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Trial registered on ANZCTR


Trial ID
ACTRN12610000915055
Ethics application status
Approved
Date submitted
21/09/2010
Date registered
26/10/2010
Date last updated
19/03/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised phase II study of Carboplatin and Bevacizumab in Recurrent Glioblastoma Multiforme (advanced brain tumours) (CABARET study)
Scientific title
The effect of Carboplatin and Bevacizumab on progression free survival in recurrent Glioblastoma Multiforme: A randomised phase II study
Secondary ID [1] 252259 0
N/A
Universal Trial Number (UTN)
U1111-1116-1446
Trial acronym
CABARET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma multiforme 257777 0
Condition category
Condition code
Cancer 257943 257943 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1

Bevacizumab plus carboplatin versus bevacizumab alone.

In Part 1, patients will be randomised as follows:

Arm A: Bevacizumab 10mg/kg given intravenously (IV) every 2 weeks until disease progression
Arm B: Bevacizumab 10mg/kg given intravenously (IV) every 2 weeks + carboplatin AUC 5 given IV every 4 weeks until disease progression

Part 2

Effects of continuing or stopping bevacizumab after disease progression.

Following disease progression in Part 1 patients who are able and who consent to continue onto Part 2 of the study will receive further treatment as follows:

Patients who were in Arm A of the study will commence carboplatin chemotherapy AUC 5 IV every 4 weeks until disease progression. If a patient decides with their doctor that they are not suitable for further chemotherapy, they will receive best supportive care rather than carboplatin. Best supportive care involves treatments to assist with controlling the symptoms of cancer such as antibiotics and pain medication. Patients will then be randomised to cease bevacizumab (Arm C) or continue bevacizumab 10mg/kg, 2 weekly until disease progression (Arm D).

Patients who were in Arm B of the study will cease carboplatin and choose between two chemotherapy agents (temozolomide or etoposide) in consultation with their doctor. As above, patients who are not suitable for additional chemotherapy may elect to receive best supportive care rather than etoposide or temozolomide. Patients will then be randomised to cease bevacizumab (Arm E) or continue bevacizumab 10mg/kg, 2 weekly until disease progression (Arm F).
Intervention code [1] 256844 0
Treatment: Drugs
Comparator / control treatment
Not applicable. There is currently no standard care for patients with recurrent glioblastoma multiforme. As such, neither treatment option can be considered a comparator/control treatment.
Control group
Active

Outcomes
Primary outcome [1] 258820 0
Progression-free survival (PFS)
Timepoint [1] 258820 0
The primary criterion for assessment of efficacy will be progression-free survival. PFS will be assessed by gadolinium-enhanced MRI (Gd-MRI), neurological examination, and steroid use. The decision on disease progression will be made based on: 1. Clinical history and physical examination prior to study entry and 4-weekly while on study treatment 2. Modified Response Assessment in Neuro-Oncology (RANO) criteria and modified Macdonald criteria to assess Gd-MRI scans at baseline, then 8-weekly or as clinically indicated until disease progression. 3. Steroid dose will be assessed at baseline, then every 2 weeks while on study treatment.
Secondary outcome [1] 264895 0
Objective radiological response rate (according to modified RANO criteria and modified Macdonald criteria)
Timepoint [1] 264895 0
Gd-MRI scans will be performed at baseline, day 1 of cycle 2 (part 1 only), day 1 of cycle 3 (part 1 and 2) then 8 weekly at day 1 of alternate cycles (e.g. 5, 7, 9) during treatment (part 1 and 2). In addition, a Gd-MRI scan will only be performed every 2 months during followup (until objective radiological disease progression) on patients who have not previously demonstrated clinical or radiological disease progression (e.g. patients who have withdrawn due to toxicities).
Secondary outcome [2] 264903 0
Cognitive function (Mini-Mental State Examination (MMSE) and Cogstate neuro-cognitive function testing)
Timepoint [2] 264903 0
MMSE will be assessed at screening, at week 4, then every 4 weeks during treatment for both parts 1 and 2 of the study, as well as at the end of treatment visit and monthly during followup.

Patients will do a practise CogState test before completing a formal test at screening, another test will be completed at baseline. Patients will then complete a formal CogState test every 4 weeks during treatment and monthly throughout followup.

Patients will attend followup assessments monthly for life.
Secondary outcome [3] 264904 0
Quality of life-Health-related quality of life (HRQOL) using European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and Brain Cancer Module (QLQ-BN20), and the EuroQol Group EQ-5D questionnaire.
Timepoint [3] 264904 0
Screening, every 4 weeks during treatment and at the end of treatment visit.
Secondary outcome [4] 264905 0
Corticosteroid dose will be obtained from the patients medical records by site staff and reported in the case report forms. At the time of each disease assessment the corticosteroid intake will be compared to corticosteroid intake at the time of the last disease assessment. The changes will be recorded as increased, unchanged or decreased. Increases and decreases in corticosteroid intake should be clinically justified and significant.
Timepoint [4] 264905 0
Screening, every 2 weeks during study treatment, end of treatment visit, then monthly during followup (until objective radiological disease progression)
Secondary outcome [5] 264906 0
Toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0)
Timepoint [5] 264906 0
Screening, every 2 weeks during study treatment, end of treatment visit and 30 days after last study drug dose
Secondary outcome [6] 264907 0
Overall Survival (OS) is calculated from date of patient study randomisation to date of patient death from any cause. Survival follow-up information will be collected via telephone calls and/or clinic visits every 4 weeks until death, loss to follow-up, or study termination by the Sponsor. If the patient withdraws from study treatment but not from study follow-up, the study staff may use a public information source (e.g., death registry records) to obtain information about survival status only.
Timepoint [6] 264907 0
Monthly during followup. Patients will attend followup assessments monthly for life.
Secondary outcome [7] 264908 0
Time to treatment failure
Timepoint [7] 264908 0
Time to treatment failure is calculated from the date of first (Part 1) or second (Part 2) randomisation to cessation of drug (separate for part 1 and part 2) due to progression, toxicity, death, patient refusal or any other cause.

Cessation in this context refers to the situation when the adminstration of a drug has been stopped due to disease progression, toxicity, death, patient refusal or any other cause.

Eligibility
Key inclusion criteria
For inclusion in this study, all of the following inclusion criteria must be fulfilled: 1. Patients with glioblastoma multiforme (GBM) with a tissue diagnosis that has been established following either a surgical resection or biopsy, and who have had prior treatment with both radiotherapy and temozolomide (concurrently and/or sequentially); 2. Recurrent/progressive disease confirmed by surgical resection or MRI (measurable disease according to RANO criteria). Measurable disease will be characterised by all of the following: at least one site of bi-dimensionally measurable disease, two perpendicular diameters of at least 10mm, visible on 2 or more axial slices that are preferably, at most, 5mm thick with 0-mm skip (or at least two times the slice thickness if the MRI is performed with thicker slices), must be measured using contrast enhanced MRI, MRI showing progression must be performed within 14 days before randomisation and at least 12 weeks post cessation of radiotherapy or stereotactic radiosurgery. The MRI must be compared with a prior MRI performed post-radiotherapy; 3. Craniotomy or intracranial biopsy site must be adequately healed; free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomisation. Study treatment should be initiated greater than or equal to 28 days following the last surgical procedure (including biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity); 4. WHO/Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2; 5. At least 12 weeks must have elapsed since the cessation of radiotherapy or stereotactic radiosurgery; 6. Adequate renal function (within 2 weeks prior to randomisation): creatinine less than or equal to 1.25x ULN or creatinine clearance rate greater than or equal to 60ml/min AND urine dipstick for proteinuria less than 2+ OR urine protein/creatinine ratio (UPC) less than or equal to 1.0. Patients discovered to have greater than or equal to 2+ proteinuria on dipstick urinalysis at screening should undergo a urine protein/creatinine ratio (or 24 hour urine collection if preferred) and must demonstrate less than or equal to 1.0g of protein in 24 hours; 7. Laboratory values (within 2 weeks prior to randomisation): absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, Leucocyte count greater than 3.0 x 109/L, Platelets greater than or equal to 100 x 109/L, Haemoglobin greater than or equal to 100 g/L, Total bilirubin less than or equal to 1.5 x ULN, AST, ALT and ALP less than or equal to 2.5 x ULN (less than or equal to 5 x ULN when attributable to anticonvulsants); 8. International normalized ratio (INR) or prothrombin time (PT) (secs) and activated partial thromboplastin time (aPTT) less than or equal to 1.5 x ULN (except for subjects receiving anticoagulation therapy at the time of screening) in the absence of therapeutic intent to anticoagulate the subject, OR within therapeutic limits (according to the medical standard in the institution) in the presence of therapeutic intent to anticoagulate the subject at the time of screening.
NOTE: As per American Society of Clinical Oncology (ASCO) guidelines, low molecular weight heparin (LMWH) is the preferred approach; 9. Signed informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients are not eligible for this study if they fulfil one or more of the following exclusion criteria: 1. Prior therapy with bevacizumab or any other VEGF/VEGFR inhibitor or EGFR inhibitor; 2. Prior chemotherapy (other than temozolomide) or investigational agent for the treatment of glioma; 3. Investigational agent (for reason other than treatment of GBM) within 28 days prior to randomisation or at any time during the study; 4. Chemotherapy (i.e. temozolomide) within 21 days prior to randomisation (with the exception of dose dense/continuous low dose ‘metronomic’ temozolomide in which chemotherapy must cease greater than or equal to 7 days prior to randomisation); 5. Treatment with biologic agent/s within 28 days prior to randomisation; 6. Known hypersensitivity to any excipients of bevacizumab formulation or to carboplatin; 7. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanised antibody; 8. Have had any surgery, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 4 weeks prior to start of treatment on this study or who have not recovered from side effects of such therapy;
9. Core biopsy (excluding intracranial biopsy) within 7 days prior to randomisation, or other minor surgical procedure including placement of a central venous access device (CVAD) within 2 days prior to bevacizumab administration; 10. Pregnancy or lactation; 11. Patient (male or female) is not willing to use highly effective methods of contraception (e.g. double barrier method) during treatment and for 6 months (male or female) after the end of treatment; 12. Evidence of recent haemorrhage on MRI of the brain. However patients with clinically asymptomatic presence of haemosiderin, resolving haemorrhagic changes related to surgery, and presence of punctate haemorrhage in the tumour are permitted entry into the study; 13. Calculated creatinine clearance (Cockroft-Gault) less than 60ml/min; 14. Inability to undergo MRI (e.g. has a pacemaker); 15. 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; 16. Any of the following conditions: a) Inadequately controlled hypertension (defined as systolic blood pressure greater than150 mmHg and/or diastolic blood pressure greater than 100 mm Hg); or prior history of hypertensive crisis or hypertensive encephalopathy, b) New York Heart Association (NYHA) Grade II or greater congestive heart failure, c) History of myocardial infarction, unstable angina, stroke or transient ischaemic attack (TIA), or significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomisation,
d) History of greater than or equal to grade 2 haemoptysis according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 criteria within 1 month prior to randomisation, e) History of abdominal fistula, gastrointestinal perforation, or intracranial abscess within 6 months prior to randomisation, f) History of coagulation disorder associated with bleeding or recurrent thrombotic events, g) Prior or co-existent malignancy except non-melanomatous skin cancer, or malignancy treated and disease free for greater than 5 years, h) Concurrent illness, including serious non-healing wound, active ulcer or untreated bone fracture, that may jeopardize the ability of the patient to receive the procedures outlined in this protocol with reasonable safety

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 coordinated by the National Health and Medical Research Council (NHMRC) Clinical Trials Centre (CTC).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using the method of minimisation stratified by centre, age, gender and performance status in part 1.

Randomisation in part 2 will be additionally stratified by treatment allocation in part 1.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
2 randomisation phases (Part 1 and 2). Additional consent will be obtained from participants who agree to continue onto Part 2 of the study.
Phase
Phase 2
Type of endpoint(s)
Safety/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,VIC,QLD,SA,WA,TAS
Recruitment postcode(s) [1] 3265 0
3084
Recruitment postcode(s) [2] 3266 0
3050
Recruitment postcode(s) [3] 3267 0
4019
Recruitment postcode(s) [4] 3268 0
2065
Recruitment postcode(s) [5] 3269 0
2217
Recruitment postcode(s) [6] 3270 0
2050
Recruitment postcode(s) [7] 3271 0
3168
Recruitment postcode(s) [8] 3272 0
2031
Recruitment postcode(s) [9] 3273 0
3065
Recruitment postcode(s) [10] 3274 0
7000
Recruitment postcode(s) [11] 3275 0
2298
Recruitment postcode(s) [12] 3276 0
3121
Recruitment postcode(s) [13] 3277 0
5011
Recruitment postcode(s) [14] 3278 0
2444
Recruitment postcode(s) [15] 3279 0
4101
Recruitment postcode(s) [16] 3280 0
6009
Recruitment postcode(s) [17] 3281 0
7250

Funding & Sponsors
Funding source category [1] 257342 0
Commercial sector/Industry
Name [1] 257342 0
Roche Products Pty Limited
Address [1] 257342 0
Roche Products Pty Limited
4-10 Inman Rd
Dee Why
NSW 2099
Country [1] 257342 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Level 4, 92-94 Parramatta Road,
Camperdown NSW Australia 2050
Country
Australia
Secondary sponsor category [1] 256551 0
None
Name [1] 256551 0
Address [1] 256551 0
Country [1] 256551 0
Other collaborator category [1] 251400 0
Other Collaborative groups
Name [1] 251400 0
Cooperative Trials Group for Neuro-Oncology (COGNO)
Address [1] 251400 0
NHMRC Clinical Trials Centre Level 4, 92-94 Parramatta Road, Camperdown NSW Australia 2050
Country [1] 251400 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259331 0
Cancer Institute NSW (Cancer Institute NSW Clinical Research Ethics Committee )
Ethics committee address [1] 259331 0
Australian Technology Park
Level 1, 1 Central Avenue
EVELEIGH NSW 2015
Australia
Ethics committee country [1] 259331 0
Australia
Date submitted for ethics approval [1] 259331 0
05/07/2010
Approval date [1] 259331 0
16/09/2010
Ethics approval number [1] 259331 0
Cancer Insitute NSW reference number: 2010C/07/135
Ethics committee name [2] 290744 0
Sydney Local Health District (RPAH zone) Human Research Ethics Committee
Ethics committee address [2] 290744 0
Research Development Office, Royal Prince Alfred Hospital, Missenden Rd, Camperdown NSW 2050 Australia
Ethics committee country [2] 290744 0
Australia
Date submitted for ethics approval [2] 290744 0
04/09/2013
Approval date [2] 290744 0
04/10/2013
Ethics approval number [2] 290744 0
HREC/13/RPAH/416

Summary
Brief summary
This study looks at the effectiveness of bevacizumab when combined with a type of chemotherapy called carboplatin in treating recurrent Glioblastoma Multiforme (a type of brain tumour).

Who is it for?
You can join this study if you are a person with glioblastoma multiforme (GBM) (brain tumour) which has been previously treated with both radiotherapy and the drug temozolomide.

Trial details
Participants will be divided into two groups. One group (Arm A) will receive bevacizumab intravenously every 2 weeks until disease progression. The other group (Arm B) will receive bevacizumab intravenously every 2 weeks and carboplatin every 4 weeks until disease progression. Following disease progression, people in Arm A will receive carboplatin or best supportive care and either stop bevacizumab (Arm C) or continue bevacizumab (Arm D). People in Arm B will receive temozolomide or etopside or best supportive care and either stop bevacizumab (Arm E) or continue bevacizumab (Arm F). Best supportive care involves treatments to assist with controlling the symptoms of cancer such as antibiotics and pain medication.

The study aims to measure the effectiveness of the different treatment regimes in terms of survival and well being.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 31409 0
Dr Kathryn Field
Address 31409 0
Department of Medical Oncology Royal Melbourne Hospital Grattan Street Parkville Victoria 3050 Australia
Country 31409 0
Australia
Phone 31409 0
+61 (0)3 9342 4642
Fax 31409 0
Email 31409 0
Kathryn.Field@mh.org.au
Contact person for public queries
Name 14656 0
Ms CABARET Trial Coordinator
Address 14656 0
National Health and Medical Research Council (NHMRC) Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 14656 0
Australia
Phone 14656 0
+61 (0)2 9562 5000
Fax 14656 0
+61 (0)2 9562 5094
Email 14656 0
cabaret@ctc.usyd.edu.au
Contact person for scientific queries
Name 5584 0
Dr Kathryn Field
Address 5584 0
Department of Medical Oncology
Royal Melbourne Hospital
Grattan Street
Parkville
Victoria 3050
Australia
Country 5584 0
Australia
Phone 5584 0
+61 (0)3 9342 4642
Fax 5584 0
+61 (0)3 9342 8548
Email 5584 0
Kathryn.Field@mh.org.au