Ibrutinib + Ixazomib for Waldenstrom's Macroglobulinemia

No longer recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Strong CYP3A inducers

Disqualifiers: Surgery, Cardiovascular, Neuropathy, 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: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how well two medications, ibrutinib (Imbruvica) and ixazomib (Ninlaro), work together to treat Waldenstrom's macroglobulinemia, a type of blood cancer. Researchers aim to determine if this combination stops cancer cells from growing in patients who are newly diagnosed, have had their cancer return, or have cancers that don't respond to treatment. Individuals with Waldenstrom's macroglobulinemia who have a measurable amount of the disease and have not previously used ixazomib might be suitable for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take strong CYP3A inducers or participate in other clinical trials during the study.

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

Research has shown that using ibrutinib and ixazomib together might help treat Waldenstrom's Macroglobulinemia. In some studies, a number of patients stopped the treatment due to side effects, with 28.5% discontinuing because these reactions were hard to manage.

Ibrutinib alone has FDA approval for other conditions, indicating a certain level of safety. However, combining it with ixazomib might increase side effects. Patients should weigh these potential side effects against the benefits when deciding whether to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for Waldenstrom's Macroglobulinemia, which often involve chemotherapy, ibrutinib combined with ixazomib brings a fresh approach by targeting specific pathways in the cancer cells. Ibrutinib inhibits Bruton's tyrosine kinase (BTK), which is crucial for cancer cell survival, while ixazomib inhibits the proteasome, helping to dismantle proteins that cancer cells need to grow. This dual-action approach is exciting for researchers because it offers a more precise attack on cancer cells, potentially leading to more effective outcomes with fewer side effects compared to traditional chemotherapy.

What evidence suggests that ibrutinib and ixazomib could be effective for Waldenstrom's macroglobulinemia?

This trial will evaluate the combination of ibrutinib and ixazomib for treating Waldenstrom's macroglobulinemia. Research has shown that using these drugs together may help treat this condition. Studies have found that this combination can block certain enzymes that cancer cells need to grow, potentially stopping or slowing the disease. Early results indicated that patients, whether newly diagnosed or with recurring forms of the condition, responded well to the treatment. These findings suggest that this combination could effectively manage the disease and might improve patient outcomes. ^{1 2 3 5 6}

Who Is on the Research Team?

Asher A. Chanan-Khan, M.D.

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults with Waldenstrom macroglobulinemia, whether newly diagnosed, relapsed or treatment-resistant. Participants must be able to give consent, provide blood and bone marrow samples, have certain minimum blood counts and organ function levels, not be pregnant or breastfeeding, use effective contraception if of childbearing potential, and have no major surgery planned.

Inclusion Criteria

My condition is confirmed Waldenstrom macroglobulinemia, whether new, relapsed, or refractory.

I have signs of disease like specific proteins in my blood, swollen lymph nodes, or more than 10% of my bone marrow is affected.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I do not have any uncontrolled heart or blood pressure problems.

I have moderate to severe nerve damage in my hands or feet, or mild nerve damage with pain.

I have an active hepatitis B or C infection, or I am HIV positive.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ixazomib citrate orally on days 1, 8, and 15 and ibrutinib daily on days 1-28. Treatment repeats every 28 days for up to 24 cycles.

24 months

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3 months for up to 2 years.

24 months

Quarterly visits

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Ixazomib Citrate

Trial Overview The study tests the effectiveness and side effects of combining two enzyme inhibitors: Ibrutinib citrate and Ixazomib citrate in treating Waldenstrom macroglobulinemia. It includes laboratory biomarker analysis along with pharmacodynamic and pharmacokinetic studies to understand how these drugs work together against cancer cells.

How Is the Trial Designed?

Group I: Treatment (ixazomib citrate, ibrutinib) Experimental Treatment 5 Interventions

Patients receive ixazomib citrate PO on days 1, 8, and 15 and ibrutinib PO daily on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38286472/

A phase II study of ibrutinib in combination with ixazomib ... This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; ...

2. iwmf.com iwmf.com/wp-content/uploads/2024/02/ixazomib_WM_Jan2024.pdf

A phase II study of ibrutinib in combination with ixazomib in ... We report preclini- cal data evaluating the efficacy and mechanisms of action of ibrutinib and ixazomib in WM cell lines as well as the results.

3. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/9331/490741/Phase-II-Study-of-Ibrutinib-in-Combination-with

Phase II Study of Ibrutinib in Combination with Ixazomib in ... We report preliminary data from a phase 2 trial evaluating the efficacy of ixazomib and ibrutinib in pts with newly diagnosed (NDWM) as well as relapsed/ ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03506373

Ibrutinib and Ixazomib Citrate in Treating Newly Diagnosed ... This phase II trial studies the side effects of ibrutinib citrate when given with ixazomib, and determines how well they work in treating patients with ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/bjh.19320

A phase II study of ibrutinib in combination with ixazomib ... We report preclinical data evaluating the efficacy and mechanisms of action of ibrutinib and ixazomib in WM cell lines as well as the results ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4959643/

Ibrutinib in Waldenström macroglobulinemia Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor, which has recently gained approval by the United States (US) Food and Drug Administration (FDA)