Venetoclax + Rituximab for Waldenstrom Macroglobulinemia
Recruiting in Palo Alto (17 mi)
+98 other locations
Overseen bySikander Ailawadhi
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: CYP3A inducers, CYP3A inhibitors
Disqualifiers: Prior systemic therapy, Active infection, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial studies the effects of venetoclax and rituximab in comparison to ibrutinib and rituximab in treating patients with previously untreated Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving venetoclax and rituximab may work better in treating patients with previously untreated Waldenstrom's macroglobulinemia than ibrutinib and rituximab alone.
Will I have to stop taking my current medications?
The trial requires that participants do not use certain medications that affect liver enzymes (CYP3A inducers or inhibitors) within 7 days before starting the study drug. If you are on such medications, you may need to switch to a different one to participate.
What data supports the effectiveness of the drug combination Venetoclax and Rituximab for Waldenstrom Macroglobulinemia?
Research shows that the combination of ibrutinib and rituximab is effective for treating Waldenström's macroglobulinemia, with ibrutinib helping to reduce cancer cell growth and rituximab aiding the immune system in targeting cancer cells. This suggests that combining drugs like venetoclax, which also targets cancer cells, with rituximab could be beneficial.
12345Is the combination of Venetoclax and Rituximab safe for treating Waldenstrom Macroglobulinemia?
The combination of Ibrutinib (a drug similar to Venetoclax) and Rituximab has been shown to be generally well-tolerated in people with Waldenström's macroglobulinemia, although some patients experienced heart-related side effects. This suggests that similar treatments may also be safe, but it's important to discuss potential risks with your doctor.
12567How is the drug combination of Venetoclax and Rituximab unique for treating Waldenstrom Macroglobulinemia?
The combination of Venetoclax and Rituximab is unique because it has shown promising results in other conditions like chronic lymphocytic leukemia, offering a potentially effective option with a manageable safety profile, which might be beneficial for Waldenstrom Macroglobulinemia as well.
89101112Eligibility Criteria
This trial is for adults with untreated Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma who have symptoms like anemia, neuropathy, or significant weight loss. They must not be on certain drugs that affect the body's enzyme systems and should have good kidney function and acceptable blood test results.Inclusion Criteria
I do not have any active infections or hepatitis C.
Participants must have IgM Spike ≥ 500 mg/dL (≥ 5 g/L)
I haven't had any cancer treatment except for rituximab over 6 months ago.
+14 more
Exclusion Criteria
I cannot make medical decisions and do not have a legal representative.
I have had cancer before, but it doesn't meet the trial's specific criteria.
My lymphoma has become more aggressive or I have Bing-Neel syndrome.
+2 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive either ibrutinib and rituximab or venetoclax and rituximab for up to 24 cycles, with each cycle lasting 28 days
24 months
Monthly visits for drug administration and monitoring
Crossover Treatment
Participants with progressive disease may switch to the alternative treatment arm for up to an additional 24 cycles
24 months
Follow-up
Participants are monitored every 3 months until progression, death, or 5 years after initial registration, whichever occurs first
Up to 5 years
Quarterly visits
Participant Groups
The study compares two treatments: Venetoclax with Rituximab versus the usual Ibrutinib with Rituximab. It aims to see if blocking a protein needed by cancer cells (with Venetoclax) plus helping the immune system target cancer cells (with Rituximab) is more effective than current standard treatment.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm II (venetoclax, rituximab)Experimental Treatment7 Interventions
Patients receive venetoclax PO QD on days 1-28 of each cycle and rituximab IV on days 1, 8, 15, and 22 of cycles 1 and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm II may receive ibrutinib and rituximab as in Arm I for up to an additional 24 cycles. Patients undergo CT or PET/CT and bone marrow biopsy and aspiration as well as blood sample collection during screening and on the trial.
Group II: Arm I (ibrutinib, rituximab)Active Control7 Interventions
Patients receive ibrutinib PO QD on days 1-28 of cycles 1-24 and rituximab IV on days 1, 8, 15, and 22 of cycles 1 and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm I may receive rituximab and venetoclax as in Arm II for up to an additional 24 cycles. Patients undergo CT or PET/CT and bone marrow biopsy and aspiration as well as blood sample collection during screening and on the trial.
Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
- Graft-versus-host disease
🇺🇸 Approved in United States as Imbruvica for:
- Chronic lymphocytic leukemia/small lymphocytic lymphoma
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
- Graft-versus-host disease
🇨🇦 Approved in Canada as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
🇯🇵 Approved in Japan as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Chelsea HospitalChelsea, MI
Michigan Healthcare Professionals PontiacPontiac, MI
Carolinas Medical Center/Levine Cancer InstituteCharlotte, NC
Trinity Health Medical Center - CantonCanton, MI
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. [2022]In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease.
Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia. [2023]Label="WHAT IS THIS SUMMARY ABOUT?" NlmCategory="UNASSIGNED">This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo ("sugar pill") plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months).
Idelalisib in a patient with refractory Waldenström's macroglobulinemia complicated by anuric renal failure: a case report. [2019]Waldenström's macroglobulinemia is a rare B-cell lymphoma. The gold standard treatment for Waldenström's macroglobulinemia is an anti-CD20 antibody (rituximab) in combination with alkylating agents and dexamethasone. Treatment targeting the B-cell receptor such as ibrutinib (but not idelalisib) is currently approved for treatment of patients with relapsed or refractory Waldenström's macroglobulinemia.
Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. [2021]Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.
Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. [2023]The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE.
Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis. [2023]Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted.
Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III InnovateTM Trial. [2023]The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported.
Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. [2023]The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear.
Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. [2023]In the GLOW study, fixed-duration ibrutinib-venetoclax showed superior progression-free survival versus chlorambucil-obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up.
Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. [2023]In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.
Chronic lymphocytic leukemia at ASH 2017. [2020]At ASH (American Society of Hematology) 2017 three out of a plethora of trials showed remarkable and promising results. The combinations of venetoclax with rituximab and ibrutinib with venetoclax convinced with striking efficacy together with a manageable safety profile in relapsed/refractory setting as well as in first line therapy of high-risk disease. These two combinations are potential new standard treatment options in chronic lymphocytic leukemia.
Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance ≥30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations. [2021]Literature is scarce on the combination treatment of ibrutinib and venetoclax (IV) is scarce in relapsed or refractory chronic lymphocytic leukaemia (RR-CLL). Especially, the possibility of stopping ibrutinib in RR-CLL patients in deep remission is unclear.