Prospective Trial for the Diagnosis and Treatment of Intracranial Germ Cell Tumors

Study Overview
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Brief Summary
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STUDY DESIGN: Prospective, non-randomised multicentre study with patients stratified according to risk groups INVESTIGATIONAL MEDICINAL PRODUCTS The IMPs on this trial are Carboplatin, Cisplatin, Ifosfamide and Etoposide (as approved by German competent authority). PRIMARY OBJECTIVES: Germinoma To maintain current high event-free survival (EFS) rates using a risk adapted approach In localised germinoma: to omit whole brain and spinal irradiation by using combined treatment with standard chemotherapy and ventricular irradiation (+/- boosts) In bifocal tumours (pineal + suprasellar): to treat as non-metastatic disease and to omit whole brain and spinal irradiation by using combined treatment with standard chemotherapy and ventricular irradiation (+/- boosts) In metastatic disease: to maintain current excellent EFS in metastatic germinoma with craniospinal irradiation Malignant non-germinoma To improve EFS: by dose escalation of chemotherapy in patients identified as high risk at diagnosis ( age < 6 years and/or AFP serum / CSF > 1000 ng/ml) by standardising the surgical approach for residual disease after treatment Teratoma To register patients and collect data regarding diagnostics, treatment and outcome in order to develop future treatment strategies SECONDARY OBJECTIVES: Germinoma To minimise long term effects of irradiation by sparing spinal and whole brain radiotherapy in non-metastatic disease Malignant non-germinoma In standard risk to maintain EFS with chemotherapy and local irradiation Teratoma To evaluate the influence of surgery and treatment on outcome to assist in the development of a fu-ture treatment strategy For all histological subtypes To improve accuracy of diagnosis and staging in all registered patients To standardise neurosurgical intervention For all patients requiring biopsy or resection according to protocol guidelines, to collect and to store tumour material, and CSF where possible, for use in future biological studies. ENDPOINTS / Criteria for evaluation: Main end point Event-free survival, defined as minimum time from the date of diagnosis to: Death from any cause Relapse Progressive disease on therapy Or second malignancy Secondary end points Overall survival, defined as time to death from any cause, measured from the date of diagnosis Short and long term toxicity.

Detailed Description
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PATIENT POPULATION Age of patients: no lower or upper age limit; Estimated number: 400 malignant germ cell tumours Diagnosis and main criteria for inclusion/exclusion: Intracranial Germ Cell tumours of any histology and intracranial site and dissemination Inclusion criteria Main residence in one of the participating countries Primary diagnosis of an intracranial germ cell tumour Written consent for trial participation, treatment according to the protocol and consent for data trans-fer Exclusion criteria: Tumour entity other than primary intracranial germ cell tumour or CNS GCT as second malignancy Primary diagnosis pre-dating the opening of SIOP CNS GCT II in the participating country of registration Medical, psychiatric or social conditions incompatible with trial treatment or treatment according to protocol is not intended Participation within a different trial for treatment of germ cell tumours and/or concurrent treatment within any other clinical trial. The only exceptions to this are trials with different endpoints, involving aspects of supportive treatment which can run parallel to SIOP CNS GCT II without influencing the outcome of this trial e.g. trials on antiemetics, antimycotics, antibiotics, strategies for psychosocial support etc. Pregnancy and lactation Any treatment not given according to protocol prior to registration TREATMENT: GERMINOMA Chemotherapy: Non-metastatic fully staged germinoma (± teratoma) Two courses (1 and 3) of Etoposide and Carboplatin, alternating with two courses (2 and 4) of Etoposide and Ifosfamide Note: Bifocal germinoma (pineal+suprasellar) are treated as non-metastatic germinoma, if stag-ing shows no additional dissemination Metastatic or incompletely staged germinomas (± teratoma) Do not receive chemotherapy in this protocol Radiotherapy: Non-metastatic pure germinoma in PR/SD After Chemotherapy: 24 Gy (15 fractions) to whole ventricles with a 16 Gy (10 fraction) boost to tumour bed (total tumour dose 40 Gy) Non-metastatic germinoma in CR After Chemotherapy: 24 Gy (15 fractions) to whole ventricles Metastatic or incompletely staged pure germinoma 24 Gy (15 fractions) to craniospinal axis with a 16 Gy (10 fraction) boost to tumour bed and any intracranial metastases and spinal deposits (total tumour dose 40 Gy) Non-metastatic germinoma plus teratoma (incompletely resected) After Chemotherapy: 24 Gy (15 fractions) to whole ventricles; 30.4 Gy (19 fraction) boost to tumour bed (total tumour dose 54.4 Gy) Metastatic germinoma plus teratoma (incompletely resected) 24 Gy (15 fractions) to craniospinal axis ; 30.4 Gy (19 fraction) boost to tumour bed and 16 Gy (10 frac-tion) boost to metastases (total tumour dose 54.4 Gy) NON-GERMINOMA (± TERATOMA) Chemotherapy: Standard risk non-germinomatous malignant GCT Four courses of Etoposide, Cisplatin and Ifosfamide (standard treatment ) High risk non-germinomatous malignant GCT Two courses of standard Etoposide, Cisplatin and Ifosfamide, followed by two dose intensified courses of Etoposide, Cisplatin and Ifosfamide with stem cell support Resection of residual tumour after 3 courses chemotherapy (if indicated), followed by: 4th course. If vi-able cells are found in the resected tumour specimen patient is transferred to the high risk arm Radiotherapy for standard and high risk non-germinomatous malignant GCT: Patients with localised disease at diagnosis After Chemotherapy: 54 Gy focal radiotherapy in 30 fractions Patients with metastatic disease at diagnosis After Chemotherapy: 30 Gy (20 fractions) to craniospinal axis with 24 Gy (15 fraction) boosts to tumour site and any intracranial metastases (total tumour dose 54 Gy) and 20.8 Gy (13 fraction) boosts to spinal deposits (total dose 50.8 Gy) SPECIAL ASPECTS: Central response evaluation on a national basis: Germinoma: In all patients with localised germinoma a central national radiological review is mandatory for response evaluation to chemotherapy and decision if only ventricular irradiation or an additional tu-mour boost has to be performed. Non-Germinoma: After three courses of chemotherapy to evaluate response to treatment and to deter-mine necessity of surgery in case of residual before radiotherapy.

Official Title
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SIOP CNS GCT II: Prospective Trial for the Diagnosis and Treatment of Children, Adolescents and Young Adults With Intracranial Germ Cell Tumors

Conditions
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Intracranial Germ Cell Tumors

Intervention / Treatment
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* Radiation: craniospinal irradiation
* Drug: Carboplatin, Etoposide, Ifosfamide
* Radiation: ventricular irradiation
* Drug: Cisplatin, etoposide, Ifosfamide (standard)
* Drug: Cisplatin, Etoposide, Ifosfamide (high dose)
* Radiation: focal irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Main residence in one of the participating countries Primary diagnosis of an intracranial germ cell tumour Written consent for trial participation, treatment according to the protocol and consent for data transfer Exclusion Criteria: Tumour entity other than primary intracranial germ cell tumour or CNS GCT as second malignancy Primary diagnosis pre-dating the opening of SIOP CNS GCT II in the participating country of registration Medical, psychiatric or social conditions incompatible with trial treatment or treatment according to protocol is not intended Participation within a different trial for treatment of germ cell tumours and/or concurrent treatment within any other clinical trial. The only exceptions to this are trials with different endpoints, involving aspects of supportive treatment which can run parallel to SIOP CNS GCT II without influencing the outcome of this trial e.g. trials on antiemetics, antimycotics, antibiotics, strategies for psychosocial support etc. Pregnancy and lactation Any treatment not given according to protocol prior to registration
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Germinoma metastatic<br>• Metastatic or incompletely staged germinomas (± teratoma) Do not receive chemotherapy in this protocol Radiotherapy Metastatic or incompletely staged pure germinoma 24 Gy (15 fractions) to craniospinal axis with a 16 Gy (10 fraction) boost to tumour bed and any intracranial metastases and spinal deposits (total tumour dose 40 Gy) Metastatic germinoma plus teratoma (incompletely resected) 24 Gy (15 fractions) to craniospinal axis ; 30.4 Gy (19 fraction) boost to tumour bed and 16 Gy (10 frac-tion) boost to metastases (total tumour dose 54.4 Gy) | Radiation: craniospinal irradiation<br>* Metastatic or incompletely staged pure germinoma 24 Gy (15 fractions) to craniospinal axis with a 16 Gy (10 fraction) boost to tumour bed and any intracra-nial metastases and spinal deposits (total tumour dose 40 Gy) Metastatic germinoma plus teratoma (incompletely resected) 24 Gy (15 fractions) to craniospinal axis ; 30.4 Gy (19 fraction) boost to tumour bed and 16 Gy (10 frac-tion) boost to metastases (total tumour dose 54.4 Gy) Patients with metastastic non-germinomatous disease at diagnosis After Chemotherapy: 30 Gy (20 fractions) to cranio-spinal axis with 24 Gy (15 fraction) boosts to tumour site and any intracranial metastases (total tumour dose 54 Gy) and 20.8 Gy (13 fraction) boosts to spinal deposits (total dose 50.8 Gy)<br>|
| Other: germinoma non-metastatic<br>Chemotherapy: • Non-metastatic fully staged germinoma (± teratoma) Two courses (1 and 3) of Etoposide and Carboplatin, alternating with two courses (2 and 4) of Etoposide and Ifosfamide Note: Bifocal germinoma (pineal+suprasellar) are treated as non-metastatic germinoma, if staging shows no additional dissemination Radiotherapy Non-metastatic pure germinoma in PR/SD After Chemotherapy: 24 Gy (15 fractions) to whole ventricles with a 16 Gy (10 fraction) boost to tumour bed (total tumour dose 40 Gy) Non-metastatic germinoma in CR After Chemotherapy: 24 Gy (15 fractions) to whole ventricles Non-metastatic germinoma plus teratoma (incompletely resected) After Chemotherapy: 24 Gy (15 fractions) to whole ventricles; 30.4 Gy (19 fraction) boost to tumour bed (total tumour dose 54.4 Gy) | Drug: Carboplatin, Etoposide, Ifosfamide<br>* • Non-metastatic fully staged germinoma (± teratoma) Two courses (1 and 3) of Etoposide and Carboplatin, alternating with two courses (2 and 4) of Etoposide and Ifosfamide<br>Radiation: ventricular irradiation<br>* Non-metastatic pure germinoma in PR/SD After Chemotherapy: 24 Gy (15 fractions) to whole ventricles with a 16 Gy (10 fraction) boost to tumour bed (total tumour dose 40 Gy) Non-metastatic germinoma in CR After Chemotherapy: 24 Gy (15 fractions) to whole ventricles Non-metastatic germinoma plus teratoma (incompletely resected) After Chemotherapy: 24 Gy (15 fractions) to whole ventricles; 30.4 Gy (19 fraction) boost to tumour bed (total tumour dose 54.4 Gy)<br>|
| Other: Non-germinoma non-metastatic standard risk<br>Chemotherapy: • Standard risk non-germinomatous malignant GCT Four courses of Etoposide, Cisplatin and Ifosfamide (standard treatment ) After Chemotherapy: 54 Gy focal radiotherapy in 30 fractions | Drug: Cisplatin, etoposide, Ifosfamide (standard)<br>* Four courses of Etoposide, Cisplatin and Ifosfamide (standard treatment )<br>Radiation: focal irradiation<br>* • Patients with localised non-germinomatous disease at diagnosis After Chemotherapy: 54 Gy focal radiotherapy in 30 fractions<br>|
| Other: Non-Germinoma metastatic standard risk<br>Chemotherapy Four courses of Etoposide, Cisplatin and Ifosfamide (standard treatment ) Radiotherapy After Chemotherapy: 30 Gy (20 fractions) to craniospinal axis with 24 Gy (15 fraction) boosts to tumour site and any intracranial metastases (total tumour dose 54 Gy) and 20.8 Gy (13 fraction) boosts to spinal deposits (total dose 50.8 Gy) | Radiation: craniospinal irradiation<br>* Metastatic or incompletely staged pure germinoma 24 Gy (15 fractions) to craniospinal axis with a 16 Gy (10 fraction) boost to tumour bed and any intracra-nial metastases and spinal deposits (total tumour dose 40 Gy) Metastatic germinoma plus teratoma (incompletely resected) 24 Gy (15 fractions) to craniospinal axis ; 30.4 Gy (19 fraction) boost to tumour bed and 16 Gy (10 frac-tion) boost to metastases (total tumour dose 54.4 Gy) Patients with metastastic non-germinomatous disease at diagnosis After Chemotherapy: 30 Gy (20 fractions) to cranio-spinal axis with 24 Gy (15 fraction) boosts to tumour site and any intracranial metastases (total tumour dose 54 Gy) and 20.8 Gy (13 fraction) boosts to spinal deposits (total dose 50.8 Gy)<br>Drug: Cisplatin, etoposide, Ifosfamide (standard)<br>* Four courses of Etoposide, Cisplatin and Ifosfamide (standard treatment )<br>|
| Other: Non-germinoma non-metastatic high risk<br>Chemotherapy Two courses of standard Etoposide, Cisplatin and Ifosfamide, followed by two dose intensified courses of Etoposide, Cisplatin and Ifosfamide with stem cell support Radiotherapy After Chemotherapy: 54 Gy focal radiotherapy in 30 fractions | Drug: Cisplatin, Etoposide, Ifosfamide (high dose)<br>* Two courses of standard Etoposide, Cisplatin and Ifosfamide, followed by two dose intensified courses of Etoposide, Cisplatin and Ifosfamide with stem cell support<br>Radiation: focal irradiation<br>* • Patients with localised non-germinomatous disease at diagnosis After Chemotherapy: 54 Gy focal radiotherapy in 30 fractions<br>|
| Other: Non-Germinoma metastatic high risk<br>Chemotherapy Two courses of standard Etoposide, Cisplatin and Ifosfamide, followed by two dose intensified courses of Etoposide, Cisplatin and Ifosfamide with stem cell support Radiotherapy After Chemotherapy: 30 Gy (20 fractions) to craniospinal axis with 24 Gy (15 fraction) boosts to tumour site and any intracranial metastases (total tumour dose 54 Gy) and 20.8 Gy (13 fraction) boosts to spinal deposits (total dose 50.8 Gy) | Radiation: craniospinal irradiation<br>* Metastatic or incompletely staged pure germinoma 24 Gy (15 fractions) to craniospinal axis with a 16 Gy (10 fraction) boost to tumour bed and any intracra-nial metastases and spinal deposits (total tumour dose 40 Gy) Metastatic germinoma plus teratoma (incompletely resected) 24 Gy (15 fractions) to craniospinal axis ; 30.4 Gy (19 fraction) boost to tumour bed and 16 Gy (10 frac-tion) boost to metastases (total tumour dose 54.4 Gy) Patients with metastastic non-germinomatous disease at diagnosis After Chemotherapy: 30 Gy (20 fractions) to cranio-spinal axis with 24 Gy (15 fraction) boosts to tumour site and any intracranial metastases (total tumour dose 54 Gy) and 20.8 Gy (13 fraction) boosts to spinal deposits (total dose 50.8 Gy)<br>Drug: Cisplatin, Etoposide, Ifosfamide (high dose)<br>* Two courses of standard Etoposide, Cisplatin and Ifosfamide, followed by two dose intensified courses of Etoposide, Cisplatin and Ifosfamide with stem cell support<br>|
| No Intervention: Teratoma<br>collection of information on surgery, applied treatment and outcome | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival | Survival rates in respect to applied treatment , according to Kaplan-Meier estimation , 5 years event free survival | 5 years event free survival | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| short and long term toxicity | toxicity of treatment will be assessed with CTC criteria, severe toxicity will be analysed by safety desk | until 7 years after start of trial | 
| overall survival | Overall survival will be measured by Kaplan -Meier Estimation , 5 years overall survival | 7 years after start of trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SIOP CNS GCT II, Patients with the primary disease of an Intracranial Germ Cell Tumors