Tirabrutinib Maintenance Versus Placebo in Patients With Primary CNS Lymphoma in Complete Remission (JCOG2104) (TIMELY-pII)

Tirabrutinib Maintenance Versus Placebo in Patients With Primary Central Nervous System Lymphoma in Complete Remission: a Randomized Phase II Study (JCOG2104)

A double-blind, randomized phase II comparative trial will evaluate the superiority of the investigational treatment (tirabrutinib maintenance therapy) over standard care (observation with placebo) in terms of progression-free survival in patients with newly diagnosed primary central nervous system lymphoma (PCNSL) who have achieved complete response (CR or CRu) following induction therapy with high-dose methotrexate (HD-MTX)-based chemotherapy and have not undergone consolidative whole-brain irradiation.

Participants will:

Take protocol drug tirabrutinib or a placebo every day until disease progression or experience of unacceptable toxicity.

Visit the clinic once every 4 weeks for checkups and tests, as well as protocol drug prescription.

Study Overview

• Status: Recruiting
• Conditions: Primary Central Nervous System Lymphoma
• Intervention / Treatment: Drug: Placebo; Drug: Tirabrutinib

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nobuyoshi Sasaki, M.D., Ph.D.; Phone Number: +81422475511; Email: sasakinobuyoshi0308@gmail.com
• Study Contact Backup: Name: Motoo Nagane, M.D., Ph.D.; Phone Number: +81422475511; Email: mnagane@ks.kyorin-u.ac.jp

Study Locations

• Japan
  • Tokyo, Japan, 181-8611
    • Recruiting
    • Kyorin University Hospital
    • Contact: Motoo Nagane, M.D., Ph.D.; Phone Number: +81-422-47-5511; Email: mnagane@ks.kyorin-u.ac.jp
    • Contact: Nobuyoshi Sasaki, M.D., Ph.D.; Phone Number: +81-422-47-5511; Email: sasakinobuyoshi0308@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histopathological diagnosis of B cell lymphoma.
2. Newly-diagnosed PCNSL confined to the cerebrum, cerebellum and brainstem. Patients with or without interocular lymphoma are eligible.
3. Negative cerebrospinal fluid (CSF) cytology, or no evidence of leptomeningeal lymphomatosis in contrast-enhanced magnetic resonance imaging (MRI) of the brain and the whole spinal cord.
4. No evidence of systemic lymphoma before induction chemotherapy, confirmed by contrast-enhanced CT including the neck, chest, abdomen, pelvic cavity and groin, or whole-body positron-emission tomography (PET) and CT.
5. Patients with a single lesion, or multiple lesions, are eligible.
6. Patients 18 years old or older at the time of registration.
7. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, 2.
8. Have completed either of the following methotrexate (MTX)-based chemotherapy i) R-MPV (rituximab, MTX, procarbazine and vincristine) ii) MPV (MTX, procarbazine and vincristine) iii) R-MP (rituximab, MTX and procarbazine) iv) MP (MTX and procarbazine) v) R-M (rituximab and MTX) vi) MTX monotherapy
9. Complete response (CR) or complete response unconfirmed (CRu) based on the International PCNSL Collaborative Group (IPCG) criteria.
10. Within 60 days from the last dose of induction or consolidation chemotherapy.
11. No treatment history of radiotherapy for PCNSL.
12. Refused to receive consolidation radiotherapy.
13. No treatment history of chemotherapy or radiotherapy, except for stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) for non-cancer diseases (such as arteriovenous malformations).
14. Adequate organ function. i) Neutrophil count >=1,000/mm3 ii) Hemoglobin >= 8.0 g/dl iii) Platelet count >= 75,000/mm3 iv) AST <=120 U/L v) ALT <= 120 U/L vi) Total Bilirubin <= 2.25 mg/dl vii) Creatinine <= 1.5 mg/dL
15. Written informed consent.

Exclusion Criteria:

1. Synchronous or metachronous malignancies.
2. Infections requiring systemic treatment at the time of registration.
3. Body temperature >=38 degree celsius at the time of registration.
4. Serious lung disorders, such as interstitial pneumonia, obstructive lung disease, hypersensitive pneumonitis, symptomatic bronchospasm) at the time of registration.
5. History or presence of aspergillus pneumonitis or pneumocystis pneumonia.
6. History of serious drug allergy or serious anaphylaxis.
7. Heart failure (>= III in New York Heart Association functional classification), unstable angina pectoris, or history of myocardial infarction within the preceding 180 days prior to registration.
8. Treated by anticoagulants at the time of registration.
9. Treated by antiplatelets at the time of registration.
10. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
11. Immune deficiency, such as acquired immunodeficiency syndrome (AIDS), X-linked agammaglobulinemia, chronic granulomatous disease, Wiskott-Aldrich syndrome, or any other iatrogenic immunosuppressive conditions.
12. Post organ transplant immunosuppression.
13. Prednisone use of >10 mg/day for condition other than intracranial tumor, or regular use of immunosuppressants.
14. Uncontrolled diabetes mellitus.
15. Treated either by CYP3A4 inhibitors, CYP3A4 inducers, or P-gp inducers within 14 days prior to registration.
16. Gadolinium allergy.
17. Positive HIV antibody.
18. Positive HBs antigen.
19. Positive HBs antibody or HBc antibody, and HBV-DNA positive.
20. Positive HCV antibody.
21. Unable to take oral medicine,
22. Females during pregnancy, or within 28 days postpartum, or during lactation. Males who wish childbearing of his partner.
23. Prior history of treatment by BTK inhibitors.
24. Severe psychiatric disorders.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard arm; Observation with placebo	Drug: Placebo; Placebo taken orally daily at fasting condition
Experimental: Experimental arm; Tirabrutinib maintenance therapy	Drug: Tirabrutinib; Tirabrutinib (480 mg) taken orally daily at fasting condition

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival (PFS) based on independent review committee (IRC) assessment	From the date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 78 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) determined by investigator		From the date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 78 months
Overall survival (OS)		From the date of registration until the date of death from any cause, assessed up to 78 months
PFS/OS in the maintenance per protocol group		PFS: From the date of registration until the date of first progression or date of death from any cause, whichever came first, assessed up to 78 months. OS: From the date of registration until the date of death from any cause, assessed up to 78 months.
PFS/OS by the induction therapy regimen with or without consolidation therapy		PFS: From the date of registration until the date of first progression or date of death from any cause, whichever came first, assessed up to 78 months. OS: From the date of registration until the date of death from any cause, assessed up to 78 months.
Incidence rate of adverse events	The proportion of patients who experienced each adverse event	During the intervention up to 78 months, or for those who discontinued the intervention, assessed until 30 days after the last date of intervention or the date of initiation of post-study therapy, whichever came first, assessed up to 78 months.
Proportion of patients without neurological cognitive function (NCF) deterioration		Among patients eligible for NCF assessment, the proportion without deterioration in each assessment item at the following time points: pre-treatment baseline (after registration but before initiation of the study treatment), 48 weeks, 2 years, and 3 year
Proportion of patients without deterioration in health-related QOL		Among patients eligible for HR-QOL assessment, the proportion without deterioration at the following time points: pre-treatment baseline (after registration but before initiation of the study treatment), 48 weeks, 2 years, and 3 year

Collaborators and Investigators

• Sponsor: Kyorin University
• Collaborators: Ono Pharmaceutical Co. Ltd; Japan Clinical Oncology Group; National Cancer Center, Japan

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2023
• Primary Completion (Estimated): February 1, 2030
• Study Completion (Estimated): February 1, 2030

Study Registration Dates

• First Submitted: April 4, 2025
• First Submitted That Met QC Criteria: April 15, 2025
• First Posted (Actual): April 23, 2025

Study Record Updates

• Last Update Posted (Actual): April 23, 2025
• Last Update Submitted That Met QC Criteria: April 15, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Disease Progression; Pathologic Complete Response; Lymphoma
• Other Study ID Numbers: JCOG2104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No