MAKEI V

Extracranial, malignant germ cell tumors

Multicenter, prospective, randomized

Primary objectives

A randomized comparison will be used to assess whether the efficacy of carboplatin is not inferior to that of cisplatin in the treatment of intermediate-, high- or very high-risk malignant germ cell tumors in terms of event-free survival (EFS).

Secondary objectives

• Evaluation of EFS and overall survival of the defined risk groups in comparison with the results of the MAKEI 96 study and other publications.
• Evaluation of toxicity during randomized treatment with carboplatin or cisplatin in terms of duration of hospitalization and number of transfused red blood cell and platelet concentrates
• Evaluation of toxicity during and after randomized treatment with carboplatin or cisplatin with regard to ototoxicity, nephrotoxicity, cardiotoxicity and endocrine parameters relevant to fertility. Evaluation of patient-reported outcomes including health-related questionnaires on quality of life and fatigue. In adult patients: sexual function and fertility.
• Implementation of standardized documentation of surgical techniques used and evaluation of potential deviations from these techniques on the EFS.
• Evaluation of toxicity during and after randomized treatment with carboplatin or cisplatin with regard to ototoxicity, nephrotoxicity, cardiotoxicity and endocrine parameters relevant to fertility.
• Evaluation of patient-reported outcomes including health-related questionnaires on quality of life and fatigue. In adult patients: sexual function and fertility.
• Implementation of a standardized documentation of the applied surgical techniques and evaluation of potential deviations from these techniques on the EFS.
• Evaluation of the risk stratification applied in the MAKEI V study and based on standardized staging and pathological assessment compared to the MAKEI 96 study. Low risk: Evaluation of the extended watch-and-wait strategy for localized disease, including testicular tumors pT2N0M0, pT3-4N0M0 and ovarian tumors FIGO Ic1 (without vascular/lymphatic invasion for both localizations); evaluation of the prognosis after organ-preserving surgery for localized gonadal germ cell tumors. Medium risk: Evaluation of the reduction of chemotherapy cycles in testicular tumors pT1-T4N1M0 and pT3-T4N0M0 (with vascular/lymphatic invasion). Very high risk: Evaluation of treatment intensification in non-gonadal germ cell tumors > 10 years, testicular tumors pTx T2-T4, Any N, M1b and ovarian tumors FIGO IV.
• Evaluation of the radiologic response after two and possibly four cycles of carboplatin or cisplatin-containing chemotherapy.
• Evaluation of the kinetics of the standard tumor markers after each cycle of cisplatin or carboplatin-containing chemotherapy.
• Correlation of miRNA expression levels with the standard tumor markers AFP and ß-HCG as well as clinical data.

Treatment is performed according to risk stratification and within specific risk groups defined by tumor location, stage, age and resection status. At the time of surgery, preservation of tumour material is strongly recommended for all risk groups included in the randomization.
Depending on the extent of the tumor, the tumor is removed as far as possible before starting chemotherapy or, if this is not possible, a tumor biopsy is taken first. After completion of chemotherapy, a surgical re-evaluation is performed with the aim of removing the tumor.
Depending on the risk group, patients are either only observed after surgery (watch and wait) or treated with randomized chemotherapy regimens of varying intensity.

• Patients with confirmed extracranial germ cell tumor up to the age of 17 years and patients with ovarian germ cell tumor up to the age of 29 years at the time of written informed consent
• Written informed consent prior to study inclusion from parents and/or adult patient
• Diagnosis of a chemotherapy-naïve extracranial germ cell tumor
• Karnofsky index >70% or ECOG status 0-II
• Negative pregnancy test within seven days before the start of treatment in patients of childbearing age; in the case of a ß-HCG-secreting malignant germ cell tumor, pregnancy must be ruled out by other appropriate methods

Note: Patients of reproductive age should agree to use adequate contraception for the duration of study treatment and for at least 12 months after completion of therapy.

Note: Patients with a mature teratoma can be reported to the study for consiliary care - they will receive a registry number.

• Pregnancy
• Lactation
• Incomplete data on study inclusion that prevent classification into one of the risk groups
• Proof of HIV positivity
• Live vaccination within two weeks before the start of treatment
• Sexually active adolescents who are not willing to use a highly effective contraceptive method (Pearlin index under 1) until 12 months after completion of chemotherapy
• Current or recent treatment (within 30 days prior to the date of written informed consent) with another investigational drug or participation in another interventional clinical trial, excluding studies with endpoints other than MAKEI V that can be conducted in parallel with MAKEI V without interfering, e.g. studies on antiemetics, antifungals, antibiotics, psychosocial support strategies, etc.
• Any other medical, psychiatric, medication-related or social condition that is incompatible with protocol-compliant treatment

Note: Patients excluded from the study on the basis of these criteria may be eligible for registration as a follow-up patient. These patients will receive adequate treatment but will not be evaluated with regard to primary or secondary endpoints.

Indication-specific exclusion criteria:

• Presence of a second malignancy
• Presence of preoperatively negative tumor markers at diagnosis and
• an exclusively pure teratoma histology
• Known hypersensitivity to cisplatin, carboplatin, etoposide,
• Ifosfamide or other components of the drugs
• Hearing impairment grade 3 and 4 (CTCAE Vers.4.03)