Accelerated v's Standard BEP Chemotherapy for Patients With Intermediate and Poor-risk Metastatic Germ Cell Tumours

Germ Cell Tumor Clinical Trial

— P3BEP  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02582697
• Other study ID #: ANZUP1302
• Secondary ID: ACTRN12613000496
• Status: Recruiting
• Phase: Phase 3
• Start date: February 2014
• Est. completion date: July 2023

Study information

• Verified date: November 2021
• Source: University of Sydney
• Contact: P3BEP Trial Coordinator
• Phone: +6195625000
• Email: p3bep[@]ctc.usyd.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: July 2023
• Est. primary completion date: February 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 11 Years to 45 Years

Eligibility

Inclusion Criteria:

1. Age = 11 years and = 45 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 has non-seminoma and poor prognosis by IGCCC criteria 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). In these instances acceptable regimens include cisplatin 20 mg/m^2 days 1-2 and etoposide 100 mg/m^2 days 1-2; carboplatin AUC 3 days 1-2 and etoposide 100 mg/m^2 days 1-2; or baby-BOP. 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.

Related Conditions & MeSH terms

• Germ Cell Tumor
• Neoplasms, Germ Cell and Embryonal

Intervention

Drug:
• Bleomycin (active name: Bleomycin Sulfate)
Standard Arm: Bleomycin 30,000 international units IV weekly for 3 doses (eg. days 1, 8 and 15 or days 2, 9 and 16 of a 21-day cycle) for 4 cycles. Accelerated Arm: Bleomycin 30,000 international units IV weekly for 2 doses (eg. days 1 and 8 or days 2 and 9 of a 14-day cycle) for 4 cycles. Followed by Bleomycin 30,000 international units IV weekly for 4 doses.
• Etoposide
Standard Arm: Etoposide 100 mg/m2 IV on days 1, 2, 3, 4, 5 of a 21-day cycle for 4 cycles. Accelerated Arm: 100 mg/m2 IV on days 1, 2, 3, 4, 5 of a 14-day cycle for 4 cycles.
• Cisplatin
Standard Arm: Cisplatin 20 mg/m2 IV on days 1, 2, 3, 4, 5 of a 21-day cycle for 4 cycles. Accelerated Arm: Cisplatin 20 mg/m2 IV on days 1, 2, 3, 4, 5 of a 14-day cycle for 4 cycles.
• Pegylated G-CSF (Pegfilgrastim)
Standard Arm: 6 mg SCI on day 6 of a 21-day cycle for 4 cycles. Accelerated Arm: 6 mg SCI on day 6 of a 14-day cycle for 4 cycles.
• Filgrastim
Standard Arm: 10 mcg/kg/day on day6, until post-nadir absolute neutrophil count = 1.0 x 10^9/L, of a 21-day cycle for 4 cycles. Accelerated Arm: 10 mcg/kg/day on day 6, until post-nadir absolute neutrophil count = 1.0 x 10^9/L, of a 14-day cycle for 4 cycles.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Royal Brisbane & Women's Hospital	Brisbane	Queensland
Australia	Peter MacCallum Cancer Centre	East Melbourne	Victoria
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Calvary Mater Newcastle	Newcastle	New South Wales
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Australia	Sunshine Hospital	St Albans	Victoria
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Chris O'Brien Lifehouse	Sydney	New South Wales
Australia	Concord Repatriation General Hospital	Sydney	New South Wales
Australia	Macquarie Cancer Clinical Trials	Sydney	New South Wales
Australia	Nepean Hospital	Sydney	New South Wales
Australia	Prince of Wales Hospital	Sydney	New South Wales
Australia	Westmead Hospital	Sydney	New South Wales
Australia	Tweed Hospital	Tweed Heads	New South Wales
Australia	SAN Clinical Trials Unit	Wahroonga	New South Wales
Australia	Border Medical Oncology	Wodonga	Victoria
Australia	Princess Alexandra	Woolloongabba	Queensland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Dunedin Hospital	Dunedin
New Zealand	Auckland Hospital	Grafton	Auckland
New Zealand	Starship Children's Hospital	Grafton	Auckland
New Zealand	Palmerston North Hospital	Roslyn	Palmerston North
United States	Memorial Sloan Kettering Cancer Centre	New York	New York

Sponsors (7)

Lead Sponsor	Collaborator
University of Sydney	Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Cambridge University Hospitals NHS Foundation Trust, Cancer Trials Ireland, Children's Oncology Group, Dana-Farber Cancer Institute, University of Southern California

Countries where clinical trial is conducted

United States,  Australia,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory biomarker investigations	Associations between biomarkers with survival will be assessed in the future.	Baseline
Primary	Progression-free survival (disease progression or death)	PFS is measured from the date of randomisation until the criteria for disease progression are met (as defined in the protocol) or death. Participants who are not observed to progress nor die will be censored at the date of last follow-up	From randomisation up to disease progression or date of death whichever come first, assessed up to 5 years
Secondary	Initial response assessment	The assessment of response of germ cell tumours is measured by the change in size of measurable tumour masses in combination with changes in serum tumour markers after chemotherapy treatment.	At end of chemotherapy treatment, treatment planned for 12 weeks
Secondary	Final response assessment	The assessment of response of germ cell tumours is measured by changes in serum tumour markers and imaging at 6 months from randomisation, or after any post-chemotherapy surgical resection or other intervention, whichever occurs last.	At 6 months
Secondary	Adverse events (worst grade according to NCI CTCAE v4.03)	The intensity of adverse events will be assessed using the NCI Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE v4.03)	From start of chemotherapy until 30 days after last dose, an average of 4 months
Secondary	Health-related quality of life	HR-QoL measures will include the EORTC core quality of life questionnaire (QLQ-C30), a 30-item cancer-specific questionnaire that is well-validated and available in many languages.	From date of randomisation until date of 18 month follow-up
Secondary	Health-related quality of life for testicular cancer	EORTC quality of life module for testicular cancer (QLQ-TC26), a disease-specific measure with 26 items about physical symptoms, sexual functioning and emotional issues.	From date of randomisation until date of 18 month follow-up
Secondary	Treatment preference	A trial-specific preferences question will be used to determine if participants think they would prefer to be treated with accelerated BEP or standard BEP, assuming that they were equally effective.	From date of randomisation until date of 18 month follow-up
Secondary	Delivered dose-intensity of chemotherapy (relative to standard BEP)	Delivered dose-intensity of cisplatin, etoposide and bleomycin will be assessed.	From start date of chemotherapy treatment until date of end of chemotherapy, an average of 12 weeks
Secondary	Overall survival	Overall survival is measured from the date of randomisation until death from any cause, or the date of last known follow-up alive.	From randomisation up to disease progression or date of death whichever come first, assessed up to 5 years