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Trial registered on ANZCTR


Registration number
ACTRN12622000547741
Ethics application status
Approved
Date submitted
24/03/2022
Date registered
7/04/2022
Date last updated
8/03/2023
Date data sharing statement initially provided
7/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
BICICL: BTK and Immune Checkpoint Inhibitor in Central Nervous System (CNS) Lymphoma
Scientific title
Phase IB/II study of the efficacy and safety of Zanubrutinib and Tislelizumab in CNS lymphoma
Secondary ID [1] 306762 0
ISR-CL-BGB3111-BGBA317-0035
Universal Trial Number (UTN)
U1111-1276-2716
Trial acronym
BICICL (BTK and Immune Checkpoint Inhibitor in CNS Lymphoma)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Central Nervous System Lymphoma 325774 0
Condition category
Condition code
Cancer 323112 323112 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single arm phase 1B/2 study of oral zanubrutinib and intravenous tislelizumab in CNS lymphoma. Eligible patients will receive: Zanubrutinib 320mg (4 x 80mg) oral capsules once daily continuously; followed by Tislelizumab 200mg intravenously every 3-weeks commencing after 9 weeks of zanubrutinib. Treatment will be continued for up to two years in responding patients. Adherence to oral therapy will be monitored by drug tablet return every 3 week cycle.
Intervention code [1] 323213 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330881 0
Overall response rate to the combination of zanubrutinib and tislelizumab in patients with relapsed/refractory CNS lymphoma and frontline patients deemed unfit for standard chemotherapy. Response will be assessed by Magnetic Resonance Imaging (MRI) of the brain with gadolinium contrast and reported by both independent review committee and the investigator using the immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria.
Timepoint [1] 330881 0
8 weeks from commencement of combination therapy.
Secondary outcome [1] 407905 0
To determine the overall and complete response rate of zanubrutinib monotherapy by MRI scan
Timepoint [1] 407905 0
8 weeks from commencement of combination therapy.
Secondary outcome [2] 407906 0
To evaluate the safety of combination therapy with zanubrutinib and tislelizumab as determined by the rate of Common Terminology Criteria for Adverse Events (CTCAE4), toxicity grade 3 or higher, serious adverse events (SAE) and adverse events (AE) leading to drug discontinuation. Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE4), criteria. Laboratory adverse events of interest include rates of neutropenia detected on full blood examination; and thyroid function abnormalities detected on thyroid function testing performed prior to day 1 each 3-week cycle therapy. Clinical adverse events of interest include: rates of opportunistic infections and autoimmune manifestations (i.e. skin rash, thyroiditis, nephritis, colitis). These will be identified using a study-specific questionnaire and clinical examination at study visits occurring on day 1 of each cycle. Rates of unplanned hospitalisation will be captured by standard trial procedures. i.e. Unplanned hospitalisation is a serious adverse event that will be reported to the study centre within 24 hours of the trial centre being notified.
Timepoint [2] 407906 0
Safety assessments will be performed at 8 weeks, 16 weeks, 1 year and 2 years from commencement of any study related medication. Blood tests to examine safety will be undertaken prior to day 1 of each 3-week cycle therapy up to 2 years from commencement.
Secondary outcome [3] 407907 0
To determine the best overall response rate of the combination of zanubrutinib and tislelizumab in patients with relapsed/refractory CNS lymphoma and frontline patients deemed unfit for standard chemotherapy. Response will be assessed by Magnetic Resonance Imaging (MRI) of the brain with gadolinium contrast and reported by both independent review committee and the investigator using the immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria.
Timepoint [3] 407907 0
8 weeks from commencement of combination therapy.
Secondary outcome [4] 407908 0
To determine the progression free survival rate of the combination of zanubrutinib and tislelizumab in patients with relapsed/refractory CNS lymphoma and frontline patients deemed unfit for standard chemotherapy . Response will be assessed by Magnetic Resonance Imaging (MRI) of the brain with gadolinium contrast and reported by both independent review committee and the investigator using the immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria. MRI brain imaging will be performed at week 8, week 17 and then every 12 weeks up to 2 years from the commencement of any study related medication.
Timepoint [4] 407908 0
MRI brain imaging will be performed at week 8, week 17 and then every 12 weeks up to 2 years from the commencement of any study related medication.
Secondary outcome [5] 407909 0
To determine the time to treatment failure of the combination of zanubrutinib and tislelizumab in patients with relapsed/refractory CNS lymphoma and frontline patients deemed unfit for standard chemotherapy. Response will be assessed by Magnetic Resonance Imaging (MRI) of the brain with gadolinium contrast and reported by both independent review committee and the investigator using the immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria.
Timepoint [5] 407909 0
MRI brain imaging will be performed at week 8, week 17 and then every 12 weeks up to 2 years from the commencement of any study related medication.
Secondary outcome [6] 407910 0
To determine the overall survival of the combination of zanubrutinib and tislelizumab in patients with relapsed/refractory CNS lymphoma and frontline patients deemed unfit for standard chemotherapy. Survival data for patients on study will be captured by investigators and supplemented using data-linkage to hospital records.
Timepoint [6] 407910 0
12 months and 24 months from commencement of any study related medication.
Secondary outcome [7] 407911 0
To evaluate quality of life, as assessed by patient-reported outcomes, in patients treated with zanubrutinib and/or tislelizumab. Quality of life will be captured as a composite outcome using (1) the European Organisation for Research and Treatment of Cancer Quality of life Questionnaire Cancer-30 (EORTC QLQ-C30) measuring physical functioning, emotional functioning, fatigue and pain., and (2) the European Organisation for Research and Treatment of Cancer Brain Neoplasm-20 Quality of life Questionnaire (EORTC QLQ - BN20) which evaluates the effects of the tumour and its treatment on symptoms, functions and health-related quality of life. These surveys will be administered once every 21 day cycle for up to two years.
Timepoint [7] 407911 0
Every 21-day cycle and at end of treatment

Eligibility
Key inclusion criteria
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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The Intent-to-Treat (ITT) analysis set includes all patients. This will be the primary analysis population for all efficacy analysis. The Per-Protocol (PP) analysis set includes patients who received at least 1 dose of the assigned study drug and had no major protocol deviations. Major protocol deviations will be determined and documented before the database lock for the primary analysis. The Safety analysis set includes all patients who received at least 1 dose of study drug; it will be the population for the safety analyses.

A total of approximately 30 patients will be enrolled. A sample size of 21 is required to accept the hypothesis that the response rate after 8 weeks of combination therapy, p1=50% rather than rejection at p0=25% with a=0.05 and 1- ß=0.80, one-sided test. 30 patients to be recruited to allow for dropout. Descriptive statistics will be used to analyse all safety data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2023
Actual
Date of last participant enrolment
Anticipated
1/08/2024
Actual
Date of last data collection
Anticipated
1/08/2026
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 22030 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 22031 0
Concord Repatriation Hospital - Concord
Recruitment hospital [3] 24221 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 37141 0
3168 - Clayton
Recruitment postcode(s) [2] 37142 0
2139 - Concord
Recruitment postcode(s) [3] 39759 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 311101 0
University
Name [1] 311101 0
Monash University
Country [1] 311101 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Road
Clayton, Victoria 3800
Country
Australia
Secondary sponsor category [1] 312432 0
None
Name [1] 312432 0
Address [1] 312432 0
Country [1] 312432 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310634 0
Monash Health HREC
Ethics committee address [1] 310634 0
Ethics committee country [1] 310634 0
Australia
Date submitted for ethics approval [1] 310634 0
27/04/2022
Approval date [1] 310634 0
09/08/2022
Ethics approval number [1] 310634 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118338 0
Prof Stephen Opat
Address 118338 0
Monash Health
246 Clayton Road
Clayton, Victoria 3168
Country 118338 0
Australia
Phone 118338 0
+61 3 95944366
Fax 118338 0
+61 3 95946587
Email 118338 0
stephen.opat@monashhealth.org
Contact person for public queries
Name 118339 0
Stephen Opat
Address 118339 0
Monash Health
246 Clayton Road
Clayton, Victoria 3168
Country 118339 0
Australia
Phone 118339 0
+61 3 95944366
Fax 118339 0
+61 3 95946587
Email 118339 0
stephen.opat@monashhealth.org
Contact person for scientific queries
Name 118340 0
Stephen Opat
Address 118340 0
Monash Health
246 Clayton Road
Clayton, Victoria 3168
Country 118340 0
Australia
Phone 118340 0
+61 3 95944366
Fax 118340 0
+61 3 95946587
Email 118340 0
stephen.opat@monashhealth.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All data will be de-identified data
baseline clinical data
treatment received
responses by MRI and QoL surveys
adverse event data
When will data be available (start and end dates)?
After primary analysis
Available to whom?
Collaborators, Co-investigators
Available for what types of analyses?
Correlative studies, and other unspecified analyses.
How or where can data be obtained?
Monash University RedCap database managed by School of Public Health and Preventative Medicine. All requests for data access to be addressed to the coordinating principal investigator.

The coordinating principal investigator can be contacted by email: stephen.opat@monashhealth.org or by telephone through Monash Health Haematology Research unit: + 61 3 95944044


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15543Informed consent form  stephen.opat@monash.edu 383820-(Uploaded-24-03-2022-22-57-50)-Study-related document.docx



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.