Ibrutinib + Ixazomib for Waldenstrom's Macroglobulinemia

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

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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 Waldenstrom macroglobulinemia that is newly diagnosed, has come back (recurrent) or does not respond to treatment (refractory). Enzyme inhibitors, such as ibrutinib and ixazomib citrate, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

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 the combination of Ibrutinib and Ixazomib safe for humans?

Ibrutinib has been generally well-tolerated in patients with Waldenström's macroglobulinemia, but there are reports of serious heart rhythm problems, including ventricular fibrillation (a dangerous heart rhythm). There is no specific safety data available for the combination of Ibrutinib and Ixazomib. ^{1 2 3 4 5}

How is the drug combination of Ibrutinib and Ixazomib unique for treating Waldenstrom's Macroglobulinemia?

The combination of Ibrutinib and Ixazomib for Waldenstrom's Macroglobulinemia is unique because it combines two drugs with different mechanisms: Ibrutinib, which blocks a protein that helps cancer cells grow, and Ixazomib, which disrupts protein breakdown in cells, potentially offering a new approach for patients who may not respond to standard treatments. ^{1 3 4 6 7}

What data supports the effectiveness of the drug combination Ibrutinib and Ixazomib for treating Waldenstrom's Macroglobulinemia?

Research shows that Ibrutinib alone or combined with Rituximab is effective for treating Waldenstrom's Macroglobulinemia, especially in patients who have been previously treated or are resistant to Rituximab. While there is no direct data on the combination of Ibrutinib and Ixazomib, Ibrutinib has shown substantial activity in this condition. ^{1 3 4 6 7}

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 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]

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]

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

Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia. [2022]

2. 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]

3. 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]

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

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

6. England pubmed.ncbi.nlm.nih.gov

Sudden ventricular fibrillation and death during ibrutinib therapy-A case report. [2021]

7. 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]