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Abstract
BackgroundBleomycin, etoposide, and cisplatin (BEP) chemotherapy administered every 3 weeks for 4 cycles remains the standard first line treatment for patients with intermediate- and poor-risk metastatic germ cell tumours (GCTs). Administering standard chemotherapy 2-weekly rather than 3-weekly, so-called ‘accelerating chemotherapy’, has improved cure rates in other cancers. An Australian multicentre phase 2 trial demonstrated this regimen is feasible and tolerable with efficacy data that appears promising. The aim of this trial is to determine if accelerated BEP is superior to standard BEP as first line chemotherapy for adult and paediatric male and female participants with intermediate and poor risk metastatic GCTs.MethodsThis is an open label, randomised, stratified, 2-arm, international multicentre, 2 stage, phase 3 clinical trial. Participants are randomised 1:1 to receive accelerated BEP or standard BEP chemotherapy. Eligible male or female participants, aged between 11 and 45 years with intermediate or poor-risk metastatic GCTs for first line chemotherapy will be enrolled from Australia, the United Kingdom and the United States. Participants will have regular follow up for at least 5 years. The primary endpoint for stage 1 of the trial (n = 150) is complete response rate and for the entire trial (n = 500) is progression free survival. Secondary endpoints include response following treatment completion (by a protocol-specific response criteria), adverse events, health-related quality of life, treatment preference, delivered dose-intensity of chemotherapy (relative to standard BEP), overall survival and associations between biomarkers (to be specified) and their correlations with clinical outcomes.DiscussionThis is the first international randomised clinical trial for intermediate and poor-risk metastatic extra-cranial GCTs involving both adult and pediatric age groups open to both males and females. It is also the largest, current randomised trial for germ cell tumours in the world. Positive results for this affordable intervention could change the global standard of care for intermediate and poor risk germ cell tumours, improve cure rates, avoid the need for toxic and costly salvage treatment, and return young adults to long, healthy and productive lives.Trial registrationACTRN 12613000496718 on 3rd May 2013 and Clinicaltrials.gov NCT02582697 on 21st October 2015.
Highlights
Bleomycin, etoposide, and cisplatin (BEP) chemotherapy administered every 3 weeks for 4 cycles remains the standard first line treatment for patients with intermediate- and poor-risk metastatic germ cell tumours (GCTs)
This is the first international randomised clinical trial for intermediate and poor-risk metastatic extra-cranial GCTs involving both adult and pediatric age groups open to both males and females. It is the largest, current randomised trial for germ cell tumours in the world. Positive results for this affordable intervention could change the global standard of care for intermediate and poor risk germ cell tumours, improve cure rates, avoid the need for toxic and costly salvage treatment, and return young adults to long, healthy and productive lives
GCTs are rarer in females, in females aged between 10 and 30 years they account for 70% of ovarian neoplasms [3]
Summary
Study design This trial is an open label randomised, 2-arm, multi-centre, phase 3 trial. Randomisation will be implemented using a minimisation approach balancing for; ECOG performance status (0–1 vs 2–3), International germ cell cancer consensus classification (IGCCC) risk group (intermediate vs poor), primary site (mediastinal vs other), brain metastases (present vs absent), induction chemotherapy (present vs absent), age (≥ 16 years vs < 16 years), gender (male vs female), and study site. Participants who need to start therapy urgently may commence study chemotherapy prior to registration and randomisation given the treatment is identical for the first 2 weeks and forms part of standard of care management. Assessment schedule Participants are assessed at baseline, prior to each cycle of chemotherapy, at completion of study treatment, at 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months from randomisation (Table 2). 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
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