A Randomized Phase 3 Trial of Accelerated Versus Standard BEP Chemotherapy for Patients with Intermediate and Poor-Risk Metastatic Germ Cell Tumors.

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.