Ixazomib + Rituximab for Non-Hodgkin Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: CYP1A2 inhibitors, CYP3A inhibitors

Disqualifiers: Infection, Cardiovascular conditions, 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

Compensation: Varies

Number of Visits: 30

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining ixazomib citrate and rituximab to treat slow-growing non-Hodgkin lymphoma, a type of blood cancer. Ixazomib citrate blocks certain enzymes to stop cancer cell growth, while rituximab interferes with the cancer cells' ability to grow and spread. Patients who have not received standard systemic treatment for their specific type of non-Hodgkin lymphoma, such as chronic lymphocytic leukemia or follicular lymphoma, might be suitable candidates. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain strong inhibitors or inducers of specific enzymes (like some antibiotics and antifungals) within 14 days before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that the combination of ixazomib citrate and rituximab is generally well-tolerated by patients. One study found that taking ixazomib orally once a week was effective and allowed patients to maintain a healthy immune system. Rituximab, often used to treat non-Hodgkin's lymphoma and other conditions, is usually safe but can sometimes cause low white blood cell counts, known as neutropenia.

In clinical trials, patients tolerated the dosages of these drugs without major issues. While some side effects occur, they are usually manageable. This suggests that the treatment may be safe for many people. However, individual experiences can vary, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for Non-Hodgkin Lymphoma, which often rely on chemotherapy and monoclonal antibodies like rituximab alone, the combination of ixazomib citrate and rituximab offers a novel approach. Ixazomib citrate is a proteasome inhibitor that works by blocking the protein complexes responsible for breaking down unneeded proteins in cancer cells, leading to their death. This mechanism provides a unique angle for attacking cancer cells, potentially enhancing the effectiveness of rituximab. Researchers are excited about this combination because it could improve patient outcomes by targeting the cancer cells in a new way, potentially offering better results with fewer side effects.

What evidence suggests that ixazomib citrate and rituximab might be an effective treatment for non-Hodgkin lymphoma?

This trial will evaluate the combination of ixazomib citrate and rituximab for treating slow-growing B-cell non-Hodgkin lymphoma. Research shows that ixazomib citrate may stop cancer cells from growing by blocking certain necessary enzymes. Rituximab, a monoclonal antibody, can help prevent cancer cells from growing and spreading. Previous studies have shown that this combination works well, is generally easy to tolerate, and allows the immune system to keep functioning. These findings support the potential effectiveness of using these drugs together for this type of lymphoma. ^{1 2 3 5 6}

Who Is on the Research Team?

Ajay K. Gopal

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for adults with certain slow-growing B-cell non-Hodgkin lymphomas, who haven't had specific treatments before. Participants must be able to consent, have adequate organ function, and if of childbearing potential, agree to use effective contraception or practice abstinence. They should not have active infections or other serious health issues that could affect the study.

Inclusion Criteria

Your total bilirubin level is not more than 1.5 times the upper limit of the normal range.

Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

I have a tumor larger than 1.5 cm, high lymphocyte count, or measurable IgM in my blood.

Exclusion Criteria

I haven't needed antibiotics for an infection in the last 14 days.

Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol

You are allergic to ixazomib or any of its ingredients.

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, 15, and 22. Cycles repeat every 28 days for 6 cycles, followed by rituximab intravenously once weekly for 4 doses, then ixazomib citrate alone until disease progression or unacceptable toxicity.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Follow-up at 30 days, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Ixazomib Citrate
• Rituximab

Trial Overview The trial tests ixazomib citrate combined with rituximab against indolent B-cell non-Hodgkin lymphoma. Ixazomib may block enzymes needed for cancer cell growth while rituximab might prevent cancer spread by targeting specific cells.

How Is the Trial Designed?

Group I: Treatment (ixazomib citrate, rituximab) Experimental Treatment 3 Interventions

Patients receive ixazomib citrate orally (PO) on days 1, 8 ,15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Upon completion of 6 cycles of ixazomib citrate therapy, patients also receive rituximab intravenously (IV) once weekly for 4 doses total, followed by ixazomib citrate alone, until disease progression or unacceptable toxicity.

Ixazomib Citrate is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Ninlaro for:

• Multiple myeloma

Approved in United States as Ninlaro for:

• Multiple myeloma

Approved in Canada as Ninlaro for:

• Multiple myeloma

Approved in Japan as Ninlaro for:

• Multiple myeloma

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Millennium Pharmaceuticals, Inc.

Industry Sponsor

Trials

406

Recruited

46,900+

Dr. Christophe Bianchi

Millennium Pharmaceuticals, Inc.

Chief Medical Officer since 2006

MD from University of Geneva

Dr. Deborah Dunsire

Millennium Pharmaceuticals, Inc.

Chief Executive Officer since 2005

MD from University of Witwatersrand

Published Research Related to This Trial

Ixazomib, an oral proteasome inhibitor, has been shown to significantly improve progression-free survival in patients with relapsed and/or refractory multiple myeloma when combined with lenalidomide and dexamethasone, with a median survival of 20.6 months compared to 14.7 months for the placebo group.

The drug works by selectively inhibiting the 20S proteasome, leading to the accumulation of proteins that induce stress and apoptosis in myeloma cells, making it a promising treatment option for patients who have undergone prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological characteristics and clinical study results of the oral proteasome inhibitor ixazomib (NINLARO® capsules; 2.3 mg, 3 mg, and 4 mg)]. Machida, M., Fukunaga, S., Hara, T.[2019]

Ixazomib, an oral proteasome inhibitor, significantly prolongs progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma compared to placebo, as demonstrated in the TOURMALINE-MM1 trial involving adults who had received one to three prior therapies.

The treatment showed a favorable safety profile and resulted in a higher overall response rate, making ixazomib a valuable new option for patients with multiple myeloma who have undergone previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib: A Review in Relapsed and/or Refractory Multiple Myeloma. Al-Salama, ZT., Garnock-Jones, KP., Scott, LJ.[2018]

Rituximab is the first monoclonal antibody approved for treating B-cell lymphomas, showing significant effectiveness in conditions like follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.

The combination of rituximab with standard chemotherapy agents (cyclophosphamide, doxorubicin, vincristine, and prednisone) has achieved the highest efficacy reported for treating diffuse large B-cell lymphoma and follicular lymphoma, while maintaining low toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. Traullé, C., Coiffier, BB.[2015]

In a study of 90 patients with relapsed/refractory multiple myeloma, the combination of ixazomib, thalidomide, and dexamethasone showed a 51.1% overall response rate, indicating significant efficacy in treating this condition.

The treatment was well tolerated, with rare occurrences of severe toxicities, and ixazomib maintenance therapy improved response depth in 12.4% of patients, suggesting a beneficial long-term effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib-Thalidomide-Dexamethasone for induction therapy followed by Ixazomib maintenance treatment in patients with relapsed/refractory multiple myeloma. Ludwig, H., Poenisch, W., Knop, S., et al.[2021]

Rituximab significantly reduces the annualized relapse rates in patients with relapsing-remitting multiple sclerosis, with a decrease of 0.80 relapses per year based on a meta-analysis of 15 studies involving 946 patients.

The treatment is well tolerated, with only mild-to-moderate adverse events occurring in 29.6% of patients and no severe adverse events reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of rituximab for relapsing-remitting multiple sclerosis: A systematic review and meta-analysis. Hu, Y., Nie, H., Yu, HH., et al.[2019]

Ibritumomab tiuxetan radioimmunotherapy demonstrated a 74% overall response rate in patients with rituximab-refractory follicular non-Hodgkin's lymphoma, indicating its efficacy as a treatment option for this difficult-to-treat population.

The treatment was well-tolerated with acceptable safety, as radiation doses to healthy organs were below safety limits, although it did lead to significant hematologic adverse events, including grade 4 neutropenia in 35% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. Witzig, TE., Flinn, IW., Gordon, LI., et al.[2022]

Rituximab was the first monoclonal antibody approved for cancer therapy and has significantly improved survival rates in patients with diffuse large cell lymphoma when combined with CHOP chemotherapy.

Initially approved in 1997 for relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma, rituximab is also being researched for other B-cell malignancies and nonmalignant diseases like autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: review and clinical applications focusing on non-Hodgkin's lymphoma. King, KM., Younes, A.[2015]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown to induce responses in nearly 50% of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma, with complete remissions occurring in 6% of cases, highlighting its efficacy in treating this type of cancer.

The drug is generally well tolerated, with common side effects being mild to moderate fevers and chills, and it is also effective against various other B-cell malignancies, suggesting its potential for broader applications in both cancer treatment and autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. Cheson, BD.[2019]

Ixazomib is an orally taken proteasome inhibitor that works by blocking the β5 subunit of the proteasome, and it was approved by the FDA in 2015 for treating multiple myeloma in combination with lenalidomide and dexamethasone after at least one prior therapy.

Currently, ixazomib is being studied in Phase III trials for newly diagnosed multiple myeloma and other conditions, indicating its potential for broader applications in treating various cancers and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib: First Global Approval. Shirley, M.[2018]

In a phase II study involving 37 patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma, Rituximab was found to be well tolerated, with most adverse events being mild and decreasing with subsequent infusions.

The treatment resulted in a 57% overall response rate, with 14% achieving a complete response and 43% a partial response, indicating significant clinical activity and suggesting that extended Rituximab treatment may be effective for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Piro, LD., White, CA., Grillo-López, AJ., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT02339922

NCT02339922 | Ixazomib Citrate and Rituximab in Treating ... This phase II trial studies how well ixazomib citrate and rituximab work in treating patients with B-cell non-Hodgkin lymphoma that grows slowly (indolent).

2. withpower.com withpower.com/trial/phase-3-lymphoma-mantle-cell-4-2016-aec69

Ixazomib + Rituximab for Non-Hodgkin Lymphoma This phase II trial studies how well ixazomib citrate and rituximab work in treating patients with B-cell non-Hodgkin lymphoma that grows slowly (indolent).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9984960/

Efficacy, safety, and molecular response predictors of oral ... For untreated iNHL, oral weekly ixazomib alone and with rituximab is effective, tolerated, and permits retention of immune competence.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02481310?cond=%22Diffuse%20Large%20B-Cell%20Lymphoma%22&intr=%22Ixazomib%22&viewType=Table&rank=1

Combination Chemotherapy, Rituximab, and Ixazomib ... The purpose of this study is to evaluate the effects, good and bad of a new drug called ixazomib (also called MLN9708), when it is given along with a common ...

5. iwmf.com iwmf.com/wp-content/uploads/2020/10/Libby_Clinical_Trial_News.pdf

How Chemotherapy Works Proposed indications for subQ Rituximab include follicular lymphoma, diffuse large B-cell lymphoma, low grade and chronic lymphocytic leukemia.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6558009/

Overview of Targeted Drugs for Mature B-Cell Non-hodgkin ... In relapsing CLL, results of the phase I reported that the dosages were well-tolerated in a cohort of 26 patients; 1 patient had a partial response, in 17 cases ...