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Trial registered on ANZCTR


Registration number
ACTRN12619000024145p
Ethics application status
Not yet submitted
Date submitted
23/11/2018
Date registered
10/01/2019
Date last updated
10/01/2019
Date data sharing statement initially provided
10/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot study to assess whether mutations detected in baseline marginal zone lymphoma are predictive of resistance to bruton tyrosine kinase (BTK) inhibition.
Scientific title
ALLG LS21 A Biomarker Study in MZL patients treated with a BTK inhibitor
Secondary ID [1] 296697 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphoma 310543 0
Condition category
Condition code
Cancer 309255 309255 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This pilot study will assess if tumour somatic mutations identified in marginal zone lymphoma patients treated with zanubrutinib (a BTK inhibitor) are predictive of resistance to BTK inhibition and clinical relapse.
Participants will be asked to donate duplicate buccal swabs once at baseline and 30ml of blood in addition to the blood draws already performed as part of the BeiGene BGB-3111-214 clinical trial once a month (up to 9 time points) during treatment and once at time of progression if/when it occurs.
Participants are expected to be observed until disease progression or 2 years after end of treatment, whichever comes first. Treatment period is 2 years.
Intervention code [1] 313010 0
Not applicable
Comparator / control treatment
No comparator or control. This is a lab study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 308231 0
Somatic tumour mutations will be identified using cfDNA (cell free DNA) obtained from participants' plasma at baseline, at the end of specific treatment cycles (treatment cycles according to the BeiGene BGB-3111-214 clinical trial), and at progression. Presence of mutations will be correlated with clinical outcomes of the BGB-3111-214 provided by BeiGene.
Timepoint [1] 308231 0
End of treatment cycle 1,2-6,, 9, 12, 15 and at progression according to BGB-3111-214. Each treatment cycle is 28 days.
Secondary outcome [1] 354317 0
The secondary endpoint is to evaluate prediction of clinical relapse by detection of emergent resistance mutations in plasma.
Timepoint [1] 354317 0
At relapse

Eligibility
Key inclusion criteria
1. Age 18 years or older.
2. Histologically confirmed diagnosis of MZL including splenic, nodal, and extranodal subtypes. Gastric MZL must be H. pylori-negative disease or H. pylori-positive disease that has remained stable, progressed, or relapsed following antibiotic therapy.
3. Previously received one or more lines of therapy including at least one CD20-directed regimen (either as monotherapy or as chemoimmunotherapy) with documented failure to achieve at least PR or documented PD after, the most recent systemic treatment.
4. Current need for systemic therapy for MZL in the opinion of the investigator.
5. Availability of archival tissue or consent to obtain fresh tumor tissue sample from an evaluable core or excisional biopsy (approximately 10 to 15 unstained formalin fixed paraffin embedded slides or tissue box). Patients who do not have archival tissue available and are not candidates to undergo a tumor biopsy can only be enrolled after discussion with and approval of the medical monitor.
6. Measurable disease by CT or MRI. Measurable disease is defined as greater or equal to 1 lesion greater than 1.5 cm in longest diameter, and measurable in 2 perpendicular diameters. Patients with spleen-only disease are not considered to have measurable disease.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
8. Life expectancy equal to or greater than 6 months.
9. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) equal to or greater than 1,000/mm^3
(growth factor use is allowed), except for patients with bone marrow
involvement by MZL in which case ANC must be equal to or greater than
750/mm^3.
b. Platelet equal to or greater than 75,000/mm^3 (may not be post-
transfusion), except for patients with bone marrow involvement by MZL in
which case the platelet count must be equal to or greater than
50,000/mm^3.
10. Adequate organ function:
a. Creatinine clearance equal to or greater than 30 mL/min (as estimated by
the Cockcroft-Gault equation or as measured by nuclear medicine scan or
24-hour urine collection).
b. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase
and alanine aminotransferase/serum glutamic pyruvic transaminase equal
to or less than 2.5 × upper limit of normal (ULN) unless due to MZL.
c. Serum total bilirubin less than 2.0 × ULN (unless documented Gilbert’s
syndrome).
11. Female patients of childbearing potential must have a negative pregnancy test at screening and must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for at least 90 days after the last dose of zanubrutinib.
12. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for at least 90 days after the last dose of zanubrutinib.
13. Ability to provide written informed consent and can understand and comply with the requirements of the study.
14. Consent to the ALLG National Blood Cancer Registry (NBCR).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known transformation to aggressive lymphoma, eg, large cell lymphoma. Clinically suspected transformation will require a biopsy of the suspected area prior to enrollment to confirm absence of transformation.
2. Clinically significant cardiovascular disease.
3. Prior malignancy within the past 2 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer.
4. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug.
6. Severe or debilitating pulmonary disease.
7. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
8. Active fungal, bacterial and/or viral infection requiring systemic therapy.
9. Known central nervous system involvement by lymphoma.
10. Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs.
11. Known infection with HIV, or serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection.
12. Major surgery within 4 weeks of the first dose of study drug.
13. Prior treatment with a Bruton tyrosine kinase (BTK) inhibitor.
14. Last dose of prior therapy for MZL less than or equal to 21 days prior to first dose of study drug, with the following additional exclusion requirements:
a. Treatment with monoclonal antibody-based therapy within 28 days
of first dose of study drug.
b. Treatment with chimeric antigen receptor T-cell therapy within 180
days of first dose of study drug.
c. Treatment with any herbal medicine with anti-neoplastic intent
within 28 days of first dose of study drug.
d. Allogeneic hematopoietic stem cell transplantation within 12
months of first dose of study drug.
15. Any chemotherapy or radiation treatment for non-MZL indications within 21 days of first dose of study drug.
16. Toxicity from prior anti-cancer therapy that has not recovered to less tha or equal to Grade 1 (except for alopecia, ANC, and platelet count; for ANC and platelet count, see Inclusion criterion 9).
17. Pregnant or lactating women.
18. Vaccination with a live vaccine within 35 days prior to the first dose of study drug.
19. Ongoing alcohol or drug addiction.
20. Hypersensitivity to zanubrutinib or any of the other ingredients in zanubrutinib.
21. Requires ongoing treatment with a strong CYP3A inhibitor or inducer.
22. Concurrent participation in another therapeutic clinical trial.

Study design
Purpose
Duration
Selection
Timing
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 12528 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 12529 0
St George Hospital - Kogarah
Recruitment hospital [3] 12530 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 12531 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 12532 0
Box Hill Hospital - Box Hill
Recruitment hospital [6] 12533 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [7] 12534 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [8] 12535 0
Royal Perth Hospital - Perth
Recruitment hospital [9] 12536 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [10] 12537 0
Peninsula Private Hospital - Frankston - Frankston
Recruitment postcode(s) [1] 24909 0
3168 - Clayton
Recruitment postcode(s) [2] 24910 0
2217 - Kogarah
Recruitment postcode(s) [3] 24911 0
3000 - Melbourne
Recruitment postcode(s) [4] 24912 0
2139 - Concord
Recruitment postcode(s) [5] 24913 0
3128 - Box Hill
Recruitment postcode(s) [6] 24914 0
4102 - Woolloongabba
Recruitment postcode(s) [7] 24915 0
5042 - Bedford Park
Recruitment postcode(s) [8] 24916 0
6000 - Perth
Recruitment postcode(s) [9] 24917 0
2485 - Tweed Heads
Recruitment postcode(s) [10] 24918 0
3199 - Frankston

Funding & Sponsors
Funding source category [1] 301276 0
Commercial sector/Industry
Name [1] 301276 0
Beigene
Address [1] 301276 0
2929 Campus Drive, Suite 300
San Mateo, CA 94403 USA
Country [1] 301276 0
United States of America
Primary sponsor type
Charities/Societies/Foundations
Name
Australasian Leukaemia and Lymphoma Group
Address
Ground Floor, 35 Elizabeth St
Richmond, VIC 3121
Country
Australia
Secondary sponsor category [1] 300923 0
None
Name [1] 300923 0
Address [1] 300923 0
Country [1] 300923 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 302020 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 302020 0
Level 2, i Block, Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 302020 0
Australia
Date submitted for ethics approval [1] 302020 0
16/01/2019
Approval date [1] 302020 0
Ethics approval number [1] 302020 0

Summary
Brief summary
This study aims to implement and develop the identification of tumour mutations present at baseline in patients with marginal zone lymphoma and determine whether certain mutations can predict patients’ clinical outcome and survival.

Whom is it for?
You may be eligible to join if you are 18 years old or over and enrolled in the BeiGene BGB-3111-214 trial at one of the Australian sites as well as the Australasian and Leukaemia Group National Blood Cancer registry (ALLG NBCR).

Study details
All participants who consent to take part in this study will be asked to donate duplicate buccal swabs at baseline and 30ml of blood in addition to the blood draws already performed as part of the BeiGene BGB-3111-214 clinical trial. Additional lymph node and bone marrow biopsies may be required in some cases.

It is hoped that this pilot study will contribute to the identification of tumour mutations that may affect patients' responses to treatment and therefore broaden our knowledge of the mechanisms underpinning resistance to treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88862 0
Dr Gareth Gregory
Address 88862 0
Monash Medical Centre
246 Clayton Rd, Clayton VIC 3168
Country 88862 0
Australia
Phone 88862 0
+61 3 9594 6666
Fax 88862 0
+61 3 9594 6587
Email 88862 0
Gareth.Gregory@monashhealth.org
Contact person for public queries
Name 88863 0
Dr Gareth Gregory
Address 88863 0
Monash Medical Centre
246 Clayton Rd, Clayton VIC 3168
Country 88863 0
Australia
Phone 88863 0
+61 3 9594 6666
Fax 88863 0
Email 88863 0
Gareth.Gregory@monashhealth.org
Contact person for scientific queries
Name 88864 0
Dr Gareth Gregory
Address 88864 0
Monash Medical Centre
246 Clayton Rd, Clayton VIC 3168
Country 88864 0
Australia
Phone 88864 0
+61 3 9594 6666
Fax 88864 0
Email 88864 0
Gareth.Gregory@monashhealth.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
Summary results
No Results