Tirabrutinib for Central Nervous System Lymphoma

Not currently recruiting at 47 trial locations

Overseen By International Clinical Trial Support Desk

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ono Pharmaceutical Co. Ltd

Must not be taking: Anticoagulants, Corticosteroids

Disqualifiers: Active infection, Severe heart, Severe lung, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of tirabrutinib, a Bruton’s tyrosine kinase inhibitor, for primary central nervous system lymphoma (PCNSL), a blood cancer affecting the brain. The trial consists of two parts: one for patients whose cancer has returned or did not respond to previous treatments, and another for those newly diagnosed. In the second part, tirabrutinib is combined with different chemotherapy regimens. Candidates may qualify if they have a confirmed diagnosis of PCNSL and either have experienced a recurrence after treatment or have not yet received treatment. As a Phase 2 trial, this study measures how well tirabrutinib works in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting tirabrutinib treatment. Specifically, you must not have taken chemotherapy, certain antibody drugs, or investigational drugs within a specified period before starting the trial. Additionally, ongoing use of some corticosteroids, anticoagulants, and medications that affect liver enzymes must be stopped before participation.

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

Research has shown that tirabrutinib is generally safe. One study found that patients with relapsed or refractory primary central nervous system lymphoma (PCNSL) responded well to tirabrutinib, with some experiencing significant and lasting improvements. Most did not experience severe side effects from the treatment.

When combined with other drugs like methotrexate, temozolomide, and rituximab, the safety information is less clear. However, earlier studies of tirabrutinib alone indicate it is usually safe, with side effects typically not severe for most patients.

This trial is in an intermediate phase, suggesting some confidence in the safety of tirabrutinib, but more research is needed to fully understand all possible effects, especially when used with other treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about tirabrutinib for central nervous system lymphoma (PCNSL) because it targets the Bruton’s tyrosine kinase (BTK), a key enzyme in the pathways that promote cancer cell survival, offering a more direct attack on the cancer cells. Unlike the standard treatments, which often involve high-dose methotrexate, this targeted approach could potentially offer a more tailored treatment with fewer side effects. Additionally, combining tirabrutinib with other drugs like methotrexate, temozolomide, rituximab, or procarbazine in different regimens aims to enhance its effectiveness, especially in newly diagnosed patients, which adds to the excitement around its potential impact.

What evidence suggests that this trial's treatments could be effective for PCNSL?

Research shows that tirabrutinib alone may help treat primary central nervous system lymphoma (PCNSL) that has returned or is unresponsive to other treatments. In this trial, some participants will receive tirabrutinib monotherapy, which has proven effective, with some patients experiencing significant and lasting improvements. For newly diagnosed PCNSL, other participants will receive tirabrutinib combined with methotrexate, temozolomide, and rituximab (MTR) or with rituximab, methotrexate, procarbazine, and vincristine (R-MPV). These combinations might enhance treatment efficacy. Tirabrutinib has demonstrated safety in these combinations, which is promising. Overall, tirabrutinib has shown positive results in managing PCNSL, offering hope for patients with this challenging condition. ^{1 2 3 4 6}

Who Is on the Research Team?

Project Leader

Principal Investigator

Ono Pharmaceutical Co. Ltd

Are You a Good Fit for This Trial?

Adults with a confirmed diagnosis of Primary Central Nervous System Lymphoma (PCNSL) who have either not been treated before or whose disease has returned after treatment. Participants must be in good enough health, as determined by organ function tests, and have a life expectancy of at least 3 to 6 months depending on the part of the trial they're entering.

Inclusion Criteria

You are expected to live for at least 6 more months.

I can take care of myself and perform daily activities.

You need to sign a paper saying you agree to participate before you can be checked for eligibility.

Exclusion Criteria

I cannot swallow pills or have a condition affecting my stomach or intestines.

I do not have an active infection or have not been hospitalized for an infection requiring IV antibiotics in the last 28 days.

You have had an allergic reaction to the dye used in MRI scans.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment (Part A)

Patients with relapsed or refractory PCNSL receive tirabrutinib monotherapy

1 year

Regular visits for monitoring and assessment

Treatment (Part B)

Patients with newly diagnosed, treatment naïve PCNSL receive tirabrutinib in combination with high dose methotrexate based regimens

4 months

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Tirabrutinib

Trial Overview The study is testing Tirabrutinib alone for those with relapsed PCNSL (Part A), and in combination with high-dose methotrexate-based regimens for newly diagnosed patients (Part B). The goal is to see how well it works and what side effects occur.

How Is the Trial Designed?

Group I: Tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A) Experimental Treatment 1 Intervention

Patients with relapsed or refractory PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib monotherapy.

Group II: Tirabrutinib + R-MPV in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 2) Experimental Treatment 1 Intervention

Patients with newly diagnosed treatment naïve PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib + rituximab/methotrexate/procarbazine/vincristine (R-MPV)

Group III: Tirabrutinib + MTR in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 1) Experimental Treatment 1 Intervention

Patients with newly diagnosed treatment naïve PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib + methotrexate/temozolomide/rituximab (MTR)

Tirabrutinib is already approved in Japan for the following indications:

Approved in Japan as Velexbru for:

• Primary central nervous system lymphoma

Who Is Running the Clinical Trial?

Ono Pharmaceutical Co. Ltd

Lead Sponsor

Trials

182

Recruited

97,100+

Shinji Takai

Ono Pharmaceutical Co. Ltd

Chief Medical Officer since 2023

MD from an unspecified institution

Gyo Sagara

Ono Pharmaceutical Co. Ltd

Chief Executive Officer since 2024

PhD in Pharmaceutical Sciences from Kyoto University

Published Research Related to This Trial

In a Phase I study involving 17 Japanese patients with B-cell malignancies, tirabrutinib demonstrated a high overall response rate of 76.5%, indicating its efficacy as a treatment option.

While adverse events were common, with 94.1% of patients experiencing drug-related side effects, the long-term safety profile was acceptable, with some patients continuing treatment for over 4 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety profile of tirabrutinib: final results of a Japanese Phase I study in patients with relapsed or refractory B-cell malignancies. Munakata, W., Ando, K., Yokoyama, M., et al.[2023]

Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, has been shown to maintain Karnofsky Performance Status (KPS) and improve quality of life (QoL) in patients with relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) over a median follow-up of 14.9 months.

Patients experienced significant improvements in global health status and emotional functioning, indicating that tirabrutinib not only helps manage the disease but also enhances the overall well-being of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Karnofsky Performance Status and quality of life in patients with relapsed or refractory primary CNS lymphoma from a phase I/II study of tirabrutinib. Arakawa, Y., Narita, Y., Nagane, M., et al.[2023]

In a study of 5 patients with refractory or relapsed primary central nervous system lymphoma (PCNSL), tirabrutinib demonstrated a 100% response rate, indicating its potential as an effective treatment for those who cannot tolerate standard therapies.

Despite some manageable adverse reactions, tirabrutinib was well-tolerated, and the median survival for patients was 8 months, suggesting it could be a promising alternative for improving outcomes in difficult-to-treat PCNSL cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience With Tirabrutinib in the Treatment of Primary Central Nervous System Lymphoma that Is Difficult to Treat With Standard Treatment. Yoshioka, H., Okuda, T., Nakao, T., et al.[2022]

Tirabrutinib, a selective BTK inhibitor, demonstrated a complete obliteration of tumor cells in a 64-year-old patient with relapsed/refractory primary central nervous system lymphoma (PCNSL), as confirmed by autopsy after one month of treatment.

This case represents the first pathological confirmation of tirabrutinib's efficacy in humans for treating PCNSL, although the patient later died from complications unrelated to the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histological verification of the treatment effect of tirabrutinib for relapsed/refractory primary central nervous system lymphoma. Okita, Y., Kano-Fujiwara, R., Nakatsuka, SI., et al.[2021]

Tirabrutinib is an oral BTK inhibitor that irreversibly binds to Bruton's tyrosine kinase in B cells, effectively blocking harmful B cell receptor signaling associated with certain cancers and autoimmune disorders.

In March 2020, tirabrutinib received approval in Japan for treating recurrent or refractory primary central nervous system lymphoma, and it is currently under review for other conditions like Waldenström's macroglobulinemia and lymphoplasmacytic lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirabrutinib: First Approval. Dhillon, S.[2020]

Tirabrutinib, a selective Bruton's tyrosine kinase inhibitor, showed a favorable efficacy in treating relapsed/refractory primary central nervous system lymphoma (PCNSL), with an overall response rate of 64% across 44 patients in the study.

No dose-limiting toxicities were observed at the maximum tested dose of 480 mg, indicating a good safety profile, although some patients experienced serious adverse events like neutropenia and pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Narita, Y., Nagane, M., Mishima, K., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04947319

Study of Tirabrutinib (ONO-4059) in Patients With Primary ... This study will evaluate the efficacy, safety, and pharmacokinetics of tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A), ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT07104032

NCT07104032 | Study of Tirabrutinib vs Rituximab ... The purpose of this clinical trial is to evaluate efficacy and safety of tirabrutinib alone compared with rituximab and temozolomide (R-TMZ) combination therapy ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11059299/

Three-year follow-up analysis of phase 1/2 study on ... The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile.

4. stanfordhealthcare.org stanfordhealthcare.org/trials/s/NCT04947319.html

Study of Tirabrutinib (ONO-4059) in Patients With Primary ... This study will evaluate the efficacy, safety, and pharmacokinetics of tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A), and ...

5. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2023-0329.html

An open-label phase II study to investigate the efficacy, ... This study will evaluate the efficacy, safety, and pharmacokinetics of tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A),

6. trialx.com trialx.com/clinical-trials/listings/262170/study-of-tirabrutinib-ono-4059-in-patients-with-primary-central-nervous-system-lymphoma-prospect-study/?&geo_lat=38.2117&geo_lng=-84.5562&radius=25&place=Georgetown&user_country=United%20States

Study of Tirabrutinib (ONO-4059) in Patients With Primary ... This study will evaluate the efficacy, safety, and pharmacokinetics of tirabrutinib monotherapy in patients with relapsed or refractory PCNSL ( ...