Venetoclax + Rituximab for Waldenstrom Macroglobulinemia

Not currently recruiting at 139 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Prior systemic therapy, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of two different drug combinations for individuals with Waldenstrom's macroglobulinemia, a type of blood cancer. One group will receive venetoclax (a targeted therapy) and rituximab, while the other will receive ibrutinib and rituximab. The goal is to determine which combination more effectively stops cancer growth. This trial is suitable for those diagnosed with Waldenstrom's macroglobulinemia who have not received prior treatment, especially if they experience symptoms like anemia or fatigue that impact daily life. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that venetoclax and rituximab are generally well-tolerated by patients with Waldenstrom's macroglobulinemia. Studies have found that venetoclax is safe and effective for those who have already received treatment for this condition. No major safety concerns have been reported when venetoclax is combined with rituximab.

The combination of ibrutinib and rituximab is already used to treat certain blood cancers and is usually well-tolerated. While side effects can occur, they are typically manageable.

Both treatments are promising and have been used in similar situations without major safety issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the venetoclax and rituximab combination for Waldenstrom Macroglobulinemia because venetoclax offers a unique mechanism of action. Unlike traditional treatments that primarily target surface proteins on cancer cells, venetoclax works by inhibiting the BCL-2 protein, which is responsible for cancer cell survival. This approach may lead to more effective cell death in cancerous cells. Additionally, combining venetoclax with rituximab could enhance the treatment's potency, potentially leading to better outcomes for patients who don't respond adequately to existing therapies like ibrutinib and rituximab alone.

What evidence suggests that this trial's treatments could be effective for Waldenstrom's macroglobulinemia?

Research has shown that combining venetoclax and rituximab, which participants in Arm II of this trial may receive, may effectively treat Waldenstrom's macroglobulinemia. Studies have found that this combination works well and causes few side effects. In some cases, about 70% of patients experienced positive results.

Conversely, ibrutinib combined with rituximab, studied in Arm I of this trial, has successfully slowed the disease by blocking certain enzymes that cancer cells need to grow. Both treatment combinations offer promising ways to manage Waldenstrom's macroglobulinemia. ^{1 5 6 7 8}

Who Is on the Research Team?

Sikander Ailawadhi

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Rituximab
• Venetoclax

Trial Overview 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.

How Is the Trial Designed?

Group I: Arm II (venetoclax, rituximab) Experimental Treatment 7 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 2 and 5. Cycles repeat 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 throughout the trial.

Group II: Arm I (ibrutinib, rituximab) Active Control 7 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 2 and 5. Cycles repeat 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 throughout 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

After a median follow-up of 46 months in the GLOW study, patients with untreated chronic lymphocytic leukaemia who received ibrutinib-venetoclax had a significantly better progression-free survival rate (74.6%) compared to those treated with chlorambucil-obinutuzumab (24.8%), indicating the efficacy of the ibrutinib-venetoclax combination as a first-line treatment.

While there were treatment-related deaths in both groups, the overall mortality was lower in the ibrutinib-venetoclax group (15 deaths) compared to the chlorambucil-obinutuzumab group (30 deaths), suggesting a potentially safer profile for the ibrutinib-venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Niemann, CU., Munir, T., Moreno, C., et al.[2023]

Rituximab-based regimens, particularly bendamustine-rituximab (BR), showed higher response rates (46%) compared to bortezomib-dexamethasone (33%) and ibrutinib-rituximab (26%) in treating Waldenstrom macroglobulinaemia, based on a systematic review of 11 trials involving 736 patients.

The two-year progression-free survival rates were also favorable for BR (89%) compared to BDRC (81%) and IR (82%), although different regimens had varying toxicity profiles, with neuropathy being more common in bortezomib treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis. Chan, WL., Chong, VCL., Wee, IJY., et al.[2023]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a study of 31 patients with rituximab-refractory Waldenström's macroglobulinaemia, ibrutinib demonstrated a high overall response rate of 90%, with 71% achieving a major response, indicating its efficacy as a treatment option for this difficult-to-treat population.

The treatment also showed a favorable safety profile, with manageable adverse effects, and significant improvements in hemoglobin levels and quality of life measures, suggesting that ibrutinib could be a viable chemotherapy-free alternative for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Dimopoulos, MA., Trotman, J., Tedeschi, A., et al.[2022]

In the iNNOVATE study, patients with Waldenström's macroglobulinemia treated with ibrutinib-rituximab had a significantly longer progression-free survival (PFS) of not reached compared to 20.3 months for those on placebo-rituximab, indicating strong efficacy of the treatment over a median follow-up of 50 months.

The combination of ibrutinib and rituximab resulted in higher response rates (76% vs. 31%) and better hemoglobin improvement (77% vs. 43%) compared to placebo, while maintaining a manageable safety profile with fewer severe adverse events over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. Buske, C., Tedeschi, A., Trotman, J., et al.[2023]

Ibrutinib, administered at 420 mg daily, demonstrated sustained efficacy in patients with rituximab-refractory Waldenström macroglobulinemia, achieving an overall response rate of 87% and a median progression-free survival of 39 months after a median follow-up of 58 months.

The treatment was well tolerated with a manageable safety profile, showing no new safety concerns, and significant improvements in hemoglobin levels and serum IgM were observed, indicating its effectiveness in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III InnovateTM Trial. Trotman, J., Buske, C., Tedeschi, A., et al.[2023]

In a study of 150 patients with relapsed Waldenström's macroglobulinemia, the combination of ibrutinib and rituximab significantly improved progression-free survival rates to 82% compared to 28% with placebo and rituximab, indicating a strong efficacy of the treatment.

While ibrutinib-rituximab showed higher response rates and sustained hemoglobin improvements, it also had increased risks of atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%) compared to placebo-rituximab, highlighting the need to monitor for these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. Dimopoulos, MA., Tedeschi, A., Trotman, J., et al.[2021]

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

In a study of 389 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), fixed-duration venetoclax plus rituximab (VenR) showed significantly better long-term outcomes compared to bendamustine plus rituximab (BR), with 4-year progression-free survival (PFS) rates of 57.3% versus 4.6%.

Achieving undetectable minimal residual disease (uMRD) at the end of treatment was linked to superior PFS, and patients who received ibrutinib after VenR had a remarkable 100% response rate, highlighting the effectiveness of VenR and its potential for durable responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Kater, AP., Wu, JQ., Kipps, T., et al.[2023]

The HOVON 141/VISION trial is investigating the combination treatment of ibrutinib and venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia (RR-CLL), focusing on the possibility of stopping ibrutinib in patients who achieve undetectable minimal residual disease (uMRD) after 12 cycles of treatment.

The primary goal of the study is to assess progression-free survival 12 months after randomization, providing insights into the long-term efficacy and safety of discontinuing ibrutinib in patients who have reached deep remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Levin, MD., Kater, AP., Mattsson, M., et al.[2021]

A 71-year-old patient with Waldenström's macroglobulinemia, who was resistant to standard treatments, showed rapid clinical improvement when treated with idelalisib, suggesting its potential efficacy in this context.

This case highlights idelalisib as a viable treatment option for patients with Waldenström's macroglobulinemia who cannot receive ibrutinib due to complications like renal failure or other health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idelalisib in a patient with refractory Waldenström's macroglobulinemia complicated by anuric renal failure: a case report. D'Aveni-Piney, M., Divoux, M., Busby-Venner, H., et al.[2019]

In a 5-year study involving 150 participants with Waldenström's macroglobulinemia, the combination of ibrutinib and rituximab significantly improved disease outcomes and prolonged the time without disease progression compared to rituximab alone.

Participants receiving the combination treatment also reported a greater improvement in quality of life, and the side effects were manageable and decreased over time, confirming the long-term safety and efficacy of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia. Buske, C., Tedeschi, A., Trotman, J., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05099471

Study Details | NCT05099471 | Efficacy of Venetoclax in ... The hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12000436/

Outcomes of patients with relapsed/refractory ... The overall and major response rates to venetoclax were 70% and 63%, respectively. The median and 2-year progression-free survival (PFS) were ...

3. ashpublications.org ashpublications.org/bloodadvances/article/9/19/4842/546239/Long-term-follow-up-of-venetoclax-monotherapy-in

Long-term follow-up of venetoclax monotherapy in previously ... The median progression-free survival (PFS) was 36 months, and the median treatment-free survival (TFS) was 43 months. PFS and TFS were superior ...

4. trialx.com trialx.com/clinical-trials/listings/296274/efficacy-of-venetoclax-in-combination-with-rituximab-in-waldenstroms-macroglobulinemia/

Efficacy of Venetoclax in Combination With Rituximab ... First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior ...

5. swog.org swog.org/patients/trials-open-patients/combining-drugs-venetoclax-and-rituximab-first-treatment-waldenstroms

Combining the Drugs Venetoclax and Rituximab as a First ... Previous research showed that combining venetoclax and rituximab can work well against WM that came back or didn't respond to other treatment.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04840602?term=AREA%5BBasicSearch%5D(gp2013)&rank=10

NCT04840602 | Testing the Combination of Venetoclax ... Giving venetoclax and rituximab may work better in treating patients with previously untreated Waldenstrom's macroglobulinemia than ibrutinib and rituximab ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8683218/

Venetoclax in Previously Treated Waldenström ... Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect ...

8. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 Learn about VENCLEXTA® 6-year overall survival and treatment efficacy results. See full safety and Prescribing Information for more details.