Validation of a Treatment Algorithm for Poor-Risk NSGCTnon Seminomatous Germ-cell Tumors

This is a prospective multicenter, non-randomized research program that includes:

* a phase IV study (for all patients) with a collection of tissue specimens of tumor,
* a phase II study (for patients with primary mediastinal tumors and an unfavorable decline in tumor markers),
* and a diagnostic study (for all patients, except patients with brain metastases at baseline or patients for whom any brain MRI is contra-indicated).

The main question it aims to answer is improving outcome for young adults with poor-prognosis Non Seminomatous Germ Cell Tumor (NSGCT) is to validate prospectively the efficacy and safety of a personalized treatment based on early tumor marker kinetic assessment in real life for patients with poor-prognosis NSGCT.

Participants will be followed-up according to the assessment of decline kinetics of the tumor markers at the end of a first chemotherapy cycle and according to the localisation of the primary lesion if unfavorable.

* In the case of a patient with a favorable decline of the tumor markers, he will be treated by 3 additional standard chemotherapy cycles.
* In the case of a patient with a testicular or peritoneal primary tumor and an unfavorable decline of the tumor markers, the patient will be treated by a dose-dense standard therapy.
* The patient with a mediastinal primary tumor and an unfavorable decline of the tumor markers will be proposed to enter the phase II part of the study or to enter the dose-dense regimen like the other primary localisations. If the patient consents and is eligible for phase II part, he will undergo either an early surgery if feasible or a high-dose chemotherapy if the early surgery is not possible.


Eligibility Criteria:
Inclusion Criteria:

* Male patient older than 16 years old on day of signing informed consent
* Patient with evidence of NSGCT based on histologic examination or based on clinical evidence and elevated serum hCG or AFP levels (in case of clinical emergency, therapy can be started before pathologic sample is obtained if tumor markers are highly elevated)
* Patient with testicular, retroperitoneal, or mediastinal primary site
* Patient with evidence of disseminated disease (clinical stages II or III according to AJCC 8th edition)
* Patient with disease classified as poor prognosis according to IGCCCG criteria:
* Primary mediastinal NSGCT or,
* Non-pulmonary visceral metastases or,
* hCG \> 50 000 UI/L, or AFP \> 10 000 ng/mL, or LDH \> 10 times the upper normal value
* Patient with adequate renal function: measured or calculated (by Cockcroft formula) creatinine clearance \> 60 mL/min. Cockcroft formula: CrCl = \[(140-age) x weight in kg\]/\[72 x serum creatinine (mg/dL)\]
* Patient with absolute granulocyte count \> or = 1,500/mm\^3, platelets \> or = 100,000 mm\^3, bilirubin \< or = 1.5x the upper limit of normal value.
* Patient with a contra-indication of undergoing any brain MRI are eligible, but will not be part of the diagnostic study part
* Patient (and his legal guardian for under-18 patient) who had understood, signed and dated the informed consent form
* Patient affiliated to social security system or beneficiary of the same
* Male of child-bearing potential, must agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 6 months after the last treatment intake.

Inclusion criteria specific to the phase 2 study in patients with unfavorable serum marker decrease and mediastinal primary tumor (to be confirmed before the end of the 1st BEP cycle)

* Patient (and his legal guardian for under-18 patient) who had understood, signed and dated the specific Phase II informed consent form
* Patient with mediastinal primary site
* Patient with unfavorable serum marker decrease evaluated at D18-D21 of the first BEP-chemotherapy

Exclusion Criteria:

* Patient infected by the Human Immunodeficiency Virus (HIV)
* Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent
* Patient with prior chemotherapy. Patients who have received a first cycle of cisplatin-base chemotherapy (BEP) for their poor-prognosis NSGCT are eligible as far as tumor marker decline can be assessed at day 18-21.
* Patient with previous malignancy, except for basal-cell carcinoma of the skin
* Known allergy or hypersensitivity to any of the study drugs

Non inclusion criteria specific to the phase 2 study in patients with unfavorable serum marker decrease and mediastinal primary tumor (to be confirmed before the end of the 1st BEP cycle)

* Patient (and his legal guardian for under-18 patient) who withdraws his consent
* Patient with Human T-cell Leukemia Virus (HTLV) type 1 and 2
* Patient with Hepatitis B surface antigen
* Patient with Hepatitis C antibody
* Patient with prior high-dose chemotherapy (HDCT) plus hematopoietic stem cell HSCs transplant