Inclusion
Histologically proven aggressive B cell CNS lymphoma including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) or high-grade transformation of chronic lymphocytic leukaemia (CLL) or indolent lymphoma with:
Disease progression after PR or CR to the most recent therapy
Refractory to most recent therapy (failure to achieve PR or CR)
Treatment-naïve patients unsuitable for cytotoxic chemotherapy (maximum of 10 patients)
No active extra-CNS disease (apart from CLL not requiring therapy or a monoclonal B cell lymphocytosis)
ECOG performance status 0-2 and higher if activity is limited due to neurological deficit
No evidence of active infection or autoimmune disease
Not requiring corticosteroids >10mg prednisolone/day or equivalent except short term for acute management of CNS disease
No therapy with either BTK or PD1/PD-L1 inhibitor within the previous 6 months
Patients who are post-allogeneic stem cell transplant or chimeric antigen receptor (CAR)-T cell therapy will be eligible.
Exclusion
CNS lymphoma of a histological type other than that specified in Inclusion criteria. e.g., low-grade lymphoma, T-cell lymphoma etc.
Presence of lymphoma outside the CNS, i.e., systemic lymphoma, apart from CLL not requiring treatment or a monoclonal B cell lymphocytosis
Treatment with a BTK inhibitor and/or an immune checkpoint inhibitor within the 6 months prior to study entry.
Require corticosteroid therapy for management of CNS lymphoma at a dose more than 16 mg dexamethasone daily or equivalent
Corticosteroid therapy of more than 16 mg dexamethasone daily or equivalent at study entry from which, in the Investigator’s opinion, it is expected that the subject cannot be tapered off after the first 4 weeks of study treatment.
Intraocular primary CNS lymphoma without evidence of brain disease
Secondary CNS lymphoma actively receiving treatment for extra-CNS disease
Primary CNS lymphoma actively receiving concomitant local or systemic therapy for CNS disease
Active autoimmune diseases or history of autoimmune diseases that may relapse.
Any active malignancy within 2 years before first dose of study drug except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast)
Any condition, apart from the disease under examination, that required systemic treatment with either corticosteroids (more than 10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 14 days before first dose of study drug. If dexamethasone is being administered for CNS lymphoma, prednisone or equivalents should not be given concurrently.
Uncontrolled diabetes or Grade 1 or higher laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or Grade 3 or higher hypoalbuminemia within 14 days before first dose of study drug
History of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc.
Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc
Human immunodeficiency virus (HIV) infection, or active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] detected)
Any major surgical procedure requiring general anaesthesia within 28 days before first dose of study drug apart from that required to obtain a tissue biopsy.
Prior organ transplantation
Any of the following cardiovascular risk factors: Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, within 28 days before first dose of study drug; Pulmonary embolism within 28 days before first dose of study drug; Any history of acute myocardial infarction within 6 months before first dose of study drug; Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV within 6 months before first dose of study drug; Any event of ventricular arrhythmia of Grade 2 or higher in severity within 6 months before first dose of study drug; Any history of cerebrovascular accident within 6 months before first dose of study drug; Uncontrolled hypertension: systolic pressure more than 160 mmHg or diastolic pressure more than 100 mmHg despite anti-hypertension medications within 28 days before first dose of drug; Any episode of syncope or seizure within 28 days before first dose of study drug
Has taken or plans to take any chemotherapy, immunotherapy (e.g., interleukin, interferon, thymoxin), or any investigational therapies to treat leukemia or lymphoma within 28 days or 5 half-lives (whichever is shorter) of the first study drug administration, including CNS penetrating agents. Has received radiotherapy to treat leukemia or lymphoma within 21 days of the first study drug administration. Has received any herbal medicine used to control cancer within 14 days of the first study drug administration
Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline or stabilised, except for AEs not considered a likely safety risk (e.g., alopecia, neuropathy and specific laboratory abnormalities)
Was administered a live vaccine within 4 weeks before first dose of study drug
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines, and are not allowed
Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that, will be unfavourable for the administration of study drug or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct.
Concurrent participation in another therapeutic clinical study.
Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, symptomatic inflammatory bowel disease, or partial or complete bowel.
Requires ongoing treatment with a strong CYP3A inhibitor or inducer
Has QT corrected (QTc) interval (corrected by Fridericia’s method) of more than 480 msec