A Multicenter, Phase 2 Randomized, Open Label Study to Evaluate Zanubrutinib in Combination With Obinutuzumab in Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) (GELLC-10-ZANUBIO)
Overview
- Phase
- Phase 2
- Intervention
- Zanubrutinib Oral Product
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- PETHEMA Foundation
- Enrollment
- 106
- Locations
- 1
- Primary Endpoint
- Rate of Complete Remission (CR) with undetectable Measurable Residual Disease (uMRD).
- Status
- Recruiting
- Last Updated
- last year
Overview
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.
Detailed Description
This a multicenter, phase 2 randomized, open label study of the Spanish Group of CLL (GELLC) for patients with untreated CLL/SLL with 2 arms of treatment. In this study, 106 patients from 20 centers in Spain with untreated CLL/SLL will be randomized (1:1) to arm A (n= 53) or arm B (n= 53). The randomization will be stratified according to the presence/absence of deletion/mutation 17p/TP53 at the time of inclusion and based on the randomization list generated by the study statistician. Arm A: 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. Arm B: 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 (\<0.01% tumour cells by flow cytometry) 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. In addition, the efficacy and safety of the combination therapy with two different administration schedules of obinutuzumab will be analysed through the following outcome measures: i) Overall response rate, including Complete Remission (CR), CR with incomplete marrow recovery (CRi), Partial Remission (PR), and partial response with lymphocytosis; ii) MRD analysis; iiI) Duration of response and progression-free survival (PFS); iv) Safety: type, frequency, and severity of adverse events (AEs) and relationship of AEs to zanubrutinib or the combination of zanubrutinib and obinutuzumab; v) Response rate in relationship to molecular and genetic prognostic factors; vi) Immunological recovery; vii) Overall survival (OS); viii) Biomarkers for response.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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/1.73m
- •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).
Arms & Interventions
Arm Zanubrutinib+early Obinutuzumab
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.
Intervention: Zanubrutinib Oral Product
Arm Zanubrutinib+early Obinutuzumab
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.
Intervention: Obinutuzumab
Arm Zanubutinib+late Obinutuzumab
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.
Intervention: Zanubrutinib Oral Product
Arm Zanubutinib+late Obinutuzumab
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.
Intervention: Obinutuzumab
Outcomes
Primary Outcomes
Rate of Complete Remission (CR) with undetectable Measurable Residual Disease (uMRD).
Time Frame: 7.5 Years
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.
Secondary Outcomes
- Overall Survival (OS)(7.5 Years)
- Progression-Free Survival (PFS)(7.5 Years)
- Adverse Events (AE)(7.5 Years)
- Overall response rate (ORR)(7.5 Years)
- Measurable Residual Disease (MRD) analysis(7.5 Years)
- Immunological recovery(7.5 Years)