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

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 clinicalevidence and elevated serum hCG or AFP levels (in case of clinical emergency,therapy can be started before pathologic sample is obtained if tumor markers arehighly elevated)

• Patient with testicular, retroperitoneal, or mediastinal primary site

• Patient with evidence of disseminated disease (clinical stages II or III accordingto 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 inkg]/[72 x serum creatinine (mg/dL)]

• Patient with absolute granulocyte count > or = 1,500/mm^3, platelets > or = 100,000mm^3, bilirubin < or = 1.5x the upper limit of normal value.

• Patient with a contra-indication of undergoing any brain MRI are eligible, but willnot be part of the diagnostic study part

• Patient (and his legal guardian for under-18 patient) who had understood, signed anddated 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 patientand one for the partner) of medically acceptable forms of contraception during thestudy 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 anddated the specific Phase II informed consent form

• Patient with mediastinal primary site

• Patient with unfavorable serum marker decrease evaluated at D18-D21 of the firstBEP-chemotherapy

Exclusion Criteria:

• Patient infected by the Human Immunodeficiency Virus (HIV)

• Patient under guardianship or deprived of his liberty by a judicial oradministrative decision or incapable of giving its consent

• Patient with prior chemotherapy. Patients who have received a first cycle ofcisplatin-base chemotherapy (BEP) for their poor-prognosis NSGCT are eligible as faras 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 HSCstransplant