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Phase II

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

  • Study HIC#:2000032308
  • Last Updated:04/18/2024

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/ temozolimide/rituximab or rituximab/methotrexate/procarbazine/ vincristine) as first line therapy in patients with newly diagnosed, treatment naïve PCNSL (Part B).

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    Trial Purpose and Description

    Primary Outcome Measures :

    1. Overall response rate (ORR) (Part A) [ Time Frame: 1 year ]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.
    2. Tirabrutinib dose estimate (Part B) [ Time Frame: 1 month ]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
    3. Incidence and severity of AEs and SAEs during induction (Part B) [ Time Frame: 4 months ]Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.
    4. Complete response rate (CRR) (Part B) [ Time Frame: 4 months ]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.

    Eligibility Criteria

    Inclusion Criteria (Part A)

    1. Written informed consent by the patient prior to screening
    2. Patients aged ≥ 18 years on the day of consenting to the study
    3. Pathologic diagnosis of PCNSL
    4. Relapse or refractory PCNSL with at least one prior HD MTX based therapy for PCNSL
    5. 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
    6. ECOG PS of 0, 1 or 2
    7. Life expectancy of at least 3 months
    8. Adequate bone marrow, renal, and hepatic function

    Inclusion Criteria (Part B)

    1. Written informed consent by the patient prior to screening
    2. Patients aged ≥ 18 years on the day of consenting to the study
    3. Pathologic diagnosis of PCNSL within the past 3 months
    4. No prior anti-tumor treatments for PCNSL
    5. Patients who, in the opinion of the Investigator, are suitable to receive treatment with a high dose methotrexate containing regimen
    6. Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced MRI performed within 14 days before starting study treatment
    7. ECOG PS of 0, 1 or 2
    8. Life expectancy of at least 6 months
    9. Adequate bone marrow, renal, and hepatic function

    Exclusion Criteria (Part A)

    1. Intraocular PCNSL with no brain lesion
    2. Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents
    3. Patient with non-B cell PCNSL
    4. Patient with systemic presence of lymphoma
    5. 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
    6. Prior BTK inhibitor treatment
    7. 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
    8. 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
    9. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment
    10. 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
    11. Active malignancy, other than PCNSL requiring systemic therapy
    12. Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments
    13. Patient with bleeding diathesis
    14. Patients with a history of moderate or severe hepatic impairment
    15. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval
    16. 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
    17. Prior history of hypersensitivity or anaphylaxis to tirabrutinib
    18. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis
    19. Medical history of organ allografts
    20. 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.
    21. 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.
    22. Women who are pregnant or lactating
    23. Patient is found incapable of giving consent due to dementia or another such condition
    24. Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.

    Exclusion Criteria (Part B)

    1. Intraocular PCNSL with no brain lesion
    2. 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
    3. Patients with a history of intolerable toxicity, hypersensitivity, anaphylaxis to the selected backbone regimen medications
    4. Patient who is intolerant of contrast enhanced MRI due to allergic reactions to contrast agents
    5. Patient with non-B cell PCNSL
    6. Patient with systemic presence of lymphoma
    7. 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
    8. Prior BTK inhibitor treatment
    9. 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
    10. 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
    11. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before starting tirabrutinib treatment
    12. 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
    13. Active malignancy, other than PCNSL requiring systemic therapy
    14. Poorly controlled comorbidity, severe heart, severe lung disease, clinically significant liver diseases that could affect protocol compliance or safety or efficacy assessments
    15. Patient with bleeding diathesis
    16. Patients with a history of moderate or severe hepatic impairment
    17. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval
    18. 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
    19. Prior history of hypersensitivity or anaphylaxis to tirabrutinib
    20. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis
    21. Medical history of organ allografts
    22. 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.
    23. 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.
    24. Women who are pregnant or lactating
    25. Patient is found incapable of giving consent due to dementia or another such condition
    26. Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.

    Principal Investigator

    Sub-Investigators

    For more information about this study, including how to volunteer, contact: