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

Inclusion Criteria (Part A)

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 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
ECOG PS of 0, 1 or 2
Life expectancy of at least 3 months
Adequate bone marrow, renal, and hepatic function

Inclusion Criteria (Part B)

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

Exclusion Criteria (Part A)

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
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.

Exclusion Criteria (Part B)

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.