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Refractory Primary Central Nervous System LymphomaPhase 2NCT04947319

Study of Tirabrutinib (ONO-4059) in Patients With Primary Central Nervous System Lymphoma (PROSPECT Study)

A Phase 2 study testing Tirabrutinib in people with Refractory Primary Central Nervous System Lymphoma and Primary CNS Lymphoma, run by Ono Pharmaceutical Co., Ltd. at 39 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial summary

This study will evaluate the efficacy, safety, and pharmacokinetics of tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A), and tirabrutinib in combination with one of two different high dose methotrexate based regimens (methotrexate/ temozolomide/rituximab or… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Tirabrutinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
119 participants
Where
39 sitesUnited States
Study dates
29 Dec 2021to 31 Mar 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Written informed consent by the patient prior to screening
  • Patients aged ≥ 18 years on the day of consenting to the study
  • Pathologic diagnosis of PCNSL
  • Relapse or refractory PCNSL with at least one prior high dose methotrexate (HD-MTX) based therapy for PCNSL
  • Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced magnetic resonance imaging (MRI) performed within 14 days before starting tirabrutinib treatment
  • Eastern Cooperative Oncology Group performance score (ECOG PS) of 0, 1 or 2
Show all 17Show fewer
  • Life expectancy of at least 3 months
  • Adequate bone marrow, renal, and hepatic function
  • Written informed consent by the patient prior to screening
  • Patients aged ≥ 18 years on the day of consenting to the study
  • Pathologic diagnosis of PCNSL within the past 3 months
  • No prior anti-tumor treatments for PCNSL
  • Patients who, in the opinion of the Investigator, are suitable to receive treatment with a high dose methotrexate containing regimen
  • Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced MRI performed within 14 days before starting study treatment
  • ECOG PS of 0, 1 or 2
  • Life expectancy of at least 6 months
  • Adequate bone marrow, renal, and hepatic function

Who cannot join

  • Intraocular PCNSL with no brain lesion
  • Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents
  • Patient with non-B cell PCNSL
  • Patient with systemic presence of lymphoma
  • Prior chemotherapy within 21 days, nitrosourea within 42 days, an antibody drug with anticancer activity (e.g., rituximab) within 28 days, prior radiotherapy within 14 days, prior major invasive surgery within 28 days, or allogeneic stem cell transplant within 6 months before starting tirabrutinib treatment
  • Prior BTK inhibitor treatment
Show all 54Show fewer
  • Prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, before starting tirabrutinib treatment
  • Concomitant systemic corticosteroid on an ongoing basis within 14 days before starting tirabrutinib treatment, with the exception of the following:
  • Equivalent of up to 10 mg/day of prednisone for a disease other than PCNSL
  • Equivalent of up to 50 mg/day of prednisone (equal to 8 mg/day of dexamethasone) for patients with lesions of the brain or spinal cord or both
  • Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment
  • Concomitant warfarin, any other warfarin derivative anticoagulant, vitamin K antagonists, novel oral anticoagulants, or antiplatelet therapy on an ongoing basis within 7 days before starting tirabrutinib treatment
  • Active malignancy, other than PCNSL requiring systemic therapy
  • Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments
  • Patient with bleeding diathesis
  • Patients with a history of moderate or severe hepatic impairment
  • QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval
  • Active infection, including a HIV, cytomegalovirus infection or SARS-CoV-2, or has had, within 28 days before starting tirabrutinib treatment, an infection (other than nail trichophytosis) that requires hospitalization or an intravenous antibiotic
  • Prior history of hypersensitivity or anaphylaxis to tirabrutinib
  • Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis
  • Medical history of organ allografts
  • Tests positive for HIV-1 antibody and HIV-2 antibody, human T-lymphotropic virus 1 antibody, hepatitis B (HB) antigen, or hepatitis C virus (HCV) antibody. Tests positive for HBs antibody or hepatitis B virus core protein antibody and has a result of at least detectable in a hepatitis B virus deoxyribonucleic acid assay despite testing negative for HBs antigen.
  • Patient is unable to swallow tablets; has malabsorption, malabsorption syndrome, or a comorbidity that affects gastric function; has undergone complete resection of the stomach or small intestine; has ulcerative colitis or symptomatic inflammatory bowel disease; or has partial or complete intestinal obstruction.
  • Women who are pregnant or lactating
  • Patient is found incapable of giving consent due to dementia or another such condition
  • Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.
  • Intraocular PCNSL with no brain lesion
  • Patients for whom the selected backbone regimen medications (i.e, methotrexate/temozolomide/rituximab for MTR and rituximab/methotrexate/procarbazine/vincristine for R-MPV) are contraindicated
  • Patients with a history of intolerable toxicity, hypersensitivity, anaphylaxis to the selected backbone regimen medications
  • Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents
  • Patient with non-B cell PCNSL
  • Patient with systemic presence of lymphoma
  • Prior chemotherapy within 21 days, nitrosourea within 42 days, an antibody drug with anticancer activity (e.g., rituximab) within 28 days, prior radiotherapy within 14 days, prior major invasive surgery within 28 days, or allogeneic stem cell transplant within 6 months before starting tirabrutinib treatment
  • Prior BTK inhibitor treatment
  • Prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, before starting tirabrutinib treatment
  • Concomitant systemic corticosteroid on an ongoing basis within 14 days before starting tirabrutinib treatment, with the exception of the following:
  • Equivalent of up to 10 mg/day of prednisone for a disease other than PCNSL
  • Equivalent of up to 50 mg/day of prednisone (equal to 8 mg/day of dexamethasone) for patients with lesions of the brain or spinal cord or both
  • Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment
  • Concomitant warfarin, any other warfarin derivative anticoagulant, vitamin K antagonists, novel oral anticoagulants, or antiplatelet therapy on an ongoing basis within 7 days before starting tirabrutinib treatment
  • Active malignancy, other than PCNSL requiring systemic therapy
  • Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments
  • Patient with bleeding diathesis
  • Patients with a history of moderate or severe hepatic impairment
  • QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval
  • Active infection, including a HIV, cytomegalovirus infection or SARS-CoV-2, or has had, within 28 days before starting tirabrutinib treatment, an infection (other than nail trichophytosis) that requires hospitalization or an intravenous antibiotic
  • Prior history of hypersensitivity or anaphylaxis to tirabrutinib
  • Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis
  • Medical history of organ allografts
  • Tests positive for HIV-1 antibody and HIV-2 antibody, human T-lymphotropic virus 1 antibody, HBs antigen, or HCV antibody. Tests positive for HBs antibody or hepatitis B virus core protein antibody and has a result of at least detectable in a hepatitis B virus deoxyribonucleic acid assay despite testing negative for HBs antigen.
  • Patient is unable to swallow tablets; has malabsorption, malabsorption syndrome, or a comorbidity that affects gastric function; has undergone complete resection of the stomach or small intestine; has ulcerative colitis or symptomatic inflammatory bowel disease; or has partial or complete intestinal obstruction.
  • Women who are pregnant or lactating
  • Patient is found incapable of giving consent due to dementia or another such condition
  • Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.

Trial locations and contacts

39 sites in 1 country.

39 sites in 1 country

United States39 sites

  • University Of Michigan

    Ann Arbor, Michigan, 41809

  • Piedmont Healthcare

    Atlanta, Georgia, 30318

  • University of Colorado Denver

    Aurora, Colorado, 80045

  • University of Alabama at Birmingham School of Medicine

    Birmingham, Alabama, 35233

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Dana-Farber Cancer Institute - Brigham & Women's Hospital

    Boston, Massachusetts, 02215

  • Roswell Park Comprehensive Cancer Center (RPCCC) (Roswell Park Cancer Institute (RPCI))

    Buffalo, New York, 14263

  • The University of Vermont - Fletcher Allen Health Care

    Burlington, Vermont, 05401

  • Levine Cancer Center

    Charlotte, North Carolina, 28204

  • Cleveland Clinic

    Cleveland, Ohio, 44106

  • Henry Ford Hospital

    Detroit, Michigan, 48202

  • City of Hope Comprehensive Breast Cancer Center

    Duarte, California, 91010

  • Duke University School of Medicine

    Durham, North Carolina, 27705

  • Hackensack University Medical Center - John Theurer Cancer

    Hackensack, New Jersey, 07601

  • Penn State Hershey Cancer Center

    Hershey, Pennsylvania, 17033

  • Houston Methodist Research Institute (HMRI)

    Houston, Texas, 77030

  • MD Anderson Cancer Center

    Houston, Texas, 77030

  • University of California, Irvine

    Irvine, California, 92868

  • Mayo Clinic- Jacksonville

    Jacksonville, Florida, 32224

  • The University of Kansas Cancer Center (KUCC) (Kansas City Cancer Center (KCCC)) - North

    Kansas City, Missouri, 64154

  • University of Kentucky

    Lexington, Kentucky, 40536

  • University of Miami-Sylvester Cancer Center

    Miami, Florida, 33136

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Yale Cancer Center

    New Haven, Connecticut, 06510

  • Memorial Sloan Kettering

    New York, New York, 10022

  • Columbia University Irving Medical Center

    New York, New York, 10032

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

  • Orlando Health

    Orlando, Florida, 32806

  • Stanford University

    Palo Alto, California, 94304

  • Moffitt Cancer Center- Miami

    Pembroke Pines, Florida, 33028

  • Abramson Cancer Center University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Mayo Clinic- Phoenix

    Phoenix, Arizona, 85054

  • Hillman Cancer Center, University of Pittsburgh

    Pittsburgh, Pennsylvania, 15232

  • Providence Health Cancer Center

    Portland, Oregon, 97239

  • Lifespan Rhode Island Hospital

    Providence, Rhode Island, 02903

  • The University of Utah - Huntsman Cancer Institute (HCI)

    Salt Lake City, Utah, 84112

  • Seattle Cancer Care Alliance

    Seattle, Washington, 98109

  • Georgetown University, Lombardi Comprehensive Cancer Center

    Washington D.C., District of Columbia, 20037

Other trials in United States

About this study

Official title: An Open-label Phase II Study to Investigate the Efficacy, Safety, and Pharmacokinetics of Tirabrutinib in Patients With Primary Central Nervous System Lymphoma (PCNSL)

This study will evaluate the efficacy, safety, and pharmacokinetics of tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A), and tirabrutinib in combination with one of two different high dose methotrexate based regimens (methotrexate/ temozolomide/rituximab or rituximab/methotrexate/procarbazine/ vincristine) as first line therapy in patients with newly diagnosed, treatment naïve PCNSL (Part B)

Being tested
Tirabrutinib
Keywords
Bruton's Tyrosine Kinase Inhibitor, BTKi, tirabrutinib, ONO-4059, PROSPECT

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TirabrutinibDrug

    Also called ONO-4059

    Part A: Tirabrutinib 480 mg, taken orally, once a day on an empty stomach. Tirabrutinib treatment may be continued until disease progression or clinically unacceptable toxicity is observed.

  • TirabrutinibDrug

    Also called ONO-4059

    Part B, Arm 1 - Tirabrutinib 320 mg or 480 mg, taken orally, once a day on an empty stomach in combination with an MTR induction regimen. Tirabrutinib with MTR treatment will be continued for 4 induction cycles (28-day/cycle), or until disease progression or clinically unacceptable toxicity is observed.

    For patients not receiving consolidation treatment following induction, tirabrutinib 480 mg will be continued until disease progression, unacceptable toxicities are observed, or the Investigator decides to stop treatment.

  • TirabrutinibDrug

    Also called ONO-4059

    Part B, Arm 2 - Tirabrutinib 320 mg or 480 mg, taken orally, once a day on an empty stomach in combination with an R-MPV induction regimen. Tirabrutinib with R-MPV treatment will be continued for 4 induction cycles (28-day/cycle), or until disease progression or clinically unacceptable toxicity is observed.

    For patients not receiving consolidation treatment following induction, tirabrutinib 480 mg will be continued until disease progression, unacceptable toxicities are observed, or the Investigator decides to stop treatment.

Study groups in NCT04947319
Study groupRoleWhat they receive
Tirabrutinib monotherapy in patients with relapsed or refractory PCNSL (Part A)ExperimentalPatients with relapsed or refractory PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib monotherapy.
Receives: Drug: Tirabrutinib
Tirabrutinib + MTR in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 1)ExperimentalPatients with newly diagnosed treatment naïve PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib + methotrexate/temozolomide/rituximab (MTR)
Receives: Drug: Tirabrutinib
Tirabrutinib + R-MPV in patients with newly diagnosed, treatment naïve PCNSL (Part B, Arm 2)ExperimentalPatients with newly diagnosed treatment naïve PCNSL who meet eligibility criteria will be enrolled to receive tirabrutinib + rituximab/methotrexate/procarbazine/vincristine (R-MPV)
Receives: Drug: Tirabrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall response rate (ORR) (Part A)

    Overall response rate is defined as the proportion of patients with a best overall response of Complete response (CR), Complete response - unconfirmed (CRu), or (=partial response (PR) as determined by an independent review committee according to the International PCNSL Collaborative Group (IPCG) criteria.

    Measured: 1 year

  2. Tirabrutinib dose estimate (Part B)

    Estimate of tirabrutinib dose in combination with each backbone induction regimen (MTR and R-MPV) based upon treatment related AEs, SAEs, and toxicities observed during the initial cycle of induction therapy in the dose-ranging phase

    Measured: 1 month

  3. Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) during induction (Part B)

    Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.

    Measured: 4 months

  4. Complete response rate (CRR) (Part B)

    Complete response rate is defined as the proportion of patients with a best overall response of CR or CRu as determined by an independent review committee according to the IPCG criteria.

    Measured: 4 months

Secondary outcomes (10)

  1. Duration of response (DOR) (Part A and B)

    Duration of response is defined as the time between the date of first response (CR, CRu, or PR) and the date of the first PD according to the IPCG criteria, or date of death due to any cause, whichever occurs first.

    Measured: 2 years

  2. Time to response (TTR) (Part A and B)

    Time to response is defined as the time between the date of first administration of tirabrutinib and the date of first response (CR, CRu, or PR) as determined by IRC according to the IPCG criteria.

    Measured: 1 year

  3. Best overall response (BOR) (Part A and B)

    Best overall response based on independent review committee (IRC) response determination is defined as the best response and is derived programmatically based upon the visit responses determined by IRC from the date of administration of tirabrutinib to the date of PD as determined by IRC or the date of initiation of subsequent anticancer therapy for PCNSL, whichever occurs first.

    Measured: 1 year

  4. Change in corticosteroid dose (Part A)

    Descriptive statistics will be calculated for the actual corticosteroid dose and the change from baseline at each assessment point.

    Measured: 2 years

  5. Incidence and severity of AEs and SAEs (Part A and B)

    Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.

    Measured: 2 years

  6. Laboratory abnormality profile of tirabrutinib as measured by incidence and severity of clinical laboratory abnormalities (Part A and B)

    Results of laboratory tests

    Measured: 2 years

  7. ECG parameters by 12 lead ECG (Part A and B)

    Heart rate, RR and QT intervals, QTc (QTcF, QTcB), PR interval, and QRS width.

    Measured: 2 years

  8. PK parameters (Cmax) of tirabrutinib in the plasma (Part A and B)

    Measured: 29 days

  9. PK parameters (Tmax) of tirabrutinib in the plasma (Part A and B)

    Measured: 29 days

  10. PK parameters (AUC) of tirabrutinib in the plasma (Part A and B)

    Measured: 29 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jul 2021
  2. Study start29 Dec 2021
  3. Primary completion27 Jan 2026
  4. Study completion31 Mar 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
119 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04947319
Sponsor's protocol ID
ONO-4059-09
Status last verified
Mar 2026
First submitted
16 Jun 2021
Last updated
30 Mar 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Grommes C, Nayak L, Kallam A, Peereboom D, Ambady P, Mendez JS, Aregawi D, Sumrall A, Omuro A, Iwamoto FM, Dietrich J, Umemura Y, Munker R, Chukwueke UN, Schaff LR, Ip A, Gupta NK, Drappatz J, Venur VA, Peters KB, Ho KG, Merrell R, Prados S, Takazawa A, Aoi A, Batchelor TT. Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial. Blood. 2026 Oct 1:blood.2026034926. doi: 10.1182/blood.2026034926. Online ahead of print.

    PubMed 42821736

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tirabrutinib in people with Refractory Primary Central Nervous System Lymphoma and Primary CNS Lymphoma, run by Ono Pharmaceutical Co., Ltd. at 39 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 54 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 30 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 39 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall response rate (ORR) (Part A) (time frame: 1 year). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04947319, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Mar 2026.

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