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Trial registered on ANZCTR


Registration number
ACTRN12610000908033
Ethics application status
Approved
Date submitted
25/10/2010
Date registered
25/10/2010
Date last updated
27/05/2019
Date data sharing statement initially provided
27/05/2019
Date results information initially provided
27/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Rituximab in Primary Central Nervous system Lymphoma.
A randomized Dutch/Belgian Hemato-Oncology Cooperative Group (HOVON) / Australasian Leukaemia and Lymphoma Group (ALLG) intergroup study
Scientific title
Rituximab in Primary Central Nervous system Lymphoma.
A randomized Dutch/Belgian Hemato-Oncology Cooperative Group (HOVON) / Australasian Leukaemia and Lymphoma Group (ALLG) intergroup study
Secondary ID [1] 252948 0
Nederlands Trial Register NTR2427
Universal Trial Number (UTN)
Trial acronym
ALLG NHL24
Linked study record

Health condition
Health condition(s) or problem(s) studied:
primary central nervous system (CNS) lymphoma 258479 0
Condition category
Condition code
Cancer 258646 258646 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
2 courses (4 weeks each) of R-MBVP (Rituximab 375mg/m2 intravenously (i.v), course 1 days 0,7,14,21, course 2 days 0 and 14; methotrexate 3g/m2 iv days 1,15 for all courses; Teniposide 100mg/m2 i.v days 2,3 for all courses; BCNU (Carmustine) 100mg/m2 i.v day 4 for all courses; prednisolone 60mg/m2 orally or i.v days 1-5 for all courses)
Following randomisation to MBVP or R-MBVP, patients will undergo an MRI. Patients with less than a complete response (CR) or partial response (PR) will be removed from study. Responding patients undergo consolidation with cytarabine (2 g/m2 i.v days 1,2) and have another MRI. Patients greater than or equal to 61 years of age will finish protocol treatment here. Patients with relapse or progressive disease will be withdrawn from study. Patients less than or equal to 60 years of age will undergo whole brain radiotherapy- if CR or (complete remission-unconfirmed) CRu- 20 x 1.5 Gy; if PR 20 x 1.5 Gy and boost 20 x 0.5 Gy. Patients will then have another MRI.
Intervention code [1] 257477 0
Treatment: Drugs
Comparator / control treatment
2 courses (4 weeks each) of MBVP (methotrexate 3g/m2 iv days 1,15 for all courses; Teniposide 100mg/m2 i.v days 2,3 for all courses; BCNU (Carmustine) 100mg/m2 i.v day 4 for all courses; prednisolone 60mg/m2 orally or i.v days 1-5 for all courses)
Following randomisation to MBVP or R-MBVP, patients will undergo an MRI. Patients with less than a complete response (CR) or partial response (PR) will be removed from study. Responding patients undergo consolidation with cytarabine (2 g/m2 i.v days 1,2) and have another MRI. Patients greater than or equal to 61 years of age will finish protocol treatment here. Patients with relapse or progressive disease will be withdrawn from study. Patients less than or equal to 60 years of age will undergo whole brain radiotherapy- if CR or CRu- 20 x 1.5 Gy; if PR 20 x 1.5 Gy and boost 20 x 0.5 Gy. Patients will then have another MRI.
Control group
Active

Outcomes
Primary outcome [1] 259492 0
Event-free survival of all patients defined as failure (relapse, no CR or CRu) or death from any cause.
Timepoint [1] 259492 0
at 1, 3 and 5 years
Secondary outcome [1] 266083 0
Response rates by MRI
Timepoint [1] 266083 0
after (R-)MBVP, after high dose cytarabine and after completion of radiotherapy

Eligibility
Key inclusion criteria
1. Patients with a histologically confirmed diagnosis of CD20 positive diffuse large B cell lymphoma (DLBCL) based upon a representative histology specimen of brain biopsy according to the world health organisation (WHO) classification;
OR
2. Patients with a diagnosis of PCNSL based on magnetic resonance imaging (MRI) evidence of brain parenchymal lesion showing homogeneous contrast enhancement suspect for lymphoma;
AND
3. Unequivocal morphological and/or immunophenotypical evidence of cerebrospinal fluid (CSF) CD20 + large cell lymphoma;
4. AND/OR Unequivocal morphological and/or immunophenotypical evidence of CD20 + large cell lymphoma in vitreous fluid;
OR
5. Patients with unequivocal morphological and/or immunophenotypical evidence of CD20 + large cell lymphoma in vitreous fluid AND CSF but without a brain parenchymal lesion;
6. Age 18-70 years inclusive;
7. Performance status with or without administration of steroids WHO/Eastern cooperative group (ECOG) 0-3;
8. Written informed consent.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Evidence of systemic lymphoma;
2. History of intolerance of exogenous protein administration;
3. Severe cardiac dysfunction (NYHA classification III-IV, , or Left Ventricular Ejection Fraction < 45%) Congestive heart failure or symptomatic coronary artery disease or cardiac arythmias not well controlled with medication ;
4. Severe pulmonary dysfunction (vital capacity or diffusion capacity < 50% of predicted value);
5. Significant hepatic dysfunction (bilirubin or transaminase greater or equal to 2.5 x upper normal limit) at Screening;
6. Significant renal dysfunction (serum creatinine greater than or equal to 150 micromol/l or clearance < 60 ml/min) at Screening;
7. Presence of third space fluid, such as pleural effusion or ascites;
8. Prior cranial radiotherapy;
9. Active uncontrolled infection;
10. Human immunodeficiency virus (HIV)-positivity;
11. Epstein barr virus (EBV) positive post-transplant lymphoproliferative disorder;
12. Untreated hepatitis B infection (inclusion is possible if adequate antiviral medication e.g. lamivudine or alternative is started and continued for the duration of the trial);
13. Positive pregnancy test in women of reproductive potential;
14. Lactating women;
15. Unable or unwilling to use adequate contraceptive methods (all men, pre-menopausal women) until 12 months after last chemotherapy treatment;
16. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients are enrolled and randomised centrally at HOVON data centre.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
sequential generation of randomisation in order of enrolment
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not 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,TAS,WA,VIC
Recruitment hospital [1] 8256 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 8257 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 8258 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [4] 8259 0
Royal Hobart Hospital - Hobart
Recruitment hospital [5] 8260 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [6] 8261 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [7] 8262 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 3399 0
3002
Recruitment postcode(s) [2] 16316 0
5000 - Adelaide
Recruitment postcode(s) [3] 16317 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 16318 0
2050 - Camperdown
Recruitment postcode(s) [5] 16319 0
7000 - Hobart
Recruitment postcode(s) [6] 16320 0
3050 - Parkville
Recruitment postcode(s) [7] 16321 0
6009 - Nedlands
Recruitment postcode(s) [8] 16322 0
2139 - Concord
Recruitment outside Australia
Country [1] 2991 0
Netherlands
State/province [1] 2991 0
Country [2] 2992 0
Belgium
State/province [2] 2992 0

Funding & Sponsors
Funding source category [1] 257927 0
Commercial sector/Industry
Name [1] 257927 0
Roche Products Pty Ltd
Address [1] 257927 0
4-10 Inman Road
Dee Why NSW 2099
Australia
Country [1] 257927 0
Australia
Primary sponsor type
Other Collaborative groups
Name
HOVON
Address
VU University Medical Center,
P.O.Box 7057
1007 MB Amsterdam
Country
Netherlands
Secondary sponsor category [1] 257118 0
Other Collaborative groups
Name [1] 257118 0
Australasian Leukaemia and Lymphoma Group
Address [1] 257118 0
Level 2/10 St Andrews Place
East Melbourne, VIC, 3002
Country [1] 257118 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259939 0
Austin Health
Ethics committee address [1] 259939 0
Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084
Ethics committee country [1] 259939 0
Australia
Date submitted for ethics approval [1] 259939 0
23/09/2010
Approval date [1] 259939 0
01/05/2010
Ethics approval number [1] 259939 0

Summary
Brief summary
Newly diagnosed PCNS lymphoma patients will be randomised to either 2 courses of MBVP or 2 courses of MBVP+Rituximab. All patients will undergo an MRI at the end of chemotherapy and be assessed for consolidation treatment with AraC, after which these patients will undergo another MRI to determine their eligibility or need for WBRT or not. The primary objective of the trial is event free survival.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31828 0
Dr Samar Issa
Address 31828 0
North Middlemore Hospital, Auckland, New Zealand
Country 31828 0
New Zealand
Phone 31828 0
+64 9 276 0044
Fax 31828 0
Email 31828 0
samar.issa@middlemore.co.nz
Contact person for public queries
Name 15075 0
Ms Delaine Smith
Address 15075 0
Australasian Leukaemia and Lymphoma Group 35 Elizabeth Street Richmond VIC 3121
Country 15075 0
Australia
Phone 15075 0
+61 383739701
Fax 15075 0
Email 15075 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 6003 0
Dr Dr Samar Issa
Address 6003 0
Middlemore Hospital
Private Bag 93311
Auckland
Country 6003 0
New Zealand
Phone 6003 0
+ 64 9 276 0044
Fax 6003 0
Email 6003 0
Samar.Issa@middlemore.co.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
Study protocol
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 2170 0
Lancet Oncol. 2019 Feb;20(2):216-228. doi: 10.1016/S1470-2045(18)30747-2. Epub 2019 Jan 7.
Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study.
Bromberg JEC1, Issa S2, Bakunina K3, Minnema MC4, Seute T5, Durian M6, Cull G7, Schouten HC8, Stevens WBC9, Zijlstra JM10, Baars JW11, Nijland M12, Mason KD13, Beeker A14, van den Bent MJ15, Beijert M16, Gonzales M17, de Jong D18, Doorduijn JK19.
Attachments [1] 2170 0
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary