Venetoclax + Rituximab for Waldenstrom Macroglobulinemia

Recruiting at 101 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

92 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 5 6 7}

How 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. ^{8 9 10 11 12}

Research Team

Sikander Ailawadhi

Principal Investigator

SWOG Cancer Research Network

Eligibility 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.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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 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]

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]

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 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]

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]

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 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]

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]

References

1. England 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. [2022]

2. England 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Idelalisib in a patient with refractory Waldenström's macroglobulinemia complicated by anuric renal failure: a case report. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. [2021]

5. United States 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. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III InnovateTM Trial. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. [2023]

9. England 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. [2023]

10. United States 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. [2023]

11. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

12. England 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. [2021]