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Trial registered on ANZCTR


Registration number
ACTRN12613000496718
Ethics application status
Approved
Date submitted
1/05/2013
Date registered
3/05/2013
Date last updated
17/01/2019
Date data sharing statement initially provided
17/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 3 Accelerated BEP Trial:
A randomised phase 3 trial of accelerated versus standard BEP chemotherapy for patients with intermediate and poor-risk metastatic germ cell tumours
Scientific title
In patients with intermediate and poor-risk metastatic germ cell tumours is an accelerated BEP chemotherapy regimen as good as, or better than, the standard BEP chemotherapy regimen for response rate.
Secondary ID [1] 282398 0
Nil
Universal Trial Number (UTN)
U1111-1142-5396
Trial acronym
P3BEP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intermediate and poor-risk metastatic germ cell tumours (GCTs) 289031 0
Condition category
Condition code
Cancer 289369 289369 0 0
Testicular
Cancer 289370 289370 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients 16 years or older and randomised to Arm B - Accelerated BEP (Experimental) will receive 4 x 14 day cycles of;
Bleomycin 30000 IU IV weekly; Etoposide 100mg/m^2 IV days 1,2,3,4,5; Cisplatin 20mg/m^2 IV days 1,2,3,4,5 and Pegylated G-CSF 6mg SCI on day 6 followed by: 4 doses of Bleomycin 30000IU IV at weekly intervals.

Patients less than 16 years old and weighs 45 kgs or more and are randomised to Arm B - Accelerated BEP (Experimental) will receive;
Bleomycin 15,000 - 30000 IU IV weekly; Etoposide 100mg/m^2 IV days 1,2,3,4,5; Cisplatin 20mg/m^2 IV days 1,2,3,4,5 and Pegylated G-CSF 6mg SCI on day 6 followed by: 4 doses of Bleomycin 15,000-30000IU IV at weekly intervals.

Patients aged less than 16 years and weigh less than 45 kg on day 1 of the treatment cycle and are randomised to Arm B - Accelerated BEP (Experimental) will receive
Bleomycin 15,000 - 30000 IU IV weekly; Etoposide 100mg/m^2 IV days 1,2,3,4,5; Cisplatin 20mg/m^2 IV days 1,2,3,4,5 and Filgrastim 10mcg/kg/day until post-nadir absolute neutrophil count is equal to or greater than 1 x 10^9/ L - dose starting day 6 followed by: 4 doses of Bleomycin 15,000-30000IU IV at weekly intervals.

For patients less than 16 years old, the exact dose of bleomycin is decided by the treating physician and based on the patients body surface area (BSA) value.
Intervention code [1] 287069 0
Treatment: Drugs
Comparator / control treatment
Patients aged 16 years or older and randomised to Arm A - Standard BEP will receive 4 x 21 days cycles of;
Bleomycin 30000 IU IV weekly; Etoposide 100mg/m^2 IV days 1,2,3,4,5; Cisplatin 20mg/m^2 IV days 1,2,3,4,5 and Pegylated G-CSF 6mg SCI on day 6.

Patients aged less than 16 years and weighs 45 kgs or more and are randomised to Arm A - Standard BEP will receive 4 x 21 days cycles of;
Bleomycin 15,000 IU - 30000 IU IV weekly; Etoposide 100mg/m^2 IV days 1,2,3,4,5; Cisplatin 20mg/m^2 IV days 1,2,3,4,5 and Pegylated G-CSF 6mg SCI on day 6.

Patients aged less than 16 years and weigh less than 45 kg on day 1 of the treatment cycle and are randomised to Arm A - Standard BEP will receive 4 x 21 days cycles of;
Bleomycin 15,000 IU - 30000 IU IV weekly; Etoposide 100mg/m^2 IV days 1,2,3,4,5; Cisplatin 20mg/m^2 IV days 1,2,3,4,5 and Filgrastim 10mcg/Kg/day until post nadir absolute neutrophil count is equal to or greater than 1 x 10^9/ L - dose starting day 6.

For patients less than 16 years old, the exact dose of bleomycin is decided by the treating physician and based on the patients body surface area (BSA) value.
Control group
Active

Outcomes
Primary outcome [1] 289474 0
Primary Outcome 1: comparison of the two treatment arms with respect to change in size of measurable tumour masses, changes in serum tumour markers and the results of surgical resection of residual masses after chemotherapy.

Outcomes will be assessed via the following tools and/or tests: CT scan, blood serum assay and histopathological results from surgery and biopsy.

Timepoint [1] 289474 0
Timepoint: at two years after randomisation of all planned participants.
Secondary outcome [1] 302560 0
Secondary Outcome: Adverse events (worst grade according to NCI CTCAE v4.03)
Timepoint [1] 302560 0
Timepoint: 2 years after randomisation of all planned participants
Secondary outcome [2] 302561 0
Secondary Outcome: Health-related quality of life (Summary scales from QLQ-C30 & -TC14)
Timepoint [2] 302561 0
Timepoint: 2 years after randomisation of all planned participants
Secondary outcome [3] 302562 0
Secondary Outcome: Treatment preference (Proportion preferring each treatment arm)
Timepoint [3] 302562 0
Timepoint: 2 years after randomisation of all planned participants
Secondary outcome [4] 302563 0
Secondary Outcome: Delivered dose-intensity of chemotherapy (Relative to standard BEP)
Timepoint [4] 302563 0
Timepoint: 2 years after randomisation of all planned participants

Eligibility
Key inclusion criteria
1. Age greater than or equal to 11 years and less than or equal to 45 years on the date of randomisation
2. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma), except in the rare case of exceptionally raised tumour markers (AFP greater than or equal to 1000ng/mL and/or beta-HCG greater than or equal to 5000 IU/L) without histologic or cytologic confirmation where pattern of metastases consistent with GCT, high tumour burden, and a need to start therapy urgently
3. Primary arising in testis, ovary, retro-peritoneum, or mediastinum
4. Metastatic disease or non-testicular primary
5. Intermediate or poor prognosis as defined by modified IGCCC classification (modified with different LDH criteria for intermediate risk non-seminoma, and inclusion of ovarian primaries).
6. Adequate bone marrow function with ANC greater than or equal to 1.0 x 10^9/L, Platelet count greater than or equal to 100 x 10^9/L
7. Adequate liver function where bilirubin must be less than or equal to 1.5 x ULN, ALT and AST must be less than or equal to 2.5 x ULN; except if the elevations are due to hepatic metastases, in which case ALT and AST must be less than or equal to 5 x ULN
8. Adequate renal function of GFR greater than or equal to 60 ml/min. It is recommended that GFR is estimated with the Cockcroft-Gault formula, unless calculated to be less than 60 ml/min or borderline in which case by EDTA scan
9. ECOG Performance Status of 0, 1, 2, or 3
10. Study treatment both planned and able to start within 14 days of randomisation.
11. Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments
12. Able to provide signed, written informed consent
Minimum age
11 Years
Maximum age
45 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of a malignancy prior to registration except for germ cell tumour or non-melanomatous carcinoma of the skin
2. Previous chemotherapy or radiotherapy, except (a)participants with pure seminoma relapsing after radiotherapy or adjuvant chemotherapy with 1-2 doses of single agent carboplatin, (b)participants with NSGCT and poor prognosis by IGCCC criteria receiving pre-protocol chemotherapy (eg. low-dose platinum and etoposide, baby-BOP) , (c)Participants who need to start therapy urgently prior to completing study-specific baseline investigations may commence study chemotherapy prior to registration and randomisation.
3. Significant cardiac disease resulting in inability to tolerate IV fluid hydration for cisplatin
4. Significant co-morbid respiratory disease that contraindicates the use of Bleomycin
5. Peripheral neuropathy greater than or equal to grade 2 or clinically significant sensori-neural hearing loss or tinnitus
6. Concurrent illness, including severe infection that may jeopardize the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety
7. Inadequate contraception. Men must have been surgically sterilised or use a double barrier method of contraception
8. Known allergy or hypersensitivity to any of the study drugs
9. 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

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)
Participants must meet all eligibility criteria before being randomised and before starting study treatment.

Treatment should be planned to start within 14 days after randomisation.

Randomisation will be performed in one transaction via a central randomisation system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Stage I of the study will recruit 150 participants (75 per arm) which will provide 80% power at the 5% level of significance to detect an improvement in the favourable response rate from 59% with standard BEP to 80% with accelerated BEP.

If results from Stage I are sufficiently promising, Stage II of the study will recruit an additional 350 participants for a total sample size of 500 participants (250 per arm). A study of 500 patients followed until 140 PFS events are observed will provide >80% power at the 5% level of significance to detect a hazard ratio of 0.6. An effect of this size corresponds to a 7% improvement in PFS at 2 years from 81% with standard BEP to 88% with accelerated BEP.

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)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 2737 0
Prince of Wales Hospital - Randwick
Recruitment hospital [2] 2738 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [3] 2739 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 2740 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 2741 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [6] 2743 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 2746 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [8] 2748 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [9] 2749 0
Royal Hobart Hospital - Hobart
Recruitment hospital [10] 2750 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [11] 2751 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [12] 2752 0
Box Hill Hospital - Box Hill
Recruitment hospital [13] 2912 0
Macquarie University Hospital - Macquarie Park
Recruitment hospital [14] 2913 0
Westmead Hospital - Westmead
Recruitment hospital [15] 3941 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [16] 3942 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [17] 3943 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [18] 3944 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [19] 6140 0
Albury Wodonga Health - Albury campus - Albury
Recruitment hospital [20] 6141 0
Murray Valley Private Hospital - Wodonga
Recruitment hospital [21] 6699 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [22] 6700 0
Border Medical Oncology - Albury
Recruitment postcode(s) [1] 14337 0
3690 - Wodonga
Recruitment postcode(s) [2] 14336 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 5055 0
New Zealand
State/province [1] 5055 0
Country [2] 21209 0
United Kingdom
State/province [2] 21209 0
Country [3] 21210 0
United States of America
State/province [3] 21210 0

Funding & Sponsors
Funding source category [1] 287198 0
Government body
Name [1] 287198 0
Cancer Australia
Address [1] 287198 0
PO Box 1201
Dickson
ACT 2602
Country [1] 287198 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country
Australia
Secondary sponsor category [1] 285961 0
Other Collaborative groups
Name [1] 285961 0
Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Address [1] 285961 0
Level 6, 119 – 143 Missenden Road, Camperdown NSW 2050
Country [1] 285961 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289191 0
Sydney Local Health District Ethics Review Committee (RPAH zone)
Ethics committee address [1] 289191 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 289191 0
Australia
Date submitted for ethics approval [1] 289191 0
03/06/2013
Approval date [1] 289191 0
05/07/2013
Ethics approval number [1] 289191 0
HREC/13/RPAH/226
Ethics committee name [2] 302398 0
Sydney Local Health District Ethics Review Committee (RPAH zone)
Ethics committee address [2] 302398 0
Research Development Office Royal Prince Alfred Hospital Missenden Road CAMPERDOWN NSW 2050
Ethics committee country [2] 302398 0
Australia
Date submitted for ethics approval [2] 302398 0
20/03/2018
Approval date [2] 302398 0
01/05/2018
Ethics approval number [2] 302398 0
X18-oo76 HREC/13/RPAH/226

Summary
Brief summary
The purpose of this study is to determine whether accelerated BEP chemotherapy is more effective than standard BEP chemotherapy in males and females with intermediate and poor-risk metastatic germ cell tumours.

Who is it for?
Male and female participants aged 11 years to 45 years old and you have been diagnosed with metastatic germ cell tumour/s in the testes, ovary, retro-peritoneum or mediastineum and considering first-line chemotherapy.

Study details
Participants in this study will be randomly (by chance) allocated to one of two groups. Participants in one group will receive the current gold standard treatment for germ cell tumours, which is a chemotherapy combination called BEP (bleomycin, etoposide and cisplatin) administered on a 3 weekly cycle. BEP is given with a drug called pegfilgrastim which encourages white blood cell production and prevents blood cell complications of chemotherapy. Participants in the other group will receive the same dose of BEP but on a 2 weekly schedule. This is called 'accelerated BEP'.

Participants will be regularly assessed for treatment response, side effects and quality of life for a period of up to 2 years. This will enable us to determine whether giving the dose of BEP on a 2 weekly schedule is more effective than a 3 weekly schedule. We will also be able to track whether the shorter schedule causes more, the same, or less side effects.
Trial website
http://www.anzup.org.au/content.aspx?page=trials-p3bep
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39558 0
Dr Peter Grimison
Address 39558 0
Royal Prince Alfred Hospital
Oncology Department
Missenden Road
Camperdown, NSW 2050
Country 39558 0
Australia
Phone 39558 0
+61 2 9515 5894
Fax 39558 0
Email 39558 0
p3bep@ctc.usyd.edu.au
Contact person for public queries
Name 39559 0
Ms Phase III BEP Trial Coordinator
Address 39559 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 39559 0
Australia
Phone 39559 0
+61 2 9562 5000
Fax 39559 0
Email 39559 0
p3bep@ctc.usyd.edu.au
Contact person for scientific queries
Name 39560 0
Dr Peter Grimison
Address 39560 0
Royal Prince Alfred Hospital
Oncology Department
Missenden Road
Camperdown, NSW 2050
Country 39560 0
Australia
Phone 39560 0
+61 2 9515 5894
Fax 39560 0
Email 39560 0
p3bep@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
Data for this trial will only be available to NHMRC CTC trial statisticians.
What supporting documents are/will be available?
No other documents available
Summary results
No Results