A trial of zanubrutinib treatment of patients with relapsed and refractory primary central nervous system lymphoma

Plain English Summary

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-zanubrutinib-for-lymphoma-of-the-brain-and-spinal-cord-prizm

Background and study aims
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 this study 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 that 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. The researchers will be looking at the effects zanubrutinib has against lymphoma, how long these effects last, and what the side effects of the drug are.

Who can participate?
Patients who have not responded to standard chemotherapy for PCNSL or have relapsed afterwards. Patients with this type of brain tumour often have impaired cognitive function due to their disease and previous therapy, but this has been known to improve in patients who respond well to treatment, so these patients are included in this trial.

What does the study involve?
Participants will receive 28-day cycles of continuous zanubrutinib treatment orally twice daily. The participants will continue until disease progression, development of unacceptable side effects, or their choice. Participants no longer on treatment will be followed up every 3 months for survival, progression and subsequent treatment.

What are the possible risks and benefits of participating?
There is always a risk associated with taking any drug. There may be risks of the study drug that are unknown or cannot be predicted at this time, but patients will be carefully monitored for any problems or adverse side effects. The treatments may or may not improve patients’ underlying disease.

Where is the study run from?
University of Birmingham and the Cancer Research UK Clinical Trials Unit (UK)

When is the study starting and how long is it expected to run for?
April 2019 to October 2026

Who is funding the study?
Beigene (China) and Cure Leukaemia (UK)

Who is the main contact?
Clare Morland (trial coordinator)
PRiZM+@trials.bham.ac.uk

Study website

Type

Principal Investigator

Contact name

Prof Chris Fox

ORCID ID

Contact details

Dept Clinical Haematology
Nottingham University Hospital
Hucknall Rd
Nottingham
NG5 1PB
United Kingdom
-
Christopher.Fox2@nuh.nhs.uk

Type

Scientific

Contact name

Dr Clare Morland

ORCID ID

Contact details

Cancer Research UK Clinical Trials Unit
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 371 7861
PRiZM+@trials.bham.ac.uk

EudraCT/CTIS number

2020-005218-16

IRAS number

290665

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 50538, IRAS 290665

Scientific title

PRiZM+: a Phase II platform study of zanubrutinib monotherapy and combination therapy for relapsed and refractory primary central nervous system lymphoma

Acronym

PRiZM+

Study hypothesis

Is zanubrutinib (a new drug that interferes with signals that B cells need to survive and grow) a safe and effective treatment for patients with an aggressive brain tumour known as primary central nervous system lymphoma (PCNSL), who have either not responded to initial chemotherapy, or have relapsed after chemotherapy?

Ethics approval(s)

Approved 05/11/2021, East Midlands – Leicester Central REC (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 104 8115; leicestercentral.rec@hra.nhs.uk), ref: 21/EM/0224

Study design

Non-randomized; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Non randomised study

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Relapsed and refractory primary CNS lymphoma

Intervention

This is a prospective, multicentre, sequential single-arm phase II study for zanubrutinib for the treatment of RR-PCNSL.

Patients and legal representatives who consent to participate will have a screening period of up to 28 days before trial registration for the following assessments to take place. The patient will be asked their demographic and medical history, physical exam (including vital signs, height and weight), pregnancy test (for women of childbearing potential [WOCBP]), blood tests, lumbar puncture and cerebrospinal fluid (CSF) evaluation, Eastern Cooperative Oncology Group (ECOG) performance status, Neurologic Assessment for Neuro-Oncology (NANO), functional assessment, ophthalmological slit lamp exam, MRI scan and a PET-CT scan (or CT-NCAP [neck-chest-abdomen-pelvis]).

Once registered to the study, patients will receive 28-day cycles of continuous zanubrutinib monotherapy orally twice daily. The patient will continue until disease progression, development of unacceptable side effects, or patient choice.

Patients will be seen on day 1 of cycle 1 for vital signs, physical exam, pregnancy test (for WOCBP), blood tests, ECOG performance status and NANO. Days 7 and 14 of cycle 1 they will be seen again for blood tests, lumbar puncture and CSF evaluation and an ECOG performance status. Day 1 of cycle 2 the patient will be seen for vital signs, blood tests, lumbar puncture and CSF evaluation, ECOG performance status and a multimodal MRI scan. On day 1 of cycle 3 the patient will be seen for the same assessments as mentioned for cycle 2, but also a physical exam, NANO, functional assessment, ophthalmological slit lamp exam and a Gd-enhanced MRI. Following cycle 3, patients will be seen on day 1 of each cycle for vital signs, blood tests and ECOG performance status assessment. Every 3 months during treatment the patient will be seen for a NANO, functional assessment and Gd-enhanced MRI. Every 6 months they will be seen for an additional blood test for circulating tumour DNA.

If the patient experiences disease progression, they will be seen for vital signs, blood tests, ECOG performance status, NANO and functional assessment. They will be seen 28 days after the last dose of trial treatment for an End of Treatment visit, this will include vital signs, blood tests, ECOG performance status, NANO and Gd-enhanced MRI.

Patients no longer on treatment will be followed up every 3 months for survival, progression date and subsequent therapy.

Intervention type

Drug

Pharmaceutical study type(s)

Phase

Phase II

Drug/device/biological/vaccine name(s)

Zanubrutinib

Primary outcome measure

Overall response (complete response [CR] + unconfirmed CR [CRu] + partial response [PR]) after two cycles of treatment, assessed locally using international consensus criteria (Abrey et al., 2005). Patients will be followed up for 1 year.

Secondary outcome measures

Patients will be followed up for 1 year:
1. Complete response at response assessment by MRI scan after two cycles of treatment, response assessed locally or by central MRI scan review
2. Overall response assessed by MRI scan after two cycles of treatment, assessment by central MRI review
3. Best overall response assessed by MRI scan within 12 months of registration, response assessed locally or by central MRI scan review
4. Progression-free survival, defined as the time from trial entry to the date of progressive disease or death from any cause
5. Overall survival, defined as the time from trial entry to the date of death from any cause
6. Event-free survival, defined as the time from trial entry to the first of initiation of a new anti-lymphoma treatment, progressive disease, or death from any cause
7. Toxicity, defined as the proportion of patients experiencing one or more: grade 2 or higher non-haematological adverse events (AE), grade 3 or higher haematological AE, or any serious AE (SAE)

Overall study start date

12/04/2019

Overall study end date

20/10/2026

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Aged ≥16 years of age
2. Histologically confirmed CD20+ diffuse large B cell lymphoma (DLBCL) confined to the CNS
3. Relapsed or refractory PCNSL (defined as disease progression following complete response (CR)/unconfirmed complete response (CRu)/partial response (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 [≥1 g/m²])
4. Measurable disease on contrast-enhanced MRI of brain (and/or spinal cord)
5. ECOG performance status of 0 to 2, or 3 if attributed to lymphoma
6. Ability to swallow capsules
7. Adequate renal and liver function defined as:
7.1. Creatinine clearance ≥30 ml/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24-hour urine collection)
7.2. Serum total bilirubin <3.0 x ULN (unless due to Gilbert’s syndrome)
7.3. Up to and including moderate impairment (Child-Pugh class B)
8. Adequate bone marrow function, defined as unsupported platelets >50 x10e9/l, neutrophils >1 x10e9/l, haemoglobin >80 g/l
9. Patient willing and able to comply with scheduled visits, treatment plan, investigations and other study procedures
10. Written informed consent for the trial

Participant type(s)

Patient

Age group

Adult

Lower age limit

16 Years

Sex

Both

Target number of participants

Planned Sample Size: 20; UK Sample Size: 20

Participant exclusion criteria

1. Current evidence or prior history of systemic lymphoma
2. Exclusive intraocular involvement
3. Active infection requiring intravenous antimicrobials
4. Chemotherapy for lymphoma within 2 weeks of the first dose of zanubrutinib
5. Whole-brain radiotherapy within 4 weeks of the first dose of zanubrutinib
6. Contra-indication to lumbar puncture
7. Prior exposure to BTK inhibitor
8. Known bleeding disorder e.g haemophilia or severe Von-Willebrand Disease
9. Current use of warfarin, or dual anti-platelet therapy. Therapeutic anticoagulation with direct oral anticoagulants or low molecular weight heparin is permitted
10. Evidence of active HIV, HBV or HCV infection, except:
10.1. HIV-positive patients established on anti-retroviral treatment, with undetectable HIV RNA, after discussion with the patient’s HIV physician
10.2. HBV core antibody-positive patients who are (i) surface antigen-negative and (ii) HBV DNA PCR negative, who take prophylaxis as per institutional guidelines
11. Patients who are pregnant or breastfeeding (women of childbearing potential must have a negative urine or serum pregnancy test prior to trial entry)
12. 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
13. Clinically significant cardiac or respiratory dysfunction that, in the opinion of the investigator, would jeopardise the safety of the patient in the trial
14. Active malignancy treated in the last 2 years, except:
14.1. Non-melanoma skin cancer
14.2. Carcinoma in situ of the cervix or breast
14.3. Incidental finding of prostate cancer (T1a or T1b)

Recruitment start date

20/10/2022

Recruitment end date

20/10/2025

Countries of recruitment

England, Northern Ireland, Scotland, United Kingdom, Wales

Study participating centre

Aberdeen Royal Infirmary
Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom

Study participating centre

Churchill Hospital
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom

Study participating centre

Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Study participating centre

Belfast City Hospital
51 Lisburn Rd
Belfast
BT9 7AB
United Kingdom

Study participating centre

Clatterbridge Cancer Centre
65 Pembroke PLACE
Liverpool
L7 8YA
United Kingdom

Study participating centre

Christie Hospital
Wilmslow Road
Manchester
M20 4BX
United Kingdom

Study participating centre

King's College Hospital
Denmark Hill
London
SE5 9RS
United Kingdom

Study participating centre

Freeman Road Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Study participating centre

Nottingham University Hospital
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom

Study participating centre

Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom

Study participating centre

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Study participating centre

St. Bartholomews Hospital
West Smithfield
London
EC1A 7BE
United Kingdom

Study participating centre

St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Study participating centre

University Hospital Birmingham
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom

Study participating centre

University College London Hospital
250 Euston Road
London
NW1 2BU
United Kingdom

Study participating centre

University Hospital of Wales
Heath Park
Cardiff
CF14 4XW
United Kingdom

Organisation

University of Birmingham

Sponsor details

Edgbaston
Birmingham
B15 2TT
England
United Kingdom
+44 (0)1214158011
researchgovernance@contacts.bham.ac.uk

Sponsor type

University/education

Website

http://www.birmingham.ac.uk/index.aspx

ROR

https://ror.org/03angcq70

Funder type

Charity

Funder name

Cure Leukaemia

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

BeiGene

Alternative name(s)

百济神州的, BeiGene Ltd, BeiGene, Ltd.

Funding Body Type

government organisation

Funding Body Subtype

For-profit companies (industry)

Location

China

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal

Intention to publish date

30/06/2026

Individual participant data (IPD) sharing plan

The data-sharing plans for the current study are unknown and will be made available at a later date

IPD sharing plan summary

Data sharing statement to be made available at a later date

Study outputs