IRB Study Number 22-088
Status Recruiting
Phase Phase 2
Institute Taussig Cancer Institute
Description
Primary Objective
To evaluate the efficacy of tirabrutinib monotherapy in patients with R/R PCNSL.
Secondary Objectives
To evaluate the efficacy of tirabrutinib monotherapy in patients with R/R PCNSL
To evaluate the safety of tirabrutinib monotherapy in patients with R/R PCNSL
To evaluate the PK of tirabrutinib monotherapy in patients with R/R PCNSL.
Inclusion Criteria
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
• Relapse disease: Patients who had prior response (CR, CRu or PR) with evidence of disease progression or new lesions have been detected ≥ 3 months of prior treatment
• Refractory disease: Patients who either: a) had prior response with evidence of disease progression within less than 3 months of prior treatment, or b) had no response to prior treatment
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
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1 or 2
Life expectancy of at least 3 months
Adequate bone marrow, renal, and hepatic function defined as:
• Absolute neutrophil count (ANC) ≥ 1,000/mm3
• Platelets (PLT) ≥ 100,000/mm3
• Hemoglobin ≥ 8.0 g/dL
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 2.5 × ULN
• Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula) or 30 mL/min/1.73 m2 (Modification of Diet in Renal Disease [MDRD] formula) (Patients with a creatinine clearance value calculated using these formulas that is below the reference value may be enrolled if the value determined with 24-hour pooled urine exceeds the reference value.)
Women of childbearing potential (including women who are amenorrheic due to chemical menopause or for another medical reason) must agree to use an effective method of contraception as described in Appendix 4: Contraceptive and Barrier Guidance (Section 10.4.2) from the time of informed consent to at least 7 days after the final dose of tirabrutinib.
Men must agree to use an effective method of contraception as described in Appendix 4: Contraceptive and Barrier Guidance (Section 10.4.2) from the start of tirabrutinib treatment until at least 7 days following the last dose of tirabrutinib.
Exclusion Criteria
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, or an antibody drug with anticancer activity (e.g., rituximab) within 28 days before starting tirabrutinib treatment
Prior radiotherapy within 14 days before starting tirabrutinib treatment
Prior major invasive surgery within 28 days before starting tirabrutinib treatment, or minor invasive surgery within 7 days before starting tirabrutinib treatment
Prior allogeneic stem cell transplant within 6 months before starting tirabrutinib treatment (prior autologous stem cell transplant is NOT an exclusion)
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
Concomitant warfarin, any other warfarinderivative anticoagulant, vitamin K antagonists, novel oral anticoagulants (NOACs, e.g., Apixaban, Dabigatran, Edoxaban, Rivaroxaban), or antiplatelet therapy on an ongoing basis within 7 days before starting tirabrutinib treatment
Patient who has received a cytochrome P450 (CYP) 3A4 inducer or P-glycoprotein (P-gp) inducer (Appendix 7: Drug-Interactions List [Section 10.7]) within 14 days before starting tirabrutinib treatment
Active malignancy, other than PCNSL requiring systemic therapy (Patients with history of non-melanoma skin cancers can be enrolled. Also, patients who have been diagnosed with either low grade cervical and prostate cancer, that does not require systemic therapy and are not actively progressive and who have received a stable dose of hormone therapy for a minimum of 6 months prior to entering this study can be enrolled.)
Poorly controlled comorbidity, severe heart disease (e.g., New York Heart Association functional class III or greater heart disease, unstable conduction disorder, angina pectoris, myocardial infarction within the past 180 days, uncontrolled hypertension despite optimal medical management), severe lung disease (e.g., interstitial lung disease, obstructive lung disease, hypersensitivity pneumonia, symptomatic bronchospasm), clinically significant liver diseases (including active viral or other hepatitis, or current alcohol abuse or severe cirrhosis) that could affect protocol compliance or safety or efficacy assessments
Patient with bleeding diathesis
Patients with a history of moderate or severe hepatic impairment (e.g., Child-Pugh Class B or C, respectively) (Appendix 8 [Section 10.8])
QTc interval corrected according to Fredericia’s formula (QTcF) > 480 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval
Active infection, including a human immunodeficiency virus (HIV), cytomegalovirus infection or severe acute respiratory syndrome coronavirus 2 (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, hepatitis B virus surface protein (HBs) antigen, or hepatitis C virus (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. Patients found to be incompetent to give informed consent because of their primary disease may be enrolled if a legally acceptable representative gives written informed consent.
Patient is found to be otherwise ineligible for the study by the Investigator or sub-Investigator.
