Zanubrutinib + Rituximab for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: M.D. Anderson Cancer Center
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial studies how well zanubrutinib and rituximab work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma for which the patient has not received treatment in the past (previously untreated). Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. The study is being done to find out if zanubrutinib combined with rituximab can help control previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently on warfarin (Coumadin) or any other vitamin K antagonist, unless you switch to a non-vitamin K antagonist like a NOAC/DOAC at least 7 days before starting the study. Please consult with the trial team for more details.
What data supports the idea that Zanubrutinib + Rituximab for Chronic Lymphocytic Leukemia is an effective drug?
The available research shows that Rituximab, when combined with other drugs like fludarabine and cyclophosphamide, improves survival rates for patients with Chronic Lymphocytic Leukemia (CLL). Although specific data on Zanubrutinib combined with Rituximab is not provided, Rituximab's effectiveness in combination with other treatments suggests it could be beneficial. Rituximab has been shown to increase the time patients live without the disease getting worse and overall survival when used with other chemotherapy drugs. This suggests that combining Rituximab with Zanubrutinib might also be effective, given Rituximab's proven track record in improving outcomes in CLL.
12345What safety data is available for Zanubrutinib and Rituximab in treating CLL?
Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, has been studied in combination with Rituximab for treating chronic lymphocytic leukemia (CLL). In the SEQUOIA trial, Zanubrutinib showed improved progression-free survival compared to bendamustine plus Rituximab. Common adverse events included upper respiratory tract infections, neutropenia, contusion, cough, diarrhea, and fatigue. Grade 3/4 adverse events were primarily neutropenia and pneumonia. Zanubrutinib was generally well tolerated, with some patients requiring dose adjustments or discontinuation due to adverse events.
678910Is the drug Rituximab, Zanubrutinib a promising treatment for Chronic Lymphocytic Leukemia?
Yes, Rituximab, Zanubrutinib is a promising treatment for Chronic Lymphocytic Leukemia. Studies show that it significantly improves progression-free survival, meaning patients can live longer without the disease getting worse. It also has a better safety profile compared to some older treatments, making it a preferred option for many patients.
6781112Eligibility Criteria
Adults with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma, who are generally healthy and not pregnant. They should be able to perform daily activities with ease to moderate difficulty (ECOG 0-2), have normal liver and kidney function tests, and no recent history of other cancers except certain skin cancers or localized cancer that has been treated.Inclusion Criteria
I can take care of myself and am up and about more than half of the day.
I have been diagnosed with CLL/SLL and have not received any treatment.
My kidneys work well enough, with a creatinine clearance over 30 mL/min.
+7 more
Exclusion Criteria
I am currently pregnant or breastfeeding.
My blood tests show very low white blood cells or platelets.
I have had minor surgery or a biopsy within the last week, but bone marrow procedures are okay.
+14 more
Participant Groups
The trial is testing the combination of zanubrutinib, an enzyme blocker, and rituximab, a monoclonal antibody against previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. The goal is to see if this drug combo can control these blood cancers effectively.
1Treatment groups
Experimental Treatment
Group I: Treatment (zanubrutinib, rituximab)Experimental Treatment2 Interventions
See Detailed Description.
Rituximab is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Rituxan for:
- Non-Hodgkin's lymphoma
- Chronic lymphocytic leukemia
- Rheumatoid arthritis
- Granulomatosis with polyangiitis
- Microscopic polyangiitis
🇪🇺 Approved in European Union as MabThera for:
- Non-Hodgkin's lymphoma
- Chronic lymphocytic leukemia
- Rheumatoid arthritis
- Granulomatosis with polyangiitis
- Microscopic polyangiitis
🇨🇦 Approved in Canada as Rituxan for:
- Non-Hodgkin's lymphoma
- Chronic lymphocytic leukemia
- Rheumatoid arthritis
- Granulomatosis with polyangiitis
- Microscopic polyangiitis
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
[Monoclonal Antibodies in the Treatment of Chronic Lymphocytic Leukemia in 2015]. [2019]Chemotherapy combinations with monoclonal antibodies are now the basis for treatment of chronic lymphocytic leukemia. Rituximab, the most widely used anti-CD20 antibody in routine clinical practice, led not only to improvement of progression-free survival, but also to improvement of overall survival in previously untreated patients with good performance status in combination with fludarabine and cyclophosphamide. This regimen has become the standard treatment for patients in good physical condition. Rituximab and the newest anti-CD20 antibody obinutuzumab in combination with chlorambucil, as compared with chlorambucil alone, prolonged overall survival in previously untreated patients with significant comorbidities, and the combination of anti-CD20 antibody with chlorambucil has become the standard regimen in this group of patients. Alemtuzumab and ofatumumab improved treatment results in refractory chronic lymphocytic leukemia. Targeted therapy with combination chemotherapy and monoclonal antibody in patients with chronic lymphocytic leukemia represents a significant advance in the treatment of this disease.
Modelling the cost effectiveness of rituximab in chronic lymphocytic leukaemia in first-line therapy and following relapse. [2021]The efficacy and safety of adding rituximab to fludarabine and cyclophosphamide (R-FC) for the treatment of chronic lymphocytic leukaemia (CLL) has been demonstrated in two randomised trials: CLL-8 was conducted in previously untreated patients, and REACH was conducted in previously treated patients. In both trials, progression-free survival was increased in the R-FC treatment groups compared with the FC treatment groups. In CLL-8, overall survival was also significantly increased.
Rituximab in chronic lymphocytic leukemia. [2023]Rituximab (Rituxan; iogen Idec, San Diego, CA, USA) is a human-mouse chimeric monoclonal antibody specific for CD20, a surface glycoprotein expressed on B lymphocytes. Administration of rituximab as a single agent to patients with chronic lymphocytic leukemia (CLL) has limited clinical activity, but generally does not eradicate leukemia from the marrow. However, when administered in combination with chemotherapy, rituximab can improve the survival of patients relative to those treated with chemotherapy alone. As a result of this, the US Food and Drug Administration approved the use of rituximab in previously untreated and previously treated CD20-positive CLL in combination with fludarabine monophosphate and cyclophosphamide. The results of clinical studies evaluating the activity of rituximab when used alone or in combination with other antileukemia agents for the treatment of this disease are reviewed here.
Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. [2021]The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited.
Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline. [2018]Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario. Data were extracted from randomised controlled trials of rituximab-containing chemotherapy regimens for patients with lymphoma or CLL. Fifty-six primary randomised controlled trials were retrievable and met all inclusion criteria. Clinically important benefits in progression-free survival or overall survival were seen in the following settings: (i) addition of rituximab to combination chemotherapy for initial treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma, Burkitt lymphoma and HIV-related lymphoma with CD4 count ≥50/mm3; (ii) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; (iii) use of rituximab maintenance in patients with indolent B-cell lymphomas who have responded to chemoimmunotherapy; (iv) addition of rituximab to fludarabine-based chemotherapy or chlorambucil for initial treatment of CLL. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.
Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. [2023]Zanubrutinib is a highly selective, next-generation Bruton's tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted in significantly improved progression-free survival compared to bendamustine plus rituximab (BR) in adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) without del(17p). The current analysis compared the effects of zanubrutinib versus BR on patients' health-related quality-of-life (HRQoL).
Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. [2023]Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.
Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.
Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. [2022]Bruton's tyrosine kinase inhibitors have changed the treatment landscape for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma dramatically. In 2019, acalabrutinib was approved by the US FDA for the treatment of treatment-naive and relapsed/refractory CLL and MCL. Acalabrutinib monotherapy was found to be effective and safe in CLL patients. In ASCEND and ELEVATE treatment-naive studies, acalabrutinib monotherapy and the combination with obinutuzumab demonstrated improved efficacy and an acceptable safety profile. The triple combination with venetoclax showed a high rate of molecular remission without an impaired safety profile. Adverse events, with an occurrence rate of >20%, were as follows: grade 1-2 myelosuppression, gastrointestinal toxicity, rash, constitutional symptoms; grade 3 or 4 toxicities were syncope, pneumonia, hypertension, atrial fibrillation, neutropenia and thrombocytopenia.
Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.
Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. [2023]Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a next-generation irreversible inhibitor of Bruton's tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.
Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. [2023]Ibrutinib, the first-in-class Bruton's tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine-rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu's advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.