Clinical trial NCT02582697: Accelerated v's Standard BEP Chemotherapy for Patients With Intermediate and Poor-risk Metastatic Germ Cell Tumours
Official title: Phase 3 Accelerated BEP: A Randomised Phase 3 Trial of Accelerated Versus Standard BEP Chemotherapy for Patients With Intermediate and Poor-risk Metastatic Germ Cell Tumours
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Germ Cell Tumor
Keywords: Germ Cell
Intermediate and poor-risk metastatic germ cell tumours
Lead sponsor: University of Sydney
Sponsor class: OTHER
Collaborators: name: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: Cambridge University Hospitals NHS Foundation Trust
name: Cancer Trials Ireland
name: Children's Oncology Group
name: Dana-Farber Cancer Institute
name: University of Southern California
First posted: 2015-10-21
Enrollment: 500
Sex: ALL
Minimum age (years): 11
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: Bleomycin, Etoposide, Cisplatin (BEP) administered 3-weekly x 4 remains standard 1st line chemotherapy for intermediate- and poor-risk metastatic germ cell tumours (GCTs). Cure rates are over 90% for good-risk disease, 85% with intermediate-risk, and about 70% for poor-risk disease. Previous strategies to improve first-line chemotherapy have failed to improve cure rates and were more toxic than BEP. New strategies are needed for patients with intermediate and poor-risk disease. BEP is accelerated by cycling Cisplatin and etoposide 2-weekly instead of 3-weekly. The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) is conducting a trial comparing accelerated BEP with standard BEP. The aim of this study is to determine if accelerated BEP is superior to standard BEP as first-line chemotherapy for intermediate and poor risk metastatic GCTs.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 11 years and ≤ 50 years on the date of randomisation
2. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma); or Exceptionally raised tumour markers (AFP ≥ 1000ng/mL and/or HCG ≥ 5000 IU/L) without histologic or cytologic confirmation in the rare case 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 IGCCC classification3 (modified with different LDH criteria for intermediate risk non-seminoma, and inclusion of ovarian primaries). (See protocol for more information).
6. Adequate bone marrow function with ANC ≥1.0 x 10\^9/L, Platelet count ≥100 x 10\^9/L
7. Adequate liver function where bilirubin must be ≤1.5 x ULN, except participants with Gilbert's Syndrome where bilirubin must be ≤2.0 x ULN; ALT and AST must be ≤2.5 x ULN, except if the elevations are due to hepatic metastases, in which case ALT and AST must be ≤ 5 x ULN
8. Adequate renal function with estimated creatinine clearance of ≥60 ml/min according to the Cockcroft-Gault formula, unless calculated to be \< 60 ml/min or borderline in which case GFR should be formally measured, eg. with 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

Exclusion Criteria:

1. Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the skin, germ cell tumour, or other malignancy treated at least 5 years previously with no evidence of recurrence)
2. Previous chemotherapy or radiotherapy, except if patient has pure seminoma relapsing after adjuvant radiotherapy or adjuvant chemotherapy with 1-2 doses of single agent carboplatin or if patient hasb. non-seminoma by IGCCC criteria or stage IV malignant ovarian germ cell tumour in the rare case where low-dose induction chemotherapy is given prior to registration because patient is not fit enough to receive protocol chemotherapy (eg. organ failure, vena cava obstruction, overwhelming burden of disease). Acceptable regimens include cisplatin 20 mg/m2 days 1-2 and etoposide 100 mg/m2 days 1-2; carboplatin AUC 3 days 1-2 and etoposide 100 mg/m2 days 1-2; or baby-BOP.43 Patients must meet all other inclusion and exclusion criteria at the time of registration.

   Additionally participants who need to start therapy urgently prior to completing study-specific baseline investigations may commence study chemotherapy prior to registration and randomisation. Such patients must be discussed with the coordinating centre prior to registration, and must be registered within 10 days of commencing study chemotherapy.
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 ≥ grade 2 or clinically significant sensorineural 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 use 2 effective methods of contraception, including use of a condom, during chemotherapy and for a year after completing chemotherapy.
8. Known allergy or hypersensitivity to any of the study drugs
9. Presence of any psychological, familial, sociological or geographical condition that in the opinion of the investigator would hamper compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse

The above inclusion and exclusion criteria will apply to stage 1 (n=150) and stage 2 (n=500 including stage 1) of the study. All sites will participate in both stages of the study with the exception of the Children's Oncology Group who will be participate in stage 1 only.

Primary outcomes:
measure: Progression-free survival (disease progression or death)
timeFrame: From randomisation up to disease progression or date of death whichever come first, assessed up to 5 years
Secondary outcomes:
measure: Initial response assessment
timeFrame: At end of chemotherapy treatment, treatment planned for 12 weeks
measure: Final response assessment
timeFrame: At 6 months
measure: Adverse events (worst grade according to NCI CTCAE v4.03)
timeFrame: From start of chemotherapy until 30 days after last dose, an average of 4 months
measure: Health-related quality of life
timeFrame: From date of randomisation until date of 18 month follow-up
measure: Health-related quality of life for testicular cancer
timeFrame: From date of randomisation until date of 18 month follow-up
measure: Treatment preference
timeFrame: From date of randomisation until date of 18 month follow-up
measure: Delivered dose-intensity of chemotherapy (relative to standard BEP)
timeFrame: From start date of chemotherapy treatment until date of end of chemotherapy, an average of 12 weeks
measure: Overall survival
timeFrame: From randomisation up to disease progression or date of death whichever come first, assessed up to 5 years
Other outcomes:
measure: Exploratory biomarker investigations
timeFrame: Baseline
Locations:
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Centre
state: New York
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Sydney
country: Australia
facility: Macquarie Cancer Clinical Trials
state: New South Wales
city: Sydney
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Tweed Heads
country: Australia
facility: Tweed Hospital
state: New South Wales
city: Wahroonga
country: Australia
facility: SAN Clinical Trials Unit
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: St Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Wodonga
country: Australia
facility: Border Medical Oncology
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Grafton
country: New Zealand
facility: Starship Children's Hospital
state: Auckland
city: Grafton
country: New Zealand
facility: Auckland Hospital
state: Auckland
city: Roslyn
country: New Zealand
facility: Palmerston North Hospital
state: Palmerston North
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
Study officials:
affiliation: Chris O'Brien Lifehouse
name: Peter Grimison
role: STUDY_CHAIR
References:
citation: Lawrence NJ, Chan H, Toner G, Stockler MR, Martin A, Yip S, Wong N, Yeung A, Mazhar D, Pashankar F, Frazier L, McDermott R, Walker R, Tan H, Davis ID, Grimison P; ANZUP. Protocol for the P3BEP trial (ANZUP 1302): an international randomised phase 3 trial of accelerated versus standard BEP chemotherapy for adult and paediatric male and female patients with intermediate and poor-risk metastatic germ cell tumours. BMC Cancer. 2018 Aug 29;18(1):854. doi: 10.1186/s12885-018-4745-3.