COVID-19 studies are our top priority. For all other trials, there is a 4-week delay in processing a trial submitted/resubmitted to the ANZCTR and additional delays for updates of registered trials. We appreciate your patience.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12620000048987
Ethics application status
Approved
Date submitted
12/12/2019
Date registered
22/01/2020
Date last updated
10/11/2020
Date data sharing statement initially provided
22/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The Multi-Arm GlioblastoMa Australasia (MAGMA) Trial is a platform trial that will assess a number of options in standard of care for the management of glioblastoma. Initial questions of interest are: QUESTION 1 whether or not to give a cycle of temozolomide prior to chemoradiotherapy and QUESTION 2: whether to give 6 or 12 cycles of temozolomide after chemoradiotherapy.
Scientific title
A multi-arm multi-stage, multi-centre, phase III (MAMS) platform trial that aims to assess hypotheses against a common standard-of-care control arm for the management of people with glioblastoma. Initial questions of interest are: QUESTION 1: whether to give metronomic temozolomide as soon as possible following surgery prior to chemoradiotherapy; and QUESTION 2: whether to give a plan for 6 cycles of standard schedule adjuvant temozolomide chemotherapy (5/28 day cycles) after chemoradiotherapy, or continue temozolomide until progression.
Secondary ID [1] 300075 0
COGNO 19/03
Secondary ID [2] 300076 0
CTC 0252
Universal Trial Number (UTN)
Trial acronym
MAGMA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma 315598 0
Condition category
Condition code
Cancer 313891 313891 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For each treatment question, patients will be randomised to a specific arm, unless they specifically choose not to participate in that randomisation, in which case treatment will be at patient/doctor discretion. Temozolomide is administered orally and daily at below described doses for patients allocated to Arm 1 (intervention) of each question. Compliance will be determined at each clinic visit by obtaining the patient history and estimating the level of compliance.

QUESTION 1 whether to give temozolomide as soon as possible following surgery prior to chemoradiotherapy or start at same time when radiotherapy begins. Intervention Arm 1 - After surgery, start temozolomide as soon as possible prior to chemoradiotherapy. Initial treatment will be at 75mg/m2 per day and will continue through radiotherapy.

QUESTION 2 whether to give 6 cycles of adjuvant temozolomide after chemoradiotherapy or continue adjuvant temozolomide until disease progression. Intervention Arm 1 - After chemoradiotherapy, take adjuvant temozolomide until disease progression. Treatment will commence approximately 4 weeks following chemoradiotherapy. Cycle 1 will be given at 150mg/m2 and subsequent cycles at 200mg/m2 for days 1-5 of a 28 day cycle.

Participation in both or either questions will determined by patient eligibility and at the patient/doctor discretion.
Intervention code [1] 316348 0
Treatment: Drugs
Comparator / control treatment
For each treatment question, patients will be randomised to a specific arm, unless they specifically choose not to participate in that randomisation, in which case treatment will be at patient/doctor discretion. Temozolomide is administered orally and daily at below described doses for patients allocated to Arm 2 (control) of each question. Compliance will be determined at each clinic visit by obtaining the patient history and estimating the level of compliance.

QUESTION 1 whether to give temozolomide as soon as possible following surgery prior to chemoradiotherapy or start at same time when radiotherapy begins. Control Arm 2 - After surgery, start temozolomide at the same time as radiotherapy. Daily treatment at 75mg/m2 and will continue through radiotherapy.

QUESTION 2 whether to give 6 cycles of adjuvant temozolomide after chemoradiotherapy or continue adjuvant temozolomide until disease progression. Control Arm 2 - After chemoradiotherapy, take adjuvant temozolomide for 6 cycles. Treatment will commence approximately 4 weeks following chemoradiotherapy. Cycle 1 will be given at 150mg/m2 and subsequent cycles at 200mg/m2 for days 1-5 of a 28 day cycle for a maximum of 6 cycles in total.
Control group
Active

Outcomes
Primary outcome [1] 322282 0
The primary objective for each investigational question is to assess the effectiveness of that treatment on overall survival versus usual care.
Timepoint [1] 322282 0
Overall survival is defined as the interval from the date of initial surgery to the date of death from any cause, or censoring at the date of last known follow-up alive, and will be calculated using the Kaplan-Meier method. For the initial two questions of interest this timepoint will be assessed until 18 months follow-up.
Secondary outcome [1] 377943 0
Determine progression-free survival
Timepoint [1] 377943 0
Progression-free survival is defined as the interval between the date of initial surgery and the date of tumour progression or death from any cause, with censoring at last follow up if alive and progression-free. For the initial two questions of interest this timepoint will be assessed until 18 months follow-up.
Secondary outcome [2] 377944 0
Determine time to first non-temozolomide treatment for recurrent disease (including systemic treatment, re-resection, re-irradiation)
Timepoint [2] 377944 0
The time to first treatment for recurrent disease is defined as the interval between the date of initial surgery and the date of first treatment (e.g. re-resection, re-irradiation, 2nd line chemotherapy or a clinical trial treatment) or death from any cause, with censoring at last follow up if alive with no treatment for recurrent disease. For the initial two questions of interest this timepoint will be assessed until 18 months follow-up.
Secondary outcome [3] 377945 0
Understand clinically significant toxicity due to treatment will be assessed by clinical examinations. For the initial two questions of interest minor treatment-related toxicities will not recorded as the tolerance of temozolomide is well understood. Treatment-related toxicities clinically assessed grade 3 or grade 4 will be recorded.
Timepoint [3] 377945 0
Treatment-related Grade 3 or 4 adverse events will be recorded. Minor toxicity is not recorded for the initial two study arms as the tolerance of temozolomide is well understood. For the initial two questions of interest this timepoint will be assessed at the start of chemoradiotherapy (CRT), 4 weeks after start of CRT, 4 weeks after completion of CRT then 12 weekly until 30 days after completion of all study treatments,
Secondary outcome [4] 377946 0
Understand health-related quality of life
Timepoint [4] 377946 0
Health-related quality of life will be reported by participants using the EORTC core quality of life questionnaire (QLQ C-30) and brain cancer specific module (BN-20), and the EuroQol EQ-5D-5L.. All components will be combined into a single questionnaire and for the initial two questions of interest this timepoint will be assessed at registration for the trial, at the start of chemoradiotherapy, 4 weeks after the completion of chemoradiotherapy, then every 12 weeks for a minimum 18 months.

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older, with newly diagnosed histologically confirmed grade IV malignant glioblastoma (any IDH mutation status) or glioma with molecular features of GBM (e.g. IDH-wildtype grade III high grade glioma, which have been confirmed to have the same prognosis as glioblastoma (grade IV) patients, and are now functionally treated as GBM39)
2. Adequate recovery from surgical resection
3. ECOG performance status of 0-2
4. Previous surgery for a low-grade glioma is allowed, if there was no radiation or chemotherapy administered at that time
5. Adequate bone marrow function (platelets greater than or equal to 100 x 109/L, ANC greater than or equal to 1.5 x 109/L)
6. Adequate liver function (ALT/AST less than 3 x ULN)
7. Adequate renal function (creatinine clearance greater than 30ml/min)
8. Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments
9. Signed, written informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Recurrence of glioblastoma
2. Comorbidities considered to provide a safety concern for use of TMZ, e.g. idiopathic autoimmune thrombocytopenia or other haemotalogical diease causing cytopaenias
3. Other contraindications to TMZ or cranial irradiation in the past 2 years
4. Other co-morbidities or conditions that may compromise assessment of key outcomes
5. History of another malignancy within 2 years prior to registration. Patients with adequately treated carcinoma-in-situ of the prostate, breast or cervix, melanoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-muscle invasive transitional cell carcinoma of the bladder or low grade prostate cancer not requiring treatment (ISUP 1; Gleason grade less than or equal to 6) may be included in this study.
6. Concurrent illness, including severe or chronic bacterial or viral infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety. Patients with adequately treated hepatitis B, hepatitis C or human immunodeficiency virus at low risk of acquired immunodeficiency syndrome-related outcomes may be included in this study.
7. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse
8. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Consenting participants will be allocated to treatment in a partial factorial design with optional randomisation. For each treatment question, patients will be randomised to a specific arm, unless they specifically choose not to participate in that randomisation, in which case treatment will be at patient/doctor discretion.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
For the initial treatment questions, consenting participants will be randomly allocated to treatment in a partial factorial design with optional randomisation. For each treatment question, patients will be randomised to a specific arm, unless they specifically choose not to participate in that question, in which case treatment will be at patient and doctor discretion.
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The overall design is a multi-arm, multi-stage, multi-centre, phase III platform study, Interim analyses will facilitate any of the following: closing of treatment questions/arms, introduction of new treatment questions/arms, graduation of successful treatments into the revised standard-of-care, and periodic re-estimation of effect size for sample size adaptation. Advisory stopping boundaries for efficacy and futility will be made available to the Independent Data Safety Monitoring Committee.

Only those patients randomised to at least one treatment question will be included in the primary analysis. Data from patients not randomised to either question will be collected and may be used in exploratory analyses.

For the initial two questions of interest, with 3 years’ accrual and 18 months’ follow-up a sample size of at least 125 patients per arm (250 randomised for each question, 200 observed deaths) would give 80% power at 5% two-sided alpha to detect a 33% improvement in deaths (HR 0.667) or an increase in median survival from 12 to 18 months. The study plan is to recruit a total of at least 300 patients, but as additional questions are approved by the Trial Management Committee, and if additional budget is available, the sample size may expand after appropriate ethics approvals.

Recruitment
Recruitment status
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,TAS,WA
Recruitment hospital [1] 17984 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [2] 17985 0
Gold Coast University Hospital - Southport
Recruitment hospital [3] 17986 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [4] 17987 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 31942 0
2298 - Waratah
Recruitment postcode(s) [2] 31943 0
4215 - Southport
Recruitment postcode(s) [3] 31944 0
6009 - Nedlands
Recruitment postcode(s) [4] 31945 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 304523 0
Government body
Name [1] 304523 0
Medical Research Future Fund
Address [1] 304523 0
Sirius Building, 23 Furzer Street, Woden Town Centre, ACT, 2606
Country [1] 304523 0
Australia
Primary sponsor type
University
Name
NHMRC Clinical Trials Centre (CTC), University of Sydney
Address
The University of Sydney (USYD), City Rd, Darlington New South Wales 2008
Country
Australia
Secondary sponsor category [1] 304795 0
None
Name [1] 304795 0
Address [1] 304795 0
Country [1] 304795 0
Other collaborator category [1] 281307 0
Other Collaborative groups
Name [1] 281307 0
The Cooperative Trials Group for Neuro-Oncology (COGNO)
Address [1] 281307 0
Lifehouse, Level 6, 119-143 Missenden Road, Camperdown NSW 2050
Country [1] 281307 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304954 0
Royal Prince Alfred Hospital Ethics committee
Ethics committee address [1] 304954 0
Suite 210A
RPA Medical Centre
Cnr Missenden Road and Carillon Avenue
NEWTOWN NSW 2042
Ethics committee country [1] 304954 0
Australia
Date submitted for ethics approval [1] 304954 0
02/12/2019
Approval date [1] 304954 0
28/02/2020
Ethics approval number [1] 304954 0

Summary
Brief summary
This study aims to evaluate the use of temozolomide in different regimes for Glioblastoma. The trial is testing two changes to the usual schedule of treatment.

Who is it for?

You may eligible for this study if you are a male or female aged 18 years or older, with newly diagnosed, histologically confirmed grade IV malignant glioblastoma.

For the initial questions of interest, participants will be randomly allocated (50/50) chance to one of two treatment groups, to either

QUESTION 1:
Intervention Arm 1: After surgery, start temozolomide as soon as possible prior to chemoradiotherapy
Control Arm 2: After surgery, start temozolomide at the same time as radiotherapy


QUESTION 2:
Intervention Arm 1: After chemoradiotherapy, take adjuvant temozolomide until disease progression
Control Arm 2: After chemoradiotherapy, take adjuvant temozolomide for 6 cycles

For participants that choose not to be randomly allocated treatment will be at patient/doctor discretion.

All participants will be asked to have blood tests and scans as you would for usual treatment, the extra things requested are to fill out questionnaires and donate extra blood tests.

It is hoped this research will help identify if starting temozolomide earlier than usual and/or continuing treatment with temozolomide for longer than usual will improve the outcomes of people with glioblastoma and assist development of future treatments.
Trial website
https://www.cogno.org.au/content.aspx?page=currenttrials
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98758 0
A/Prof Craig Gedye
Address 98758 0
NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050
Country 98758 0
Australia
Phone 98758 0
+61 2 9562 5000
Fax 98758 0
Email 98758 0
magma@ctc.usyd.edu.au
Contact person for public queries
Name 98759 0
Dr MAGMA Trial Operations Coordinator
Address 98759 0
NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050
Country 98759 0
Australia
Phone 98759 0
+61 2 9562 5000
Fax 98759 0
Email 98759 0
magma@ctc.usyd.edu.au
Contact person for scientific queries
Name 98760 0
Dr MAGMA Trial Operations Coordinator
Address 98760 0
NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050
Country 98760 0
Australia
Phone 98760 0
+61 2 9562 5000
Fax 98760 0
Email 98760 0
magma@ctc.usyd.edu.au

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?
No other documents available
Summary results
No Results