Therapy Optimization Trial for the Treatment of Relapsed or Refractory Brain Tumors in Children (HIT-REZ-2005)

July 18, 2018 updated by: Gudrun Fleischhack, University Hospital, Bonn

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

174

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Aachen, Germany, 52074
        • Universitätskinderklinik Aachen
      • Augsburg, Germany, 86156
        • Klinikum Augsburg, Klinik für Kinder- und Jugendmedizin
      • Berlin, Germany, 13125
        • Helios Klinikum Berlin-Buch, Klinik für Kinderheilkunde und Jugendmedizin
      • Berlin, Germany, 13353
        • Charité Klinikum Campus Virchow, Kinderklinik
      • Bielefeld, Germany, 33617
        • Klinik ür Kinder- und Jugendmedizin in Bethel
      • Bonn, Germany, 53113
        • Universitätskinderklinik Bonn
      • Braunschweig, Germany, 38118
        • Städtisches Klinikum Braunschweig, Kinderklinik
      • Bremen, Germany, 28177
        • Klinikum Bremen-Mitte
      • Cottbus, Germany, 03048
        • Carl-Thiele-Klinikum Cottbus, Zentrum für Kinderheilkunde
      • Datteln, Germany, 45711
        • Vestische Kinder- und Jugendklinik Datteln
      • Dortmund, Germany, 44137
        • Klinikum Dortmund, Klinik für Kinder- und Jugendmedizin
      • Dresden, Germany, 01307
        • Universitätsklinikum Dresden, Kinderklinik
      • Duisburg, Germany, 47055
        • Klinikum Duisburg, Klinik für Kinder-und Jugendmedizin
      • Düsseldorf, Germany, 40225
        • Universitätskinderklinik Düsseldorf
      • Erfurt, Germany, 99089
        • Helios Klinikum Erfurt, Zentrum für Kinderheilkunde
      • Erlangen, Germany, 91054
        • Universitätskinderklinik Erlangen
      • Essen, Germany, 45122
        • Universitätskinderklinik Essen
      • Frankfurt/Main, Germany, 60590
        • Klinikum der Wolfgang Goethe Universität, Klinik für Kinderheilkunde
      • Freiburg, Germany, 79106
        • Universitätskinderklinik Freiburg
      • Gießen, Germany, 35385
        • Universitätsklinikum Gießen und Marburg, Zentrum für Kinderheilkunde
      • Greifswald, Germany, 17475
        • Universitätskinderklinik Greifswald
      • Göttingen, Germany, 37075
        • Universitätskinderklinik Göttingen
      • Halle/Saale, Germany, 06120
        • Martin-Luther-Universität Halle Wittenberg
      • Hamburg, Germany, 20246
        • Universitätskinderklinik Hamburg-Eppendorf
      • Hannover, Germany, 30625
        • Medizinische Hochschule, Zentrum für Kinderheilkunde
      • Heidelberg, Germany, 69120
        • Universitätskinderklinik Heidelberg
      • Heilbronn, Germany, 74078
        • SLK Kinderklinik Heilbronn
      • Herdecke, Germany, 58313
        • Gemeinschaftskrankenhaus Herdecke, Kinderklinik
      • Homburg/Saar, Germany, 66421
        • Universitätskinderklinik
      • Jena, Germany, 07745
        • Friedrich Schiller Universität, Klinik für Kinder-und Jugendmedizin
      • Karlsruhe, Germany, 76133
        • Städtisches Krankenhaus, Klinik für Kinder- und Jugendmedizin
      • Kassel, Germany, 34125
        • Klinikum Kassel, Kinderklinik
      • Kiel, Germany, 24105
        • UKSH, Campus Kiel, Klinik für Allg. Pädiatrie
      • Koblenz, Germany, 56073
        • Städtisches Klinikum Kemperhof, Klinik für Kinder- und Jugendmedizin
      • Köln, Germany, 50924
        • Universitätskinderklinik Köln
      • Leipzig, Germany, 04317
        • Universitätskinderklinik Leipzig
      • Lübeck, Germany, 23538
        • Universitätskinderklinik Lübeck
      • Magdeburg, Germany, 39120
        • Otto-von-Guericke-Universität, Zentrum für Kinderheilkunde
      • Mainz, Germany, 55131
        • Universitätskinderklinik Mainz
      • Mannheim, Germany, 68167
        • Universitätskinderklinik Mannheim
      • Marburg, Germany, 35043
        • Universitätskinderklinik Marburg
      • Minden, Germany, 32432
        • Klinikum Minden III, Klinik für Kinder-und Jugendheilkunde
      • München, Germany, 80337
        • Dr. von Haunersches Kinderspital
      • München, Germany, 80804
        • Städtisches Krankenhaus München-Schwabing, Kinderklinik der TU München
      • Münster, Germany, 48129
        • Universitätskinderklinik Münster
      • Nürnberg, Germany, 90419
        • Cnopf'sche Kinderklinik
      • Oldenburg, Germany, 26131
        • Klinikum Oldenburg, Zentrum für Kinder-und Jugendmedizin
      • Regensburg, Germany, 93042
        • Universitäts-Kinderklinik
      • Rostock, Germany, 18057
        • Universitätskinderklinik Rostock
      • Sankt Augustin, Germany, 53757
        • Asklepios Klinik Sankt Augustin GmbH
      • Stuttgart, Germany, 70176
        • Olgahospital-Pädiatrisches Zentrum
      • Tübingen, Germany, 72076
        • Universitätskinderklinik Tübingen
      • Ulm, Germany, 89075
        • Univeritätsklinikum Ulm, Abteilung Kinder-und Jugendmedizin
      • Würzburg, Germany, 97080
        • Universitätskinderklinik Würzburg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 26 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1: P-HIT-REZ 2005

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
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
Other Names:
  • Carboplatin IV
Drug: etoposide
100mg/m²/d continuously IV on day 1-4 of each 21-28 day cycle. Number of cycles: until disease progression, maximum 4 cycles
Other Names:
  • etoposide IV
Drug: thiotepa, carboplatin, etoposide
high dose chemotherapy followed by to autologous stem cell transplantation
Other Names:
  • thiotepa, carboplatin, etoposide IV, high dose
Procedure: autologous stem cell transplantation
autologous stem cell transplantation following HD-chemotherapy
Other Names:
  • ASCT
Drug: intraventricular etoposide
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
Other Names:
  • etoposide intra-CSF
Drug: trofosfamide, etoposide
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
Other Names:
  • trofosfamide, etoposide orally
Experimental: 2: P-HIT-REZ 2005

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
Procedure: autologous stem cell transplantation
autologous stem cell transplantation following HD-chemotherapy
Other Names:
  • ASCT
Drug: intraventricular etoposide
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
Other Names:
  • etoposide intra-CSF
Drug: temozolomide
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
Other Names:
  • temozolomide orally
Drug: temozolomide, thiotepa
high dose chemotherapy followed by autologous stem cell transplantation
Other Names:
  • temozolomide, thiotepa IV
Experimental: 3: E-HIT-REZ 2005
Phase II: oral chemotherapy with temozolomide after progression oral trofosfamide, etoposide
Drug: intraventricular etoposide
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
Other Names:
  • etoposide intra-CSF
Drug: trofosfamide, etoposide
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
Other Names:
  • trofosfamide, etoposide orally
Drug: temozolomide
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
Other Names:
  • temozolomide orally
Experimental: Intraventricular Etoposide
Phase II, intraventricular chemotherapy with etoposide
Drug: intraventricular etoposide
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
Other Names:
  • etoposide intra-CSF

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
P-HIT-REZ 2005 study: two Chemotherapy-arms: response evaluation after the fourth therapy course
Time Frame: 4 months for each patient (8 years for the whole study population)
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
Time Frame: 2 months for each patient (8 years for the whole study population)
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
Time Frame: 6 weeks for each patient (8 years for the whole study population)
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
Time Frame: 10 years
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
Time Frame: 8 years
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
Time Frame: 10 years
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)
Time Frame: 10 years
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)
Time Frame: 8 years
rate of adverse events of CTC°1-4 according to CTCAE v3.0
8 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Bonn

Investigators

  • Principal Investigator: Gudrun Fleischhack, MD, Department of Pediatric Hematology & Oncology, Pediatrics III, University Children's Hospital Essen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2006

Primary Completion (Actual)

January 31, 2015

Study Completion (Actual)

January 31, 2016

Study Registration Dates

First Submitted

September 5, 2008

First Submitted That Met QC Criteria

September 5, 2008

First Posted (Estimate)

September 9, 2008

Study Record Updates

Last Update Posted (Actual)

July 20, 2018

Last Update Submitted That Met QC Criteria

July 18, 2018

Last Verified

July 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EUDRACT 2005-002618-40
  • BfArM-4030755 (Other Identifier: Federal Institute for Drugs and Medical Devices (BfArM))
  • EC-105/05 (Other Identifier: Leading Ethic Committee University Hospital of Bonn)
  • DKS 2006.01, 2008.17, 2012.03 (Other Grant/Funding Number: German Children Cancer Foundation)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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