PRiZM+: A phase II platform study of zanubrutinib monotherapy and combination therapy for relapsed and refractory primary CNS lymphoma

Study ID: 50538
Short Title: PRiZM+
Trust Name: UHS
Recruitment Site: Southampton General Hospital
Disease Area: Haematology
Phase: II
Expected End Date: 07/09/2023
Postcode: SO16 6YD
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

•> = 16 years of age •Histologically confirmed CD20+ DLBCL confined to the CNS •Relapsed or refractory PCNSL (defined as disease progression following CR/CRu/PR, or failure to achieve PR after one or more lines of therapy; one therapy line must have included at least 1 cycle of high-dose methotrexate (> = 1g/m2)) •Measurable disease on contrast-enhanced MRI of brain (and/or spinal cord) •ECOG performance status of 0 to 2, or 3 if attributed to lymphoma •Ability to swallow capsules •Adequate renal and liver function defined as: o Creatinine clearance > = 30 mL/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24-hour urine collection) o Serum total bilirubin < 3.0 x ULN (unless due to Gilbert’s syndrome) o Up to and including moderate impairment (Child-Pugh class B) • Adequate bone marrow function, defined as unsupported platelets > 50 x109/L, neutrophils > 1 x109/L, haemoglobin > 80 g/L • Patient willing and able to comply with scheduled visits, treatment plan, investigations and other study procedures • Written informed consent for the trial

• Current evidence or prior history of systemic lymphoma • Exclusive intraocular involvement • Active infection requiring intravenous antimicrobials • Chemotherapy for lymphoma within 2 weeks of first dose of zanubrutinib • Whole-brain radiotherapy within 4 weeks of first dose of zanubrutinib • Contra-indication to lumbar puncture • Prior exposure to BTK inhibitor • Known bleeding disorder e.g haemophilia or severe Von-Willebrand Disease • Current use of warfarin, or dual anti-platelet therapy o Therapeutic anticoagulation with direct oral anticoagulants or low molecular weight heparin is permitted • Evidence of active HIV, HBV or HCV infection, except o HIV positive patients established on anti-retroviral treatment, with undetectable HIV RNA, after discussion with the patient’s HIV physician o HBV core antibody positive patients who are (i) surface antigen negative and (ii) HBV DNA PCR negative, who take prophylaxis as per institutional guidelines • Patients who are pregnant or breastfeeding (women of childbearing potential must have a negative urine or serum pregnancy test prior to trial entry) • Patients and patients with partners of childbearing potential (pre-menopausal female capable of becoming pregnant) not willing to use highly effective contraception (see Section 9.6) during and for 12 months after cessation of therapy • Clinically significant cardiac or respiratory dysfunction that, in the opinion of the investigator, would jeopardise the safety of the patient in the trial • Active malignancy treated in the last 2 years, except o Non-melanoma skin cancer o Carcinoma in situ of the cervix or breast o Incidental finding of prostate cancer (T1a or T1b)

Primary central nervous system lymphoma (PCNSL) is a rare type of brain tumour. It is an aggressive type of non-Hodgkin lymphoma that is found only in the brain or spinal cord. PCNSL is often treated with high-doses of chemotherapy. The first treatment doesn’t work for some patients (called ‘refractory’), and the lymphoma can come back (called ‘relapse’). Refractory or relapsed (RR) PCNSL is much more difficult to treat. There is currently no standard treatment for RR-PCNSL and further chemotherapy treatment is often unsuccessful. Radiation treatment to the brain can sometimes be used but can cause significant long-term side-effects. Clinical trials are now focused on testing new drugs that are better at targeting the tumour, and are likely to have fewer side-effects. The treatment being tested in the PRiZM+ trial is a drug called zanubrutinib. Zanubrutinib is a new type of drug (a Bruton’s tyrosine kinase inhibitor), which works by targeting lymphoma cells. Previous studies have shown that similar drugs can cause RR-PCNSL to shrink or disappear. It is thought that zanubrutinib could be a more effective treatment, which can be given safely without too many side effects. The aim of the study is to find out how effective and safe zanubrutinib is for patients with RR-PCNSL. We will be looking at the effects zanubrutinib has against lymphoma, how long these effects last, and what the side-effects of the drug are.

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