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

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.

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.