JCOG2314: A phase II/III randomized trial of salvage treatment for Refractory PCNSL using Tirabrutinib (ReSTART)
JCOG2314: A phase II/III trial of Tirabrutinib therapy for Refractory PCNSL (ReSTART)
SAITO Ryuta
Nagoya University School of Medicine
65 Tsurumai-cho, Showa-ku, Nagoya, Japan.
+81-52-744-2353
saito.ryuta.b1@f.mail.nagoya-u.ac.jp
Ohka Fumiharu
Nagoya University School of Medicine
65 Tsurumai-cho, Showa-ku, Nagoya, Japan.
+81-52-744-2353
ooka.fumiharu.j7@f.mail.nagoya-u.ac.jp
Recruiting
Jan. 19, 2026
94
Interventional
randomized controlled trial
open(masking not used)
active control
parallel assignment
treatment purpose
(1) Histologically proven diffuse large B-cell lymphoma from surgical resection or biopsy of an intracranial lesion.
(2) Primary lesion exists in the central nervous system (CNS)-the cerebrum, cerebellum, or brainstem-excluding the spinal cord.
(3) No lesions are detected outside the CNS and the intraocular region on contrast-enhanced computed tomography (CT) from the neck to the groin or whole-body PET performed before the initiation of induction therapy.
(4) Single or multiple lesions are allowed.
(5) Aged 18 years and older.
(6) Eastern Cooperative Oncology Group (ECOG) PS of 0-2, or 3 due to neurological symptoms caused by the tumor.
(7) Residual intracranial lesions confirmed on contrast-enhanced brain magnetic resonance imaging (MRI) at registration.
(8) Cerebrospinal fluid (CSF) cytology at registration confirms either the absence of lymphoma cells or equivocal findings. Patients for whom CSF examination is contraindicated are eligible if both contrast-enhanced brain MRI and whole-spine MRI demonstrate no evidence of leptomeningeal dissemination.
(9) At registration, patients have received one of the MTX-based induction regimens described in (i)-(iv) below for PCNSL and have been diagnosed with PD on contrast-enhanced brain MRI during induction therapy. Alternatively, patients are eligible if they have completed >= 5 cycles (up to 7 cycles) of one of the MTX-based induction regimens described in (i)-(iv) below, have been assessed as PR or SD on contrast-enhanced brain MRI, and are considered to require salvage therapy.
(i) R-MPV regimen: rituximab, methotrexate, and vincristine each administered 1-7 times, and procarbazine administered at least once.
(ii) MPV regimen: methotrexate and vincristine each administered 1-7 times, and procarbazine administered at least once.
(iii) R-M regimen: rituximab and methotrexate each administered 1-7 times.
(iv) M regimen: methotrexate administered 1-7 times.
(10) Within 30 days after the last day of induction therapy.
(11) No prior radiotherapy (RT) for PCNSL.
(12) No prior chemotherapy or RT for other malignancies or lymphoma. However, hormone therapy for prostate or breast cancer is allowed. RT alone for prostate cancer, breast cancer, or early glottic cancer is allowed if >= 5 years have passed without recurrence.
(13) All of the following laboratory values are met.
(i) Neutrophil count >= 1,000 /mm3
(ii) Hemoglobin >= 8.0 g/dl
(iii) Platelet count >= 75,000 /mm3
(iv) AST <= 100 U/L
(v) ALT <= 100 U/L
(vi) T-bil <= 2.25 mg/dL
(vii) Serum creatinine <= 1.5 mg/dL
(14) Written informed consent.
(1) Simultaneous or metachronous (within two years) double cancers, with the exception of intramucosal tumor curable with local therapy.
(2) Active infection requiring systemic therapy.
(3) Fever over 38 degrees Celsius.
(4) Female during pregnancy, within 28 days of post parturition, or during lactation.
(5) Psychological disorder difficult to participate in this clinical study.
(6) Receiving continuous systemic corticosteroid or immunosuppressant treatment due to the diseases except for brain tumors.
(7) Uncontrolled diabetes mellitus.
(8) History of unstable angina pectoris within three weeks or myocardial infarction within 6 months before registration.
(9) Interstitial pneumonia, pulmonary fibrosis, or severe emphysema on chest CT.
(10) Gadolinium allergy.
(11) Positive HBs antigen.
(12) Positive HIV antibody.
18age old over
No limit
Both
Primary central nervous system lymphoma
Arm A: Radiotherapy
* Whole-brain radiotherapy 30 Gy (2 Gy per fraction, once daily, 5 days per week, 15 fractions), followed by a local boost of 10 Gy (2 Gy per fraction, once daily, 5 days per week, 5 fractions) to the tumor bed.
Arm B: Tirabrutinib therapy
* One course consists of 28 days. Tirabrutinib 480 mg/day is administered orally once daily in a fasting state. Treatment is continued daily unless a protocol-defined discontinuation criterion is met.
Phase II: Proportion of patients who continue tirabrutinib without disease progression at 4 weeks after treatment initiation
Phase III: Overall survival
Phase II: Frequency of adverse events, frequency of severe adverse events
Phase III: Progression-free survival, hospitalization-free survival, response rate, disease control rate, frequency of adverse events, frequency of severe adverse events, proportion of Karnofsky performance status preservation, proportion of neurocognitive function preservation, proportion of health-related QOL preservation, proportion of patients in arm B who undergo radiotherapy within 24 weeks
