Please note the ANZCTR will be unattended from Friday 20 December 2019 for the holidays. The Registry will re-open on Tuesday 07 January 2020. Submissions and updates will not be processed during that time.

Please be advised that as the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

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
ACTRN12615000407594
Ethics application status
Approved
Date submitted
17/04/2015
Date registered
30/04/2015
Date last updated
18/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Phase II study of Veliparib, Radiotherapy and Temozolomide in patients with unmethylated O (6)-methylguanine-DNA methyltransferase (MGMT) Glioblastoma (brain cancer) (VERTU study)
Scientific title
A Randomised Phase II study of veliparib and radiotherapy with adjuvant temozolomide and veliparib versus standard radiotherapy and temozolomide followed by temozolomide in patients with newly diagnosed glioblastoma with unmethylated O (6)-methylguanine-DNA methyltransferase
Secondary ID [1] 286267 0
Nil known
Universal Trial Number (UTN)
U1111-1167-6365
Trial acronym
VERTU
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma Multiforme 294329 0
Condition category
Condition code
Cancer 294649 294649 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible participants will be randomised to the study in 2:1 ratio to either Experimental group or Standard group.

The experimental group will receive veliparib capsules 200mg per oral two times per day for 6 weeks with concurrent radiotherapy (60Gy/30 fractions) followed 4 weeks later by a 6 month course of adjuvant temozolomide capsules (150-200mg/m2* per oral days 1-5, every 28 days) given concurrently with veliparib capsules (40mg per oral two times per day).

The standard treatment group will receive radiotherapy (60Gy/30 fractions) for 6 weeks plus concurrent temozolomide capsules daily per oral (75mg/m2) followed 4 weeks later by a 6 month course of adjuvant temozolomide capsules per oral (150-200mg/m2*) days 1-5 every 28 days

* During the adjuvant treatment phase all patients will start to receive temozolomide capsules at dose level 150mg/m2 per oral once daily days 1-5 in the first cycle of therapy. If this dose level is well tolerated, then the dose of temozolomide should be increased in subsequent cycles to 200 mg/m2. If the dose is not escalated in cycle 2, then the dose of temozolomide should remain at 150 mg/m2 for all 6 cycles.

To ensure appropriate control on the distribution of experimental treatment the Pharmacy Department at participating institutions will maintain a record of veliparib study drug received from the sponsor, the amounts dispensed for each patient, the amounts of study drug returned and the amounts destructed. Patients assigned to the veliparib study drug arm will be asked to return unused and empty study drug containers at each return visit to assess compliance to the treatment. Temozolomide is part of standard of care and drug dispensing and compliance will be monitored according to local hospital practices.

The radiotherapy treatment is standard of care and consists of a conventionally fractionated regimen, delivering a total dose of 60Gy, in a once daily schedule of 2 Gy per fraction for a total of 30 fractions, completed optimally in 6 weeks but up to a maximum of 7 weeks.
Intervention code [1] 291284 0
Treatment: Drugs
Intervention code [2] 291285 0
Treatment: Other
Comparator / control treatment
Standard treatment: radiotherapy (60Gy/30 fractions) for 6 weeks plus concurrent temozolomide daily (75mg/m2) followed 4 weeks later by a 6 month course of adjuvant temozolomide (150-200mg/m2) days 1-5 every 28 days
Control group
Active

Outcomes
Primary outcome [1] 294407 0
Progression-free survival rate at 6 months (PFS-6) by neuro-radiological review using Response Assessment in Neuro-Oncology (RANO) criteria
Timepoint [1] 294407 0
6 months
Secondary outcome [1] 313215 0
To correlate baseline expression levels of DNA repair proteins with clinical outcomes

Expression of DNA repair proteins will be assessed with immunohistochemistry in a central laboratory. Expression will be correlated with progression free survival.
Timepoint [1] 313215 0
on occurrence of clinical outcomes
Secondary outcome [2] 313216 0
Worst toxicity as per NCI CTC v 4.03
Timepoint [2] 313216 0
on occurrence of clinical outcomes
Secondary outcome [3] 313217 0
To assess feasibility (accrual, compliance)
Timepoint [3] 313217 0
18 months after first subject first visit
Secondary outcome [4] 313218 0
Overall Survival (OS)
Timepoint [4] 313218 0
Date of randomisation to date of death, or censoring at the date of last known follow-up alive
Secondary outcome [5] 313219 0
Quality of Life (QoL) outcomes as assessed by EORTC QLQ 30 and BN-20
Timepoint [5] 313219 0
- week 4
- week 8
- week 10, then monthly until end of treatment
- 1 month post treatment
Secondary outcome [6] 313220 0
Cognitive function assessment using Mini-Mental State Examination (MMSE)
Timepoint [6] 313220 0
- week 4
- week 8
- week 10, then monthly until end of treatment
- 1 month post treatment
Secondary outcome [7] 313221 0
Progression Free Survival at 9 months (to identify subjects with potential pseudo-progression)
Timepoint [7] 313221 0
9 months

Eligibility
Key inclusion criteria
1) Adults, aged 18 years or older, newly diagnosed histologically confirmed GBM (WHO grade IV glioma) following surgery, with unmethylated MGMT promoter gene whom are considered suitable for radiotherapy (RT) plus concurrent temozolomide (TMZ), followed by adjuvant temozolomide (TMZ)
NOTE - Patients who undergo biopsy only are eligible only if standard RT and TMZ treatment is considered appropriate;
2) Available tissue for MGMT and biomarker analysis;
3) ECOG 0-2 if 70 years or younger, or ECOG 0 if older than 70 years;
4) Life expectancy of more than 12 weeks;
5) Adequate bone marrow function (platelets greater than 100 x 109/L, ANC greater than 1.5 x 109/L);
6) Adequate liver function (ALT/AST less than 1.5 x ULN);
7) Adequate renal function (creatinine clearance greater than 50 ml/min measured using Cockroft-Gault see appendix 16.4);
8) Willing and able to comply with all study requirements, including treatment, timing and/or 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) Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may impact with the administration of study related treatments or procedures;
2) Other co-morbidities or conditions that may compromise assessment of key outcomes;
3) No prior chemotherapy or recent cranial radiation within the last 2 years. No other prior or concomitant therapies for GBM allowed, excepting surgery
NOTE - Patients who had previous grade I-III glioma and have progressed to GBM are eligible assuming that they have not received prior cranial radiotherapy or TMZ for the treatment of glioma;
4) History of another malignancy within 2 years prior to registration. Patients with a past history of adequately 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. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 2 years after definitive primary treatment.

NOTE - Patients with localised cancer free of metastatic disease and of very low risk of recurrence are eligible. Eligibility of patients with localised cancer must be confirmed by the Study Chair.
5) Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated;
6) Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety;
7) Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol;
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;
9) Patients with a duration of more than 7 weeks from surgery to the start of RT.

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 not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed centrally using the method of minimisation to assign patients to active or control intervention in a 2:1 ratio. Randomisation will be stratified by hospital site and ECOG performance, age and gender
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
One hundred and twenty patients will be randomised in a 2:1 ratio to the experimental and standard treatment arms, respectively. The randomisation will protect against selection bias and allow response to be estimated in a contemporary control group but no formal comparison between the randomised arms is planned.

Eighty patients on the experimental arm will have 80% power at alpha equal to 0.1 to detect an increase in response rate (proportion alive and progression-free at 6 months) from 53% to 65% using Fleming’s one-stage design.

A safety and feasibility analysis will be conducted when 60 patients have completed radiotherapy. The intervention is declared feasible if overall accrual achieved within 18 months, adequate treatment adherence (e.g. at least 70% of patients on experimental arm completed at least 70% of the treatment) and less than or equal to 30% of patients on the experimental therapy experience a grade 3 or 4 adverse event. If this is achieved, further patients will be enrolled to a total of 120 (80 on experimental and 40 on control arm). If these safety and feasibility conditions are not met then consideration will be given to stopping or modifying the study. If the study did stop at that point it would provide initial estimates of efficacy (approximately 40 patients on the active intervention would have 80% power at alpha equal to 0.1 to detect a large increase in response rate from 53% to 70%). Correlation with the DNA repair protein signature will be explored

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)
ACT,NSW,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 290823 0
Charities/Societies/Foundations
Name [1] 290823 0
Cure Brain Cancer Foundation
Address [1] 290823 0
Level 1, 351 Crown Street, Surry Hills, NSW 2010, Australia
Country [1] 290823 0
Australia
Funding source category [2] 294172 0
Charities/Societies/Foundations
Name [2] 294172 0
Cancer Council New South Wales
Address [2] 294172 0
153 Dowling Street, Woolloomooloo, NSW 2011, Australia
Country [2] 294172 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Level 4, 92-94 Parramatta Road,
Camperdown NSW Australia 2050
Country
Australia
Secondary sponsor category [1] 289510 0
None
Name [1] 289510 0
Address [1] 289510 0
Country [1] 289510 0
Other collaborator category [1] 278368 0
Other Collaborative groups
Name [1] 278368 0
Cooperative Trials Group for Neuro-Oncology (COGNO)
Address [1] 278368 0
NHMRC Clinical Trials Centre Level 4, 92-94 Parramatta Road, Camperdown NSW Australia 2050
Country [1] 278368 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292443 0
Sydney Local Health District (RPAH zone) Human Research Ethics Committee
Ethics committee address [1] 292443 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 292443 0
Australia
Date submitted for ethics approval [1] 292443 0
11/11/2014
Approval date [1] 292443 0
20/02/2015
Ethics approval number [1] 292443 0
HREC/14/RPAH/494

Summary
Brief summary
This study aims to evaluate the safety and effectiveness of a combination of veliparib with radiotherapy, followed by a combination of veliparib with temozolomide (a chemotherapy), to treat patients with newly diagnosed glioblastoma multiforme (a type of brain tumour).

Who is it for?
You can join this study if you are a person who is recently diagnosed with glioblastoma multiforme (brain tumour), underwent surgery (or have been scheduled to undergo surgery) for this diagnosis and are considered for further treatment with radiotherapy plus temozolomide treatment.

Study details:
If you like to join this study you will first be screened by your specialist to see if you meet the eligibility criteria to participate in this study. If you are deemed eligible to participate you will be randomly (by chance) assigned to one of two possible treatment groups:
Group 1 will receive veliparib together with radiotherapy for 6-7 weeks, followed by a 4 week treatment break, which is again followed by a 6 month treatment with a combination of temozolomide and veliparib.
Group 2 will receive receive temozolomide together with radiotherapy for 6-7 weeks, followed by a 4 week treatment break, which is again followed by a 6 month treatment with temozolomide.
Your chance to receive the group 1 treatment is twice as high as to receive the group 2 treatment.
Participants will be asked to attend clinic visits every 2-4 weeks during the treatment period and then two times more (1 month and 3 months after having received the last treatment). During these visits the specialist will assess the status of your glioblastoma and your physical and mental health, and ask you about your well-being. Participants will also be asked to undergo tests and procedures, such as blood testing, urine testing, scans, and questionnaire completion and to give tissue samples for laboratory research.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55326 0
Dr Mustafa Khasraw
Address 55326 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 55326 0
Australia
Phone 55326 0
+61 (0)2 9562 5000
Fax 55326 0
Email 55326 0
vertu@ctc.usyd.edu.au
Contact person for public queries
Name 55327 0
Mr VERTU Trial Coordinator
Address 55327 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 55327 0
Australia
Phone 55327 0
+61 (0)2 9562 5000
Fax 55327 0
Email 55327 0
vertu@ctc.usyd.edu.au
Contact person for scientific queries
Name 55328 0
Dr VERTU Trial Coordinatoer
Address 55328 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 55328 0
Australia
Phone 55328 0
+61 (0)2 9562 5000
Fax 55328 0
Email 55328 0
vertu@ctc.usyd.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary