| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| International germ cell classification catergory (IGCCC) intermediate or poor-risk metastatic germ cell tumours |
|
| E.1.1.1 | Medical condition in easily understood language |
| intermediate or poor-risk germ cell tumours |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068971 |
| E.1.2 | Term | Germ cell cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the effects of giving bleomycin, etoposide & cisplatin (BEP) every two weeks (accelerated BEP) with giving BEP every 3 weeks (standard BEP) as a first line chemotherapy and to compare the two treatment arms with respect to progression-free survival (PFS, disease progression or death). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives will attempt to compare the following in accelerated vs. standard BEP arms:
i. Response following treatment completion (protocol-specific response criteria)
ii. Overall survival (death from any cause)
iii. Delivered dose-intensity of chemotherapy (relative to standard BEP)
iv. Treatment preference (proportion preferring each treatment arm)
v. Health-related quality of life (summary scales from QLQ-C30 & TC-26)
vi. Adverse events (worst grade according to NCI CTCAE v4.03)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients will be eligible for inclusion into this study if they meet all of the following criteria.
1. Able and willing to provide signed, written informed consent/assent
2. Male or female
3. Aged between 11 and 45 years inclusive on the date of consent
4. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma); or exceptionally raised tumour markers (AFP ≥1000ng/mL and/or HCG ≥5000IU/L) without histologic or cytologic confirmation in the rare case where pattern of metastases is consistent with GCT, high tumour burden, and a need to start therapy urgently
5. Primary arising in the testis, ovary, retro-peritoneum or mediastinum
6. Metastatic disease or non-testicular primary
7. Intermediate or poor prognosis as defined by IGCCC classification3 (modified with different LDH criteria for intermediate risk non-seminoma and inclusion of ovarian primaries).
8. Adequate bone marrow function with ANC ≥1.0 x 109/L
9. Adequate liver function where bilirubin must be ≤1.5 x ULN,
- except if the elevations are due to hepatic metastases, in which case ALT and AST must be ≤ 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
10. 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 the opinion of the investigator, in which case GFR should be formally measured, e.g. with EDTA scan
11. ECOG Performance Status of 0, 1, 2 or 3
12. Study treatment both planned and able to start within 14 days of randomisation
13. Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from this study if they meet any of the following 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:
- Pure seminoma relapsing after adjuvant radiotherapy of adjuvant chemotherapy with 1-2 doses of single agent carboplatin
- 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 (e.g. 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.37 Patients must meet all other inclusion and exclusion criteria at the time of registration
- 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. Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and 12 months post treatment. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration
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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the comparison of progression free survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage I analysis to be conducted once first 150 patients have been recruited.
Stage II analysis will be conducted in two parts first at 30% & then at 60% of completed progression free survival events |
|
| E.5.2 | Secondary end point(s) |
Secondary objectives will attempt to compare the following in accelerated vs. standard BEP arms:
i. Response following treatment completion (protocol-specific response criteria)
ii. Overall survival (death from any cause)
iii. Delivered dose-intensity of chemotherapy (relative to standard BEP)
iv. Treatment preference (proportion preferring each treatment arm)
v. Health-related quality of life (summary scales from QLQ-C30 & TC-26)
vi. Adverse events (worst grade according to NCI CTCAE v4.03)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage I analysis to be conducted once first 150 patients have been recruited.
Stage II analysis will be conducted in two parts first at 30% & then at 60% of completed progression free survival events |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| New Zealand |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The primary measure of this study is to compare progression free survival.
The end of trial is defined as when 140 progression free survival events have been recorded.
However patients will be followed up post progression until death of any cause, whilst the study is open. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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