• Pregnant or lactating females.

Sponsors & Collaborators

• PETHEMA Foundation: lead

Study Sites (1)

H. Vall d'Hebron

Barcelona, Spain

RECRUITING

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

zanubrutinib; obinutuzumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Pau Abrisqueta

  Hospital Universitari Vall d'Hebrón

  PRINCIPAL INVESTIGATOR

• Francesc Bosch

  Hospital Universitari Vall d'Hebrón

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Pau Abrisqueta

CONTACT

+34934 89 30 00; pabrisqueta@vhio.net

Francesc Bosch

CONTACT

+34934 89 30 00; fbosch@vhio.net

Study Design

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

Study Record Dates

• First Submitted: August 5, 2024
• First Posted: August 9, 2024
• Study Start: September 2, 2024
• Primary Completion (Estimated): May 31, 2032
• Study Completion (Estimated): May 31, 2032
• Last Updated: October 24, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)