Target subject population Male and female patients with PCNSL who have failed to achieve a response or who have relapsed after prior therapy (R/R) or who are treatment naïve but are not candidates of standard high-dose methotrexate-based induction chemotherapy. Patients are not to have been previously treated with immune checkpoint inhibitors or Bruton tyrosine kinase (BTK) inhibitors; prior treatment with rituximab is allowed.~Duration of treatment Rituximab will be administered for up to 8 cycles or until intolerance or excessive toxicities relevant to the trial therapy, or withdrawal of consents; acalabrutinib and durvalumab will be continued until disease progression, intolerance, or excessive toxicities relevant to the trial therapy, or withdrawal of consents.~Investigational product, dosage, and mode of administration Dose level 1 Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO once every day Durvalumab 1500mg infusion once every 4 weeks Dose level 2 Rituximab 375mg/m2 infusion once every 4 weeks for 8 cycles Acalabrutinib 100mg PO twice every day Durvalumab 1500mg infusion once every 4 weeks Expansion Determined by the result of the dose escalation phase Statistical methods~This study will use the 3+3 design in the dose escalation phase. Analyses will be primarily descriptive in nature; no formal statistical hypothesis testing will be performed. The populations used for analysis will include the following:~Safety analysis set: patients who receive at least 1 dose of anyone of the study drugs will be used for safety analyses.
To evaluate the safety and tolerability and determine the recommended phase 2/phase 3 dose of RAD regimen in PCNSL