MAKEI V: An international clinical study for children, adolescents, and young adults with malignant, extracranial germ cell tumors.

Extracranial germ cell tumours of any malignant histology, primary site and stage;Therapeutic area: Diseases [C] - Cancer [C04]

(ICTRP)

Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CISPLATIN
CAS Number: 15663-27-1
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to

Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CARBOPLATIN
CAS Number: 41575-94-4
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to

Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ETOPOSIDE
CAS Number: 33419-42-0
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to

Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: IFOSFAMIDE
CAS Number: 3778-73-2
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to

(ICTRP)

Controlled: yesRandomised: yesOpen: yesSingle blind: noDouble blind: noParallel group: yesCross over: noOther: noIf controlled, specify comparator, Other Medicinial Product: yesPlacebo: noOther: noNumber of treatment arms in the trial: 2

(ICTRP)

Inclusion criteria:

• Confirmed extracranial MGCT up to 17 11/12 years of age or patients with ovarian primaries up to 29 11/12 years of age on the date of written informed consent
• Written informed consent prior to trial entry of parents and/or patient
• Diagnosis of a chemotherapy-naïve extracranial MGCT
• Karnofsky-Index of >70% or ECOG-Status 0-II
• Negative pregnancy test within 7 days prior to start of treatment for female patients of childbearing potential, in case of ß-HCG secreting MGCT pregnancy has to be excluded by appropriate methods

Note: Any patient who is of reproductive age should agree to use adequate contraception for the duration of the trial treatment and until at least 12 months after end of therapy.
Are the trial subjects under 18? yes
Number of subjects for this age range: 300
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 60
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

(ICTRP)

Exclusion criteria:
Exclusion criteria in general:

• Pregnancy
• Lactation
• Incomplete data at trial entry preventing risk group allocation
• HIV-positivity
• Live vaccine immunization within two weeks before start of protocol treatment
• Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of chemotherapy
• Current or recent (within 30 days prior to date of informed written consent) treatment with another investigational drug or participation in another interventional clinical trial, except trials with different end points than MAKEI V that can run in parallel to MAKEI V without influencing that trial, e.g., trials on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc.
• Any other medical, psychiatric or drug related condition, or social condition incompatible with protocol treatment.

Exclusion criteria in special indication:

• Second malignancies
• Negative preoperative tumour markers AFP and ß-HCG and solely pure teratoma histology
• Known hypersensitivity against Cisplatin, Carboplatin, Etoposide, Ifosfamide or other ingredients of the medicinal product
• Hearing impairment Grade 3 and 4 (CTCAE Vers.4.03)

(ICTRP)

Main Objective: To assess in a randomized comparison whether the efficacy of Carboplatin is not inferior to Cisplatin in malignant germ cell tumours (MGCT) of intermediate, high and very high risk with regard to Event-free-survival (EFSr);Secondary Objective: 1. Evaluation of EFS/OS rates in the defined risk-groups compared to results of MAKEI 96 and published data
2. Evaluation of toxicity in randomized patients in respect to numbers of days in hospital, numbers of applied platelet and red blood cell transfusions
3. Evaluation of ototoxicity, nephrotoxicity, cardiotoxicity and fertility relevant endocrine outcomes under and after treatment chemotherapy
4. Evaluation of patient-reported-outcomes
5. Implementation of standardized documentation of surgical procedures and evaluation of potential impact of variations in procedures on EFS
6. Evaluation of risk stratification for therapy implemented in MAKEI V based on standardized staging and pathological evaluation in comparison to MAKEI 96
7. Evaluation of radiological response after two or four cycles of chemotherapy
8. Evaluation of standard tumour marker kinetics after every cycle of chemotherapy
;Primary end point(s): Event-free survival, defined as minimum time from the date of randomization to the following events (EFSr):

• Death from any cause
• Progressive disease, defined as increase of standard tumour marker with or without expansion of tumour mass/metastases
• Viable tumour cells at time of final surgery
• Relapse
• Second malignancy
• or the date of the last follow-up This relates to patients randomized to Carboplatin or Cisplatin.;Timepoint(s) of evaluation of this end point: Any timepoint from the date of randomization to one of the defined events.

(ICTRP)

Timepoint(s) of evaluation of this end point: Any timepoint from the date of randomization to one of the defined events or analysis.;Secondary end point(s): - Event-free survival (EFS), defined as minimum time from the date of diagnosis to any of the events described above or to last follow-up, of all patients included in MAKEI V in respect to the defined MAKEI V risk groups

• Overall survival (OS), defined as minimum time from the date of diagnosis to death of any cause or to last follow-up, of all patients included in MAKEI V in respect to the defined MAKEI V risk groups
• Health economic parameter, e.g. hospitalization days during treatment, number of blood transfusions, in respect to treatment with Carboplatin or Cisplatin
• Short and late toxicities according to CTCAE v4.03
• Assessment of safety: Adverse events and laboratory abnormalities, CTCAE v4.03 grade, timing, seriousness and relatedness.
• Fertility relevant endocrine outcomes, e.g. Estrogen, AMH, LH, FSH, Inhibin B.
• Patient reported outcomes including HRQoL, fatigue, sexual function and fertility outcomes (in adult patients)
• Determination of risk for relapse in respect to used surgical intervention
• Radiological response rate after two (and if applicable four) cycles of either Carboplatin or Cisplatin chemotherapy
• Standard tumour marker levels after every cycle of either Carboplatin or Cisplatin chemotherapy

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