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

Sponsor
University Hospital, Bonn (Other)
Overall Status
Completed
CT.gov ID
NCT00749723
Collaborator
(none)
174
Enrollment
54
Locations
4
Arms
120
Duration (Months)
3.2
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

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 Design

Study Type:
Interventional
Actual Enrollment :
174 participants
Allocation:
Non-Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Study Start Date :
Feb 1, 2006
Actual Primary Completion Date :
Jan 31, 2015
Actual Study Completion Date :
Jan 31, 2016

Arms and Interventions

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

    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

    • 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

    		•
    Experimental: 3: E-HIT-REZ 2005

    Phase II: oral chemotherapy with temozolomide after progression oral trofosfamide, etoposide

    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: 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: 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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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)

    2. 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)

    3. 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

    1. 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

    2. 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

    3. 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

    4. 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

    5. 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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    3 Months to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Universitätskinderklinik Aachen Aachen Germany 52074
    2 Klinikum Augsburg, Klinik für Kinder- und Jugendmedizin Augsburg Germany 86156
    3 Helios Klinikum Berlin-Buch, Klinik für Kinderheilkunde und Jugendmedizin Berlin Germany 13125
    4 Charité Klinikum Campus Virchow, Kinderklinik Berlin Germany 13353
    5 Klinik ür Kinder- und Jugendmedizin in Bethel Bielefeld Germany 33617
    6 Universitätskinderklinik Bonn Bonn Germany 53113
    7 Städtisches Klinikum Braunschweig, Kinderklinik Braunschweig Germany 38118
    8 Klinikum Bremen-Mitte Bremen Germany 28177
    9 Carl-Thiele-Klinikum Cottbus, Zentrum für Kinderheilkunde Cottbus Germany 03048
    10 Vestische Kinder- und Jugendklinik Datteln Datteln Germany 45711
    11 Klinikum Dortmund, Klinik für Kinder- und Jugendmedizin Dortmund Germany 44137
    12 Universitätsklinikum Dresden, Kinderklinik Dresden Germany 01307
    13 Klinikum Duisburg, Klinik für Kinder-und Jugendmedizin Duisburg Germany 47055
    14 Universitätskinderklinik Düsseldorf Düsseldorf Germany 40225
    15 Helios Klinikum Erfurt, Zentrum für Kinderheilkunde Erfurt Germany 99089
    16 Universitätskinderklinik Erlangen Erlangen Germany 91054
    17 Universitätskinderklinik Essen Essen Germany 45122
    18 Klinikum der Wolfgang Goethe Universität, Klinik für Kinderheilkunde Frankfurt/Main Germany 60590
    19 Universitätskinderklinik Freiburg Freiburg Germany 79106
    20 Universitätsklinikum Gießen und Marburg, Zentrum für Kinderheilkunde Gießen Germany 35385
    21 Universitätskinderklinik Greifswald Greifswald Germany 17475
    22 Universitätskinderklinik Göttingen Göttingen Germany 37075
    23 Martin-Luther-Universität Halle Wittenberg Halle/Saale Germany 06120
    24 Universitätskinderklinik Hamburg-Eppendorf Hamburg Germany 20246
    25 Medizinische Hochschule, Zentrum für Kinderheilkunde Hannover Germany 30625
    26 Universitätskinderklinik Heidelberg Heidelberg Germany 69120
    27 SLK Kinderklinik Heilbronn Heilbronn Germany 74078
    28 Gemeinschaftskrankenhaus Herdecke, Kinderklinik Herdecke Germany 58313
    29 Universitätskinderklinik Homburg/Saar Germany 66421
    30 Friedrich Schiller Universität, Klinik für Kinder-und Jugendmedizin Jena Germany 07745
    31 Städtisches Krankenhaus, Klinik für Kinder- und Jugendmedizin Karlsruhe Germany 76133
    32 Klinikum Kassel, Kinderklinik Kassel Germany 34125
    33 UKSH, Campus Kiel, Klinik für Allg. Pädiatrie Kiel Germany 24105
    34 Städtisches Klinikum Kemperhof, Klinik für Kinder- und Jugendmedizin Koblenz Germany 56073
    35 Universitätskinderklinik Köln Köln Germany 50924
    36 Universitätskinderklinik Leipzig Leipzig Germany 04317
    37 Universitätskinderklinik Lübeck Lübeck Germany 23538
    38 Otto-von-Guericke-Universität, Zentrum für Kinderheilkunde Magdeburg Germany 39120
    39 Universitätskinderklinik Mainz Mainz Germany 55131
    40 Universitätskinderklinik Mannheim Mannheim Germany 68167
    41 Universitätskinderklinik Marburg Marburg Germany 35043
    42 Klinikum Minden III, Klinik für Kinder-und Jugendheilkunde Minden Germany 32432
    43 Dr. von Haunersches Kinderspital München Germany 80337
    44 Städtisches Krankenhaus München-Schwabing, Kinderklinik der TU München München Germany 80804
    45 Universitätskinderklinik Münster Münster Germany 48129
    46 Cnopf'sche Kinderklinik Nürnberg Germany 90419
    47 Klinikum Oldenburg, Zentrum für Kinder-und Jugendmedizin Oldenburg Germany 26131
    48 Universitäts-Kinderklinik Regensburg Germany 93042
    49 Universitätskinderklinik Rostock Rostock Germany 18057
    50 Asklepios Klinik Sankt Augustin GmbH Sankt Augustin Germany 53757
    51 Olgahospital-Pädiatrisches Zentrum Stuttgart Germany 70176
    52 Universitätskinderklinik Tübingen Tübingen Germany 72076
    53 Univeritätsklinikum Ulm, Abteilung Kinder-und Jugendmedizin Ulm Germany 89075
    54 Universitätskinderklinik Würzburg Würzburg Germany 97080

    Sponsors and Collaborators

    • University Hospital, Bonn

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Gudrun Fleischhack, MD, Department of Pediatric Hematology & Oncology, Pediatrics III, University Children's Hospital Essen, University Hospital, Essen
    ClinicalTrials.gov Identifier:
    NCT00749723
    Other Study ID Numbers:
    • EUDRACT 2005-002618-40
    • BfArM-4030755
    • EC-105/05
    • DKS 2006.01, 2008.17, 2012.03
    First Posted:
    Sep 9, 2008
    Last Update Posted:
    Jul 20, 2018
    Last Verified:
    Jul 1, 2018
    Keywords provided by Gudrun Fleischhack, MD, Department of Pediatric Hematology & Oncology, Pediatrics III, University Children's Hospital Essen, University Hospital, Essen
    brain tumor
    relapse
    children
    etoposide
    intraventricular
    temozolomide
    Additional relevant MeSH terms:
    Brain Neoplasms
    Ependymoma
    Medulloblastoma
    Carboplatin
    Etoposide
    Etoposide phosphate
    Temozolomide
    Thiotepa
    Trofosfamide
    Cyclophosphamide

    Study Results

    No Results Posted as of Jul 20, 2018