Triple Therapy for Lymphoma

Not currently recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Proton pump inhibitors, H2 antagonists

Disqualifiers: Brain metastases, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: 4

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—alisertib (an experimental treatment), bortezomib, and rituximab—to determine the best dose and assess their effectiveness in treating certain types of lymphoma. It targets patients whose mantle cell lymphoma or low-grade B-cell non-Hodgkin lymphoma has returned after treatment or did not respond to previous treatments. The trial aims to determine if these drugs can more effectively halt cancer cell growth. Eligible participants have experienced a recurrence of these specific lymphomas after treatment and are not currently on certain other medications. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires stopping certain medications before participating. You must stop using proton pump inhibitors at least 4 days before the first dose, and you cannot take them during the study. Other medications like H2 receptor antagonists, antacids, pancreatic enzymes, and certain antiepileptic drugs are also not allowed during the trial.

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

Research shows that the safety of using alisertib, bortezomib, and rituximab together remains under investigation. Some studies have examined parts of this combination. Trials have found that alisertib with rituximab has a manageable safety profile, with side effects that were not too severe for most participants.

Bortezomib has demonstrated good results when combined with other drugs. It has sometimes replaced vincristine in treatments, leading to improved effectiveness, suggesting it can be safely combined with drugs like rituximab.

As this is a phase 1 trial, researchers are closely studying safety. Participants might experience side effects, but this phase helps determine the optimal dose with the fewest side effects. The treatment's ability to safely manage lymphoma symptoms is still under exploration. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple therapy for lymphoma because it combines alisertib, bortezomib, and rituximab, each with unique mechanisms of action. Unlike standard chemotherapy-based treatments, alisertib is an Aurora kinase inhibitor, which can disrupt cancer cell division, while bortezomib is a proteasome inhibitor that prevents cancer cells from disposing of harmful proteins. Rituximab, an antibody therapy, specifically targets CD20 on lymphoma cells, marking them for destruction by the immune system. This combination aims to attack the cancer from multiple angles, potentially improving effectiveness and overcoming resistance seen with single-agent therapies.

What evidence suggests that this triple therapy could be effective for relapsed or refractory lymphoma?

This trial will evaluate the combination of alisertib, bortezomib, and rituximab for relapsed or hard-to-treat mantle cell lymphoma or B-cell low-grade non-Hodgkin lymphoma. Studies have shown that using alisertib and rituximab with other drugs can effectively stop tumor growth. Alisertib and bortezomib block the enzymes necessary for cancer cell growth, while rituximab, a targeted therapy, prevents cancer cells from spreading. Research on similar drug combinations suggests they might work better together than individually. Specifically, one study found that a combination including rituximab and bortezomib was at least 59% more effective with bortezomib. This evidence supports the potential of this three-drug treatment. ^{1 3 4 5 6}

Who Is on the Research Team?

Catherine S Diefenbach

Principal Investigator

Montefiore Medical Center - Moses Campus

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory mantle cell lymphoma or low grade B-cell non-Hodgkin lymphoma. Participants must have adequate organ function, no high-grade cancer transformation, and agree to use contraception. They should not have had certain treatments recently and must be able to take oral medication.

Inclusion Criteria

My lymphoma can be measured or evaluated and I've had the necessary scans and tests recently.

Platelets >= 75,000/mcL or >= 50,000/mcL with documented bone marrow involvement (obtained within 30 days of registration)

Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MLN8237 administration

Exclusion Criteria

I have had allergic reactions to medications similar to MLN8237, bortezomib, or rituximab.

You are not currently taking any other experimental medications.

I am not taking pancreatic enzymes while on this study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive alisertib orally twice daily on days 1-7, bortezomib subcutaneously on days 1, 8, and 15, and rituximab intravenously on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

3 visits per cycle (in-person)

Extended Treatment

After 8 courses, treatment with rituximab repeats once every 3 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.

12 weeks per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Alisertib
• Bortezomib
• Rituximab

Trial Overview

The trial tests the combination of alisertib and bortezomib with rituximab to find the best dose and side effects profile in treating specific types of lymphoma that are resistant or have returned after treatment. It aims to see if this combo can better inhibit cancer cell growth.

How Is the Trial Designed?

Group I: Treatment (alisertib, bortezomib, and rituximab) Experimental Treatment 4 Interventions

Patients receive alisertib PO BID on days 1-7; bortezomib SC on days 1, 8, and 15; and rituximab IV on day 1. Treatment repeats every 28 days\* in the absence of disease progression or unacceptable toxicity. Note: \*After 8 courses, treatment with rituximab repeats once every 3 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.

Alisertib is already approved in United States, European Union for the following indications:

Approved in United States as Alisertib for:

• Acute myeloid leukemia (AML)

Approved in European Union as Alisertib for:

• None approved; under investigation for various cancers

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

The CHOEA-7 chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, etoposide, and ara-C, has shown excellent results in treating patients with CD 20-positive non-Hodgkin's lymphoma.

Adding rituximab to the CHOEA-7 regimen (RCHOEA-7) further enhances treatment efficacy, indicating a promising approach for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. Uzuka, Y., Saitou, Y., Saitou, K., et al.[2015]

Rituximab is the first FDA-approved monoclonal antibody for cancer treatment, specifically targeting the CD20 antigen on B cells, and has shown efficacy in treating relapsed low-grade and follicular non-Hodgkin's lymphoma in multicenter studies.

The treatment is generally well-tolerated, with side effects mainly consisting of mild fevers and chills during the first infusion, and its low immunogenicity allows for potential future treatments without significant complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of rituximab, the new FDA-approved antibody. Leget, GA., Czuczman, MS.[2019]

Rituximab has been shown to significantly improve progression-free and overall survival in patients with various types of non-Hodgkin lymphoma and chronic lymphocytic leukaemia (CLL), based on a systematic review of 56 randomized controlled trials.

The consensus guidelines recommend rituximab for use in combination with chemotherapy for initial treatment of aggressive B-cell lymphomas, maintenance therapy for indolent B-cell lymphomas, and as part of treatment regimens for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline. Prica, A., Baldassarre, F., Hicks, LK., et al.[2018]

Rituximab has shown a response rate of approximately 70% as a first-line treatment for indolent lymphoma, with low toxicity and the ability to retreat patients successfully, leading to longer remission durations.

Combination therapies using rituximab with chemotherapy have resulted in high complete response rates and a greater likelihood of molecular complete remission compared to chemotherapy alone, indicating its potential to enhance treatment outcomes in lymphoid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibody therapy in lymphoid malignancies. Hainsworth, JD.[2019]

Recent advances in targeted therapies for non-Hodgkin lymphoma, particularly the anti-CD20 monoclonal antibody rituximab, are expected to significantly improve patient care by inhibiting specific disease pathways.

Combining rituximab with other agents, such as monoclonal antibodies, immunomodulatory drugs, and Bcl-2 inhibitors, shows promise for enhancing treatment efficacy, especially in patients who do not respond to rituximab alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies for non-Hodgkin lymphoma: rationally designed combinations. Martin, P., Leonard, JP.[2019]

Rituximab is highly effective for treating low-grade CD20+ lymphoma, especially when combined with chemotherapy, which is the standard treatment for follicular lymphoma (FL).

The efficacy of rituximab can be enhanced by combining it with biological agents like interferon-alpha-2a, bortezomib, or lenalidomide, but more research is needed to determine the best combinations and timing of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological therapy doublets: pairing rituximab with interferon, lenalidomide, and other biological agents in patients with follicular lymphoma. Kimby, E.[2021]

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]

Citations

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clinicaltrials.gov

clinicaltrials.gov/study/NCT01695941

Alisertib, Bortezomib, and Rituximab in Treating Patients ...

Giving alisertib and bortezomib together with rituximab may be a better treatment for relapsed or refractory mantle cell lymphoma or B-cell low grade non- ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11674227/

A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is ...

Alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets.

3.

clinicaltrials.gov

clinicaltrials.gov/ct2/show/results/NCT01695941

No Study Results Posted | NCT01695941 | Alisertib, ...

Alisertib, Bortezomib, and Rituximab in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or B-cell Low Grade Non-Hodgkin Lymphoma.

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5520581/

The Preclinical Discovery and Development of Bortezomib for ...

Phase III trial reports at least 59% increased efficacy when BTZ replaces vincristine in a drug combination that includes rituximab, cyclophosphamide, ...

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withpower.com

withpower.com/trial/phase-1-lymphoma-7-2012-ea4d2

Triple Therapy for Lymphoma · Info for Participants

This phase I trial studies the side effects and best dose of alisertib and bortezomib when given together with rituximab in treating patients with mantle ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7731903/

Phase I Study of the Investigational Aurora A Kinase Inhibitor ...

In conclusion, the data from this phase I study suggest alisertib in combination with rituximab plus vincristine has a manageable safety profile at the RP2D of ...