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Trial registered on ANZCTR


Registration number
ACTRN12618001944224
Ethics application status
Approved
Date submitted
28/11/2018
Date registered
30/11/2018
Date last updated
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase III Trial of Extended Temozolomide in Newly Diagnosed Glioblastoma
Scientific title
To determine if extended post-radiation temozolomide will improve survival outcomes in patients with newly diagnosed glioblastoma
Secondary ID [1] 296725 0
Nil
Universal Trial Number (UTN)
Trial acronym
EX-TEM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Brain Cancer 310588 0
Glioblastoma 310616 0
Condition category
Condition code
Cancer 309300 309300 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be comparing two standards of care, six versus 12 cycles of post-radiation temozolomide. Temozolomide is a DNA alkylating chemotherapy used in the treatment of glioblastoma.
Arm A: Will receive observation with standard clinical and radiological follow up
Arm B: Will receive an additional six cycles of post-radiation temozolomaide followed by observation with standard clinical and radiological follow up.
The dosage regimen of temozolomide is an oral capsule taken daily for five consecutive days out of every 28 days, at the dose previously tolerated by the patient to a maximum of 200mg/m^2. Adherance will be monitored at four weekly clinical assessments
Intervention code [1] 313033 0
Treatment: Drugs
Comparator / control treatment
Arm A: No treatment. Clinical assessments occur at baseline, and then as per local protocols thereafter. MRI Brain scans are scheduled at baseline, and then as per local protocols thereafter. Haematological/Biochemical assessments will be performed as clinically indicated.
Control group
Active

Outcomes
Primary outcome [1] 308267 0
To determine overall survival impact of an additional six cycles of temozolomide following concurrent chemoradiation and six cycles of post-radiation temozolomide,
Timepoint [1] 308267 0
Time from day one of cycle six plus 28 days to date of death from any cause up until 36 months post randomisation.
Secondary outcome [1] 354477 0
To determine the impact of an additional six cycles of temozolomide on progression-free surivival as assessed by neuro-radiological review using Response Assessment in Neuro-Oncology criteria
Timepoint [1] 354477 0
Time from day one of cycle six plus 28 days to date of death from any cause up until 36 months post randomisation.
Secondary outcome [2] 354478 0
To determine toxicity of an additional six cycles of temozolomide as assessed by recorded adverse event and necessity for temozolomide dose modification in patient medical records.
Timepoint [2] 354478 0
Time from day one of cycle six plus 28 days to date of adverse events up until 36 months post randomisation.

Eligibility
Key inclusion criteria
1. Males or females with newly diagnosed, histologically confirmed glioblastoma
2. Adults, aged 18 years and over
3. Completed radiation plus concurrent temozolomide, followed by six cycles of post-radiation temozolomide
4. No evidence of progressive disease on on-study screening MRI. Residual disease or enhancement is allowed, as long as stability or response according to RANO criteria has been demonstrated compared with prior MRI
5. ECOG 0-2
6. Life expectancy of > 12 weeks
7. Fit for further temozolomide
8. Able to start study treatment within four weeks of day one of cycle six
9. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
10. 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. Progressive disease on on-study screening MRI according to RANO criteria when compared with prior MRI
2. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the administration of study treatments or procedures
3. Other comorbidities or conditions that may compromise assessment of key outcomes
4. No temozolomide or cranial irradiation in the last five years prior to GBM diagnosis.
5. History of another malignancy within five years prior to registration. Patients with curatively treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or superficial transitional cell carcinoma of the bladder are eligible.
6. Significant infection, including chronic active hepatitis B, hepatitis C or HIV.
7. Concurrent illness,
8. Pregnancy, lactation, or inadequate 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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety
Statistical methods / analysis
315 patients will be randomised in a 1:1 ratio to Arm A or Arm B. 248 events will have 80% power at alpha = 0.05 to detect an improvement in overall survival with a hazard ratio of 0.7.
The duration of accrual will be 24 months, and follow up will be 36 months.

Intention-to-treat population of all randomly assigned participants will be used for survival analysis. SAEs and treatment details will be reported for patients receiving at least one dose of study treatment.
Overall survival (OS) will be measured from day one of cycle six plus 28 days and median OS estimated using the nonparametric Kaplan Meier method with 95% CI. Patients will be censored at the time of last follow-up. Hazard ratios for survival will be calculated using Cox proportional hazards and adjusted for study site, type of surgery (resection versus biopsy), ECOG (0-1 versus 2), MGMT methylation (methylated versus unmethylated), duration of radiation (long course versus short course) and residual disease on MRI (present versus absent).
PFS will be analysed in the same manner as OS.
SAEs will be described by the number and percentage of each type.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/12/2018
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
315
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
TAS,VIC
Recruitment hospital [1] 12571 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 12572 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 12574 0
Royal Hobart Hospital - Hobart
Recruitment hospital [4] 12575 0
Epworth Richmond - Richmond
Recruitment hospital [5] 12576 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [6] 12577 0
St Vincents & Mercy Private Hospital - Mercy campus - East Melbourne
Recruitment postcode(s) [1] 24948 0
3000 - Melbourne
Recruitment postcode(s) [2] 24949 0
3050 - Parkville
Recruitment postcode(s) [3] 24951 0
7000 - Hobart
Recruitment postcode(s) [4] 24952 0
3121 - Richmond
Recruitment postcode(s) [5] 24953 0
3065 - Fitzroy
Recruitment postcode(s) [6] 24954 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 301306 0
Other Collaborative groups
Name [1] 301306 0
The Walter and Eliza Hall Institute of Medical Research
Address [1] 301306 0
Walter and Eliza Hall institute
1G Royal Parade
Parkville VIC 3052
Country [1] 301306 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The Walter and Eliza Hall Institute of Medical Research
Address
Walter and Eliza Hall institute
1G Royal Parade
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 300961 0
None
Name [1] 300961 0
Address [1] 300961 0
Country [1] 300961 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302047 0
Melbourne Health, Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 302047 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
Australia
Ethics committee country [1] 302047 0
Australia
Date submitted for ethics approval [1] 302047 0
23/11/2017
Approval date [1] 302047 0
02/05/2018
Ethics approval number [1] 302047 0
HREC/17/MH/385

Summary
Brief summary
The purpose of this study is to determine if an extended use of a chemotherapy medication (temozolomide) after radiation improves survival outcome in patients with newly diagnosed brain cancer (also called a glioblastoma).

Who is it for?

You may be eligible for this study if you are an adult who has been diagnosed with a glioblastoma.

Study details

Participants will take part in one of two treatment options:
- In treatment 1, participants will continue with their usual care.
- In treatment 2, participants will receive an additional six cycles of chemotherapy for 5 days, with each cycle lasting 28 days.
The treatment that participants receive will be decided randomly.

Participants enrolled into treatment option 2 will undergo routine blood tests prior to the administration of chemotherapy as per their standard care

It is hoped that this research will determine if temozolomide is effective in increasing the overall survival rates, as well as the duration of survival of participants with glioblastoma.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88950 0
Dr Lucy Gately
Address 88950 0
Gibbs Lab
Walter and Eliza Hall institute
1G Royal Parade
Parkville VIC 3052
Country 88950 0
Australia
Phone 88950 0
+61 (0)3 9345 2555
Fax 88950 0
Email 88950 0
lucy.gately@mh.org.au
Contact person for public queries
Name 88951 0
Ms Maria Edmonds
Address 88951 0
Gibbs Lab
Walter and Eliza Hall institute
1G Royal Parade
Parkville VIC 3052
Country 88951 0
Australia
Phone 88951 0
+61 3 9345 2896
Fax 88951 0
Email 88951 0
Maria.Edmonds@mh.org.au
Contact person for scientific queries
Name 88952 0
Ms Maria Edmonds
Address 88952 0
Gibbs Lab
Walter and Eliza Hall institute
1G Royal Parade
Parkville VIC 3052
Country 88952 0
Australia
Phone 88952 0
+61 3 9345 2896
Fax 88952 0
Email 88952 0
Maria.Edmonds@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All data generated from this study will remain confidential and no published report will contains any reference to patient names or patient identifies.
What supporting documents are/will be available?
No other documents available
Summary results
No Results