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

Phase 2

Completed

• Conditions: Medulloblastomas; Ependymomas; Supratentorial PNETs; Recurrent Brain Tumors
• Interventions: Drug: temozolomide; Drug: carboplatin; Drug: temozolomide, thiotepa; Drug: etoposide; Drug: thiotepa, carboplatin, etoposide; Procedure: autologous stem cell transplantation; Drug: intraventricular etoposide; Drug: trofosfamide, etoposide

• Registration Number: NCT00749723
• Lead Sponsor: University Hospital, Bonn

Brief Summary

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

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)

Study Timeline

• Study Start: 2006-02-01
• Study First Submitted: 2008-09-05
• Study First Submitted QC: 2008-09-05
• Study First Posted: 2008-09-09
• Primary Completion: 2015-01-31
• Study Completion: 2016-01-31
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-18
• Last Update Posted: 2018-07-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 174

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
1: P-HIT-REZ 2005	thiotepa, carboplatin, etoposide	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
1: P-HIT-REZ 2005	autologous stem cell transplantation	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
1: P-HIT-REZ 2005	intraventricular etoposide	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
2: P-HIT-REZ 2005	temozolomide, thiotepa	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
2: P-HIT-REZ 2005	autologous stem cell transplantation	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
2: P-HIT-REZ 2005	intraventricular etoposide	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
3: E-HIT-REZ 2005	temozolomide	Phase II: oral chemotherapy with temozolomide after progression oral trofosfamide, etoposide
3: E-HIT-REZ 2005	intraventricular etoposide	Phase II: oral chemotherapy with temozolomide after progression oral trofosfamide, etoposide
Intraventricular Etoposide	intraventricular etoposide	Phase II, intraventricular chemotherapy with etoposide
1: P-HIT-REZ 2005	trofosfamide, etoposide	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
3: E-HIT-REZ 2005	trofosfamide, etoposide	Phase II: oral chemotherapy with temozolomide after progression oral trofosfamide, etoposide
1: P-HIT-REZ 2005	carboplatin	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
1: P-HIT-REZ 2005	etoposide	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
2: P-HIT-REZ 2005	temozolomide	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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (54)

Universitätskinderklinik Aachen; 🇩🇪 Aachen, Germany

Klinikum Augsburg, Klinik für Kinder- und Jugendmedizin; 🇩🇪 Augsburg, Germany

Helios Klinikum Berlin-Buch, Klinik für Kinderheilkunde und Jugendmedizin; 🇩🇪 Berlin, Germany

Charité Klinikum Campus Virchow, Kinderklinik; 🇩🇪 Berlin, Germany

Klinik ür Kinder- und Jugendmedizin in Bethel; 🇩🇪 Bielefeld, Germany

Universitätskinderklinik Bonn; 🇩🇪 Bonn, Germany

Städtisches Klinikum Braunschweig, Kinderklinik; 🇩🇪 Braunschweig, Germany

Klinikum Bremen-Mitte; 🇩🇪 Bremen, Germany

Carl-Thiele-Klinikum Cottbus, Zentrum für Kinderheilkunde; 🇩🇪 Cottbus, Germany

Vestische Kinder- und Jugendklinik Datteln; 🇩🇪 Datteln, Germany

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