Therapy Optimization Trial for the Treatment of Relapsed or Refractory Brain Tumors in Children

Study Overview
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Brief Summary
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The purpose of this study is to improve overall survival while maintaining a good quality of life in pediatric patients with refractory or recurrent brain tumors (medulloblastomas, supratentorial PNETs, ependymomas WHO grade II and III). Response to different chemotherapy options (intravenous versus oral chemotherapy, intraventricular chemotherapy) as part of a multimodal therapy will be assessed. Progression-free, overall survival and toxicity will be evaluated additionally.

Detailed Description
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Parts of the study: P-HIT-REZ-2005: a trial for the treatment of relapsed PNETs (medulloblastomas,supratentorial PNETs) E-HIT-REZ-2005: a trial for the treatment of relapsed ependymomas (Phase II-Study with temozolomide) Phase II-Study: intraventricular therapy with etoposide in neoplastic meningitis in relapsed PNETs and ependymomas with subarachnoid tumor manifestation (window study)

Official Title
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Therapy-Optimization Trial and Phase II Study for the Treatment of Relapsed or Refractory of Primitive Neuroectodermal Brain Tumors and Ependymomas in Children and Adolescents

Conditions
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Recurrent Brain Tumors, Supratentorial PNETs, Medulloblastomas, Ependymomas

Intervention / Treatment
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* Drug: carboplatin
* Drug: etoposide
* Drug: temozolomide
* Drug: thiotepa, carboplatin, etoposide
* Drug: temozolomide, thiotepa
* Procedure: autologous stem cell transplantation
* Drug: intraventricular etoposide
* Drug: trofosfamide, etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Characteristics Histologically confirmed Medulloblastoma, cerebral PNET or Ependymoma Refractory or relapsed disease Measurable disease by MRI or detection of tumor cells in cerebrospinal fluid Patients characteristics Performance status ECOG ≥ 3 or Karnofsky Status ≥ 40% Life expectancy ≥ 8 weeks Hematological: Absolute leukocyte count ≥ 2.0 x 10^9 /l Hemoglobin ≥ 10g/dl Platelet count ≥ 70 x 10^9/l Renal: Creatinine no greater than 1.5 times UNL No overt renal disease Hepatic: Bilirubin less than 2.5 times UNL AST and ALT less than 5 times UNL No overt hepatic disease Pulmonary: No overt pulmonary disease Cardiovascular: No overt cardiovascular disease Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No uncontrolled infection Prior concurrent therapy More than 2 weeks since prior systemic chemotherapy More than 4 weeks since prior radiotherapy No other concurrent anticancer or experimental drugs Examinations required Examination of lumbar CSF Cranial and spinal MRI within 14 days prior to start of treatment

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 30 Years

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1: P-HIT-REZ 2005<br>intravenous chemotherapy with carboplatin/etoposide,followed by high dose chemotherapy with thiotepa, carboplatin, etoposide and autologous stem cell transplantation if patient have achieved a complete remission or maintenance therapy with oral trofosfamide, etoposide | Drug: carboplatin<br>* 200 mg/m²/d continuously IV on day 1-4 of each 21-28-day-cycle. Number of cycles: until disease progression, maximum 4 cycles<br>* Other names: Carboplatin IV;Drug: etoposide<br>* 100mg/m²/d continuously IV on day 1-4 of each 21-28 day cycle. Number of cycles: until disease progression, maximum 4 cycles<br>* Other names: etoposide IV;Drug: thiotepa, carboplatin, etoposide<br>* high dose chemotherapy followed by to autologous stem cell transplantation<br>* Other names: thiotepa, carboplatin, etoposide IV, high dose;Procedure: autologous stem cell transplantation<br>* autologous stem cell transplantation following HD-chemotherapy<br>* Other names: ASCT;Drug: intraventricular etoposide<br>* prior to systemic chemotherapy as single agent in patients with neoplastic meningitis, in addition to systemic chemotherapy if proven effective in phase II study, intraventricularly age-dependent daily dose (>3m to <3y 0.7 mg; >3y 1.0 mg) for 5 days every 2 two 4 weeks. Number of cycles: at least 3 courses, maximum up to 2 years<br>* Other names: etoposide intra-CSF;Drug: trofosfamide, etoposide<br>* maintenance therapy: trofosfamide and etoposide: 100 mg/m²/d and 25 mg/m²/d, respectively, for 21 days every 4 weeks. Number of cycles: until progression or maximum up to 2 years<br>* Other names: trofosfamide, etoposide orally;|
| Experimental: 2: P-HIT-REZ 2005<br>oral chemotherapy with temozolomide, followed by high dose chemotherapy with temozolomide, thiotepa and autologous stem cell transplantation if patient have achieved a complete remission maintenance therapy with oral temozolomide or in case of progression with oral trofosfamide, etoposide | Drug: temozolomide<br>* 150mg/m²/d p.o. on day 1-5 of a 21-28-day-cycle. Number of cycles: until progression or maximum up to 2 years<br>* Other names: temozolomide orally;Drug: temozolomide, thiotepa<br>* high dose chemotherapy followed by autologous stem cell transplantation<br>* Other names: temozolomide, thiotepa IV;Procedure: autologous stem cell transplantation<br>* autologous stem cell transplantation following HD-chemotherapy<br>* Other names: ASCT;Drug: intraventricular etoposide<br>* prior to systemic chemotherapy as single agent in patients with neoplastic meningitis, in addition to systemic chemotherapy if proven effective in phase II study, intraventricularly age-dependent daily dose (>3m to <3y 0.7 mg; >3y 1.0 mg) for 5 days every 2 two 4 weeks. Number of cycles: at least 3 courses, maximum up to 2 years<br>* Other names: etoposide intra-CSF;|
| Experimental: 3: E-HIT-REZ 2005<br>Phase II: oral chemotherapy with temozolomide after progression oral trofosfamide, etoposide | Drug: temozolomide<br>* 150mg/m²/d p.o. on day 1-5 of a 21-28-day-cycle. Number of cycles: until progression or maximum up to 2 years<br>* Other names: temozolomide orally;Drug: intraventricular etoposide<br>* prior to systemic chemotherapy as single agent in patients with neoplastic meningitis, in addition to systemic chemotherapy if proven effective in phase II study, intraventricularly age-dependent daily dose (>3m to <3y 0.7 mg; >3y 1.0 mg) for 5 days every 2 two 4 weeks. Number of cycles: at least 3 courses, maximum up to 2 years<br>* Other names: etoposide intra-CSF;Drug: trofosfamide, etoposide<br>* maintenance therapy: trofosfamide and etoposide: 100 mg/m²/d and 25 mg/m²/d, respectively, for 21 days every 4 weeks. Number of cycles: until progression or maximum up to 2 years<br>* Other names: trofosfamide, etoposide orally;|
| Experimental: Intraventricular Etoposide<br>Phase II, intraventricular chemotherapy with etoposide | Drug: intraventricular etoposide<br>* prior to systemic chemotherapy as single agent in patients with neoplastic meningitis, in addition to systemic chemotherapy if proven effective in phase II study, intraventricularly age-dependent daily dose (>3m to <3y 0.7 mg; >3y 1.0 mg) for 5 days every 2 two 4 weeks. Number of cycles: at least 3 courses, maximum up to 2 years<br>* Other names: etoposide intra-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P-HIT-REZ 2005 study: two Chemotherapy-arms: response evaluation after the fourth therapy course | determination of objective repsonse rate (CR+PR) | 4 months for each patient (8 years for the whole study population) | 
| E-HIT-REZ 2005 study (Phase II Study Oral chemotherapy with temozolomide): Evaluation of response rate to the 60-days oral chemotherapy with temozolomide | determination of objective repsonse rate (CR+PR/all patients) | 2 months for each patient (8 years for the whole study population) | 
| Phase II study Intraventricular therapy with etoposide: Evaluation of response rate to the 5-week intraventricular therapy with etoposide | disease stabilization rate (CR+PR+SD/all patients) | 6 weeks for each patient (8 years for the whole study population) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P-HIT-REZ 2005 study: two Chemotherapy-arms: PFS and OS from start of therapy | progression free and overall survival from start of therapy until PD, last follow up or death, respectively | 10 years | 
| P-HIT-REZ 2005 study: two Chemotherapy-arms: toxicity rate (CTC) in both arms | rate of adverse events of CTC°3 or CTC°4 according to CTCAE v3.0 | 8 years | 
| E-HIT-REZ 2005 study: Chemotherapy-arm: PFS and OS from start of therapy | progression free and overall survival from start of therapy until PD, last follow up or death, respectively | 10 years | 
| E-HIT-REZ 2005 study: Chemotherapy-arm: toxicity rate (CTC) | progression free and overall survival from start of therapy until PD, last follow up or death, respectively | 10 years | 
| Phase II study Intraventricular therapy with etoposide: toxicity rate (CTC) | rate of adverse events of CTC°1-4 according to CTCAE v3.0 | 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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brain tumor, relapse, children, etoposide, intraventricular, temozolomide