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

Background 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). 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. Methods This 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. Discussion 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 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 registration ACTRN 12613000496718 on 3rd May 2013 and Clinicaltrials.gov NCT02582697 on 21st October 2015.


Background
The most common malignancy affecting adolescent and young adult males in Western countries is germ cell tumours (GCTs) [1]. Although most patients with good prognostic features have excellent outcomes, the cure rates for male patients with advanced disease and intermediate or poor prognostic features are only 79 and 48% respectively [2]. GCTs are rarer in females, however in females aged between 10 and 30 years they account for 70% of ovarian neoplasms [3].
The efficacy of first-line chemotherapy has not improved since the introduction of bleomycin, etoposide, cisplatin (BEP) in the mid-1980s. BEP chemotherapy given every 3 weeks for 4 cycles remain the global accepted standard of care for intermediate, and poor prognosis male patients [4]. Paediatric and female patients with GCTs are often not included in clinical trials due to the rarity of disease. The current management algorithms for these groups are based on extrapolations from other settings [3,5].
Accelerating chemotherapy by administering the same doses more frequently has increased cure rates in other cancers, including breast cancer, lymphoma (prior to rituximab) and Ewing's sarcoma [6][7][8]. The hypothesised mechanism is that accelerated chemotherapy with shorter cycles can overcome the rapid regrowth of shrinking tumours induced by chemotherapy [9,10]. Accelerating chemotherapy is feasible with the development and availability of therapeutic granulocyte colonystimulating factor (G-CSF) e.g. filgrastim, which reduces the duration of leukopenia [11]. Accelerated regimens may be preferable to patients as treatment is completed faster, it may improve compliance and has minimal additional financial cost.
A single arm phase 2 trial of 43 patients demonstrated that the regimen is feasible and tolerable [12]. The long term efficacy data appears promising with 5 year overall survival of 92% (95% CI 54% to 99%) for patients with poor prognostic features and 94% (95% CI 63% to 99%) for patients with intermediate prognostic features [13].
The aim of this phase 3 trial is to determine if accelerated BEP is superior to standard BEP as first-line chemotherapy for intermediate and poor-risk metastatic GCTs.

Study design
This trial is an open label randomised, 2-arm, multi-centre, phase 3 trial. Participants are randomised 1:1 to receive 4 cycles of either accelerated BEP chemotherapy given 2 weekly or standard BEP chemotherapy given 3 weekly (Fig. 1). Randomisation will be implemented using a minimisation approach balancing for; ECOG performance status

Study objectives
The primary objective is progression-free survival (PFS), defined as from the date of randomisation until the criteria for disease progression are met or death. Secondary objectives include response following treatment completion (protocol specific criteria), adverse events (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [14]), health related quality of life (QLQ-C30 [15] and -TC-26 [16]), treatment preference, delivered dose-intensity of chemotherapy and overall survival. Tertiary objectives include exploratory studies of biomarkers and their correlations with clinical outcome. Initial response assessment is measured at the 30-42 day safety assessment. Final response assessment at 6 months from randomisation or after all post-chemotherapy surgery and other interventions are completed. Participants will continue regular follow-up for at least 5 years.

Eligibility criteria
Key inclusion and exclusion criteria include age between 11 and 45 years, intermediate or poor prognosis germ cell tumour as defined by IGCCC (modified with different lactate dehydrogenase criteria for intermediate risk non-seminoma, and inclusion of ovarian primaries) and adequate organ function. 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. Such participants must be discussed with the coordinating centre prior to subsequent registration, and they must then be registered within 10 days of commencing chemotherapy. The full eligibility criteria are listed in Table 1.

Treatment
The experimental arm is accelerated BEP given as bleomycin 30,000 international units (IU) (15,000 IU/m 2 in participants aged less than 16) intravenous (IV) weekly on day 1 and 8, etoposide 100 mg/m 2 on days 1-5 and cisplatin 20 mg/m 2 on days 1-5 every 2 weeks for 4 cycles, followed by single agent bleomycin 30,000 IU (15,000 IU/m 2 in participants aged less than 16 years) IV once a week for a further 4 weeks to a total of 12 doses of bleomycin. The control arm is standard BEP given as bleomycin 30,000 IU (15,000 IU/m 2 in participants aged less than 16) IV weekly on day 1, 8 and 15, etoposide 100 mg/m 2 on days 1-5 and cisplatin 20 mg/m 2 on days 1-5 every 3 weeks for 4 cycles. G-CSF support is given in both treatment arms.
Every attempt should be made to deliver chemotherapy at full dose and without delay from the planned schedule, as dose and dose-intensity are important predictors of outcome. Dose reductions for etoposide are specified in the protocol. There are no dose reductions for cisplatin or bleomycin allowed. Study treatment will be permanently discontinued for unacceptable toxicity, delay of day 1 of treatment for more than 21 days due to treatment-related adverse events, unequivocal progression, occurrence of an exclusion criteria or illness affecting participant safety, failure to comply with the protocol or if the investigator does not think it is in the participant's best interest to continue. If a participant

Assessment schedule
Participants are assessed at baseline, prior to each cycle of chemotherapy, at completion of study treatment, then at 6,9,12,18,24,30,36,42,48, 54 and 60 months from randomisation ( Table 2). Assessments at each time point include performance status, adverse events, blood tests (blood count, biochemistry, tumour markers), quality of life (up to 12 months), lung function tests (for Australian sites up to 12 months), CT imaging (at baseline; after randomisation at 4, 12, 24 and 60 months; and as clinically indicated), disease status, subsequent treatment and survival. Biospecimens including tumour tissue (formalin-fixed paraffin-embedded) and blood (whole blood and plasma) at baseline will be collected from consenting participants for use in future translational research.

Statistical analysis
Stage 1 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 promising, Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma), or exceptionally raised tumour markers (AFP ≥ 1000 ng/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. c. Participants who need to start therapy urgently prior to completing study-specific baseline investigations 3. Significant cardiac disease 4. Significant co-morbid respiratory disease 5. Peripheral neuropathy ≥ grade 2 or clinically significant sensorineural hearing loss 6. Concurrent illness that prevent the completion of the interventions listed in the protocol 7. Participants who are sexually active and are not willing to use an effective contraceptive method during this study. 8. Known allergy or hypersensitivity to any of the study drugs 9. Presence of any psychological, familial, sociological or geographical condition that the investigators believe will lead to compliance issues.
Stage 2 of the study will recruit an additional 350 participants for a total sample size of 500 participants. 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.

Discussion
The results of this study will determine if accelerated BEP chemotherapy is superior to standard BEP chemotherapy in the first-line treatment of intermediate and poor-risk metastatic GCTs. The collection of biospecimens will allow for future translational research studies to determine associations between biomarkers (to be specified) and their correlations with clinical outcomes. 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.

Funding
The trial is co-funded by Cancer Council Australia and Cancer Australia (APP1041733). The funders have had no role in any of the following; the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.