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

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ClinicalTrials.gov Identifier: NCT00749723
Recruitment Status : Completed
First Posted : September 9, 2008
Last Update Posted : July 20, 2018
Sponsor:
Information provided by (Responsible Party):
Gudrun Fleischhack, University Hospital, Essen

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


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Study Type : Interventional  (Clinical Trial)
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 : February 1, 2006
Actual Primary Completion Date : January 31, 2015
Actual Study Completion Date : January 31, 2016


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 Name: 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 Name: etoposide IV

Drug: thiotepa, carboplatin, etoposide
high dose chemotherapy followed by to autologous stem cell transplantation
Other Name: thiotepa, carboplatin, etoposide IV, high dose

Procedure: autologous stem cell transplantation
autologous stem cell transplantation following HD-chemotherapy
Other Name: 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 Name: 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 Name: 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 Name: temozolomide orally

Drug: temozolomide, thiotepa
high dose chemotherapy followed by autologous stem cell transplantation
Other Name: temozolomide, thiotepa IV

Procedure: autologous stem cell transplantation
autologous stem cell transplantation following HD-chemotherapy
Other Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: etoposide intra-CSF




Primary Outcome Measures :
  1. 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)

  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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 8 years ]
    rate of adverse events of CTC°1-4 according to CTCAE v3.0



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Ages Eligible for Study:   3 Months to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00749723


  Show 54 Study Locations
Sponsors and Collaborators
University Hospital, Bonn
Investigators
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Principal Investigator: Gudrun Fleischhack, MD Department of Pediatric Hematology & Oncology, Pediatrics III, University Children's Hospital Essen

Additional Information:
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Responsible Party: Gudrun Fleischhack, MD, Department of Pediatric Hematology & Oncology, Pediatrics III, University Children's Hospital Essen, University Hospital, Essen
ClinicalTrials.gov Identifier: NCT00749723     History of Changes
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 )
First Posted: September 9, 2008    Key Record Dates
Last Update Posted: July 20, 2018
Last Verified: July 2018
Keywords provided by Gudrun Fleischhack, University Hospital, Essen:
brain tumor
relapse
children
etoposide
intraventricular
temozolomide
Additional relevant MeSH terms:
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Brain Neoplasms
Ependymoma
Medulloblastoma
Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors, Primitive
Carboplatin
Temozolomide
Etoposide
Etoposide phosphate
Thiotepa
Trofosfamide
Cyclophosphamide
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic