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JOURNAL ONKOLOGIE – STUDIE

SIOP-EP-II An International Clinical Program for the Diagnosis and Treatment of Children With Ependymoma

Rekrutierend

NCT-Nummer:
NCT02265770

Studienbeginn:
Juni 2015

Letztes Update:
16.04.2020

Wirkstoff:
16 weeks of VEC + CDDP, VEC + HD-MTX, Chemotherapy + Valproate, VEC, Chemotherapy

Indikation (Clinical Trials):
Ependymoma

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Centre Leon Berard

Collaborator:
-

Studienleiter

Pierre LEBLOND, MD
Principal Investigator
IHOP

Kontakt

Studienlocations (3 von 39)

Medical University of Graz-Department of Pediatrics and Adolescent Medicine
8036 Graz
AustriaRekrutierend» Google-Maps
Ansprechpartner:
Martin Benesch, MD
Phone: +43 (0) 316/385-80427
E-Mail: martin.benesch@klinikum-graz.at
» Ansprechpartner anzeigen
CHRU STRASBOURG - Hôpital de Hautepierre
67098 Strasbourg
FranceRekrutierend» Google-Maps
Ansprechpartner:
Natacha Entz-Werle, MD
Phone: +33 3 88 12 83 96
E-Mail: natacha.entz-werle@chru-strasbourg.fr
» Ansprechpartner anzeigen
CHU Dijon - Hôpital des Enfants
21079 Dijon
FranceNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Claire Briandet, MD
Phone: 03 80 29 34 14
Phone (ext.): +33
E-Mail: claire.briandet@chu-dijon.fr
» Ansprechpartner anzeigen
CHU de Bordeaux-Hôpital des enfants Pellegrin
33000 Bordeaux
FranceRekrutierend» Google-Maps
Ansprechpartner:
Cécile Vérité, MD
Phone: +33 5 56 82 04 38
E-Mail: cecile.verite@chu-bordeaux.fr
» Ansprechpartner anzeigen
CHU de TOULOUSE - Hôpital des Enfants
31059 Toulouse
FranceRekrutierend» Google-Maps
Ansprechpartner:
Anne-Isabelle Bertozzi-Salamon, MD
Phone: +33 5 34 55 86 13
E-Mail: bertozzi.ai@chu-toulouse.fr
» Ansprechpartner anzeigen
CHRU MONTPELLIER - Hôpital Arnaud de Villeneuve
34295 Montpellier
FranceRekrutierend» Google-Maps
Ansprechpartner:
Nicolas Sirvent, MD
Phone: +33 4 67 33 65 19
E-Mail: n-sirvent@chu-montpellier.fr
» Ansprechpartner anzeigen
CHRU Saint-Etienne
42055 Saint-Etienne
FranceRekrutierend» Google-Maps
Ansprechpartner:
Sandrine Thouvenin, MD
Phone: 04 77 82 88 08
Phone (ext.): +33
E-Mail: sandrine.thouvenin@chu-st-etienne.fr
» Ansprechpartner anzeigen
CHU Clermont- Ferrand - Hôpital Estaing
63003 Clermont-Ferrand
FranceRekrutierend» Google-Maps
Ansprechpartner:
Catherine Paillard, MD
Phone: +33 4 73 75 00 09
E-Mail: cpaillard@chu-clermontferrand.fr
» Ansprechpartner anzeigen
CHU Rouen - Hôpital Charles Nicolle
76031 Rouen
FranceRekrutierend» Google-Maps
Ansprechpartner:
Pascale Schneider, MD
Phone: 02 32 88 81 91
Phone (ext.): +33
E-Mail: pascale.schneider@chu-rouen.fr
» Ansprechpartner anzeigen
Fondazione IRCCS Istituto Nazionale dei Tumori
20133 Milan
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Maura Massimino, MD
Phone: +39 0223902593
E-Mail: Maura.Massimino@istitutotumori.mi.it
» Ansprechpartner anzeigen
Princess Maxima Center for pediatric oncology
Utrecht
NetherlandsRekrutierend» Google-Maps
Ansprechpartner:
Jasper van der Lugt, MD
Phone: +31 6 1855 96 94
E-Mail: J.vanderLugt@prinsesmaximacentrum.nl
» Ansprechpartner anzeigen
Pediatric Department, Rikshospitalet University Hospital
0304 Oslo
NorwayNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Finn Wesenberg, MD
Phone: +47 2307 3207
E-Mail: fwesenbe@ous-hf.no
» Ansprechpartner anzeigen
University Medical Center Ljubljana
1000 Ljubljana
SloveniaNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Lidija Kitanovski, MD
Phone: + 386 1 522 9215 / 522 9256
E-Mail: lidija.kitanovski@kclj.si
» Ansprechpartner anzeigen
Hospitales Universitarios Virgen Macarena y Virgen del Rocío Avda
41071 Sevilla
SpainRekrutierend» Google-Maps
Ansprechpartner:
Ana Fernández-Teijeiro, MD
Phone: +34677903132
E-Mail: anateijeiro@hotmail.com
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

The Ependymoma Program is a comprehensive program to improve the accuracy of the primary diagnosis of ependymoma and explore different therapeutic strategies in children, adolescents and young adults, accordingly. This program is opened to all patients diagnosed with ependymoma below the age of 22 years.

It will include a centralised review of pre and post-operative imaging to assess the completeness of the resection.

It will also include a central review of pathology to confirm the histological diagnosis. The biological markers 1q gain, Tenascin C status, NELL2 and LAMA2, RELA-fusion and molecular subgroup by methylation array will be prospectively assessed for prospective evaluation of disease subgroups. Further biological evaluations will be coordinated within the linked BIOMECA study.

After surgery and central review of imaging and pathology, patients will be offered the opportunity to undergo second look surgery, if possible. Patients will be enrolled in one of 3 different strata according to the outcome of the initial surgical resection (residual disease vs no residual disease), their age or eligibility / suitability to receive radiotherapy. These 3 different strata correspond to 3 therapeutic strategies according to the patient status.

1. Stratum 1 is designed as a randomised phase III study for patients who have had a complete resection, with no measurable residual disease (as confirmed by centrally reviewed MRI) and are > 12 months and < 22 years at diagnosis. Those patients will be randomised to receive conformal radiotherapy followed by either 16 weeks of chemotherapy with VEC-CDDP, or observation.

2. Stratum 2 is designed as a randomised phase II study for patients who have inoperable measurable residual disease and who are > 12 months and < 22 years at diagnosis. Those patients will be randomised to two different treatment schedules of chemotherapy either with VEC or VEC+ high dose methotrexate (VEC +HD-MTX). After completion of the frontline chemotherapy, patients will be assessed for response (MRI) and will receive second look surgery when feasible. For those patients who remain unresectable with residual disease despite frontline chemotherapy and for whom second line surgery is not feasible, there will be a study of the safety of a radiotherapy boost of 8 Gy that will be administered to the residual tumour immediately after the completion of the conformal radiotherapy. Patients without evidence of residual disease after the chemotherapy and/or a second look surgery are not eligible for radiotherapy boost. All patients who have not shown progression under chemotherapy will receive, as maintenance therapy, a 16 week course of VEC -CDDP following completion of radiotherapy.

3. Stratum 3 is designed as a randomised phase II chemotherapy study in children <12 months of age or those not eligible to receive radiotherapy. These patients will be randomised to receive a dose dense chemotherapy alternating myelosuppressive and relatively non-myelosuppressive drugs at 2 weekly intervals, with or without, the addition of the histone deacetylase inhibitor, valproate.

Registry: Patients that do not fulfil the inclusion criteria of one of the interventional strata will be enrolled and followed up via an observational study which will be analysed descriptively.

Ein-/Ausschlusskriterien

After Initial surgery, patients will be enrolled in one of 3 different interventional strata where they will be offered a set of therapeutic interventions based on the outcome of the intervention (no measurable residue vs residual inoperable disease), their age and/or their eligibility /suitability to receive radiotherapy.

Patients with centrally and histologically confirmed intracranial ependymoma meeting the following criteria will be enrolled into one of interventional stratum:

- Age < 22 years old at diagnosis

- Newly diagnosed with an ependymoma WHO grade II and III, including ependymoma variants: papillary, clear-cell and tanycytic, RELA fusion positive or anaplastic ependymoma

- Post-menarchal female not pregnant or nursing (breast feeding) and with a negative beta-HCG pregnancy test prior to commencing the trial

- Males and females of reproductive age and childbearing potential with effective contraception for the duration of their treatment and 6 months after the completion of their treatment

- No contraindication to the use if one of the study drugs proposed by the protocol

- Patients and/or their parents or legal guardians willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedure

Common inclusion criteria for Strata 1 and 2:

- Age > 12 months and < 22 years at time of study entry

- Histologically confirmed WHO Grade II-III ependymoma by central pathological review

- No metastasis on spinal MRI and on CSF cytology assessments

- No previous radiotherapy

- No previous chemotherapy (except steroids)

- No co-existent unrelated disease at the time of study entry that would render the patient unable to receive chemotherapy

- No medical contraindication to radiotherapy and chemotherapy

- No signs of infection

- Adequate bone marrow, liver and renal functions

Specific inclusion criteria for Stratum 1:

• No residual measurable ependymoma based on the central neuroradiological review (R0-1-2)

Specific inclusion criteria for Stratum 2:

• Residual non reoperable measurable ependymoma based on the central neuroradiological review (R3-4)

Inclusion criteria for Stratum 3:

- Children younger than 12 months at time of entry to study or any children ineligible to receive radiotherapy due to age at diagnosis, tumour location or clinician / parent decision and according to national criteria

- Histologically confirmed WHO Grade II-III ependymoma by central pathological review

- Adequate bone marrow, liver and renal functions

- No previous chemotherapy and radiotherapy

- No contraindication to chemotherapy

- No co-existent unrelated disease at the time of study entry that would render the patient unable to receive chemotherapy

- No signs of infection. Patients that do not fulfill the inclusion criteria of one of the interventional strata will be enrolled and followed up into an observational study and descriptive analysis will be performed.

EXCLUSION CRITERIA for all interventional strata:

- Tumour entity other than primary intracranial ependymoma

- Primary diagnosis predating the opening of SIOP Ependymoma II

- Patients with WHO grade I ependymoma including ependymoma variants: myxopapillary ependymomas and subependymomas,patients with spinal cord location of the primary tumour

- Participation within a different trial for treatment of ependymoma

- Contraindication to one of the IMP used according to the SmPCs

- Concurrent treatment with any anti-tumour agents

- Inability to tolerate chemotherapy

- Unable to tolerate intravenous hydration

- Pre-existing mucositis, peptic ulcer, inflammatory bowel disease ascites, or pleural effusion.

Strata 1 and 2:

- Ineligible to receive radiotherapy

- Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion

Stratum 3:

- Pre-existing severe hepatic and/or renal damage

- Family history of severe epilepsy

- Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial

- Elevated blood ammonium and lactate level ≥ 1.5 x upper limit of the normal

Studien-Rationale

Primary outcome:

1. Gross Total Resection rate (Time Frame - 3 years):
Overall program, depends on the stratum (from 0.5 years to 3 years)

2. Progression-Free Survival (Time Frame - from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 4.5 years)

3. Number of treatment responders (Time Frame - 15 months after final patient inclusion):
Objective response to chemotherapy is measured based on SIOP-E Neuro Imaging guidelines.

Secondary outcome:

1. Number of participants undergoing a second-look surgery (Time Frame - 9 months)

2. Overall Survival (Time Frame - from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 3 years after the final patient inclusion)

3. Quality of Survival (Time Frame - from date of randomization up to 5 years after the end of treatment):
Questionnaire

4. Evaluation of neuropsychological morbidity (Time Frame - from date of randomization up to 5 years after the end of treatment):
Scores: evaluation of processing speed (WPPSI-III, WISC-IV, WAIS-IV), verbal skills (WPPSI-III, WISC-IV, WAIS-IV), fluid intelligence (WPPSI-III / Ravens, WISC-IV / Ravens, WAIS-IV / Ravens), working memory (K-ABC / Children's Memory Scale, WISC-IV, WAIS-IV), visuo-spatial abilities (Beery-Buktenica Developmental Test of Visual-Motor Integration/Wide Range Assessment of Visual Motor Abilities - WRAVMA), regarding ability (as to national policy/WIAT-II) and motoric speed (Perdue Pegboard)

5. Comparison of neuroendocrine morbidity (Time Frame - from date of randomization up to 5 years after the end of treatment):
Weight, height and head circumference, Tanner age, early and delayed pubertal onset, blood sample analysis (evaluation of TSH, fT4, LH and FSH, oestradiol, testosterone, insulin-like growth factor 1)

6. Number of participants with adverse events as a measure of safety and tolerability (Time Frame - from date of randomization up to 5 years after the end of treatment):
Determination of short and long term safety and toxicity of frontline chemotherapy based on proportion of patients experiencing toxicity grade 3 to 4 (adverse events)

7. Radiotherapy-free survival rate (Time Frame - from date of randomization until the date of first documented progression or date of death from any cause, or radiotherapy intervention, whichever came first, up to 2.5 years after the final patient inclusion)

Studien-Arme

  • Experimental: Stratum 1 arm A
    Conformal radiotherapy followed by 16 weeks of VEC + CDDP.
  • Active Comparator: Stratum 1 arm B
    Conformal radiotherapy.
  • Experimental: Stratum 2 arm A
    VEC + HD-MTX followed by conformal radiotherapy +/- boost
  • Active Comparator: Stratum 2 arm B
    VEC followed by conformal radiotherapy +/- boost
  • Experimental: Stratum 3 arm A
    Chemotherapy + Valproate.
  • Active Comparator: Stratum 3 arm B
    Chemotherapy

Geprüfte Regime

  • 16 weeks of VEC + CDDP (Vincristine / Etoposide / Cyclophosphamide / Cisplatin / ):
    Days 1-36-71-106: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; Days 1-3-36-38-71-73-106-108: Etoposide: 100 mg/m² infused over 60 minutes; Days 1-36-71-106: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; Days 22-57-92: Cisplatin: 80 mg/m² over 4 hours + Vincristine:1.5 mg/m² (maximal dose 2 mg) i.v.
  • VEC + HD-MTX (Vincristine / Etoposide / Cyclophosphamide / Methotrexate / ):
    Days 1-22-43: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; Days 1-3-22-24-43-45: Etoposide: 100 mg/m² infused over 60 minutes; Days 1-22-43: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; Days 15-36-57: Administer methotrexate at 8000 mg/m² as a 24 hour IV infusion on days 15-36-57. 10% of the dose should be given over the first hour and 90% over the remaining 23 hours. The infusion must finish at 24 hours even if it has not been completed.
  • Chemotherapy + Valproate (Vincristine / Carboplatin / Methotrexate / Cyclophosphamide / Cisplatin / Valproate / ):
    Days 1-57-113-169-225-281-337: Vincristine and Carboplatin; Days 15-71-127-183-239-295-351: Vincristine and Methotrexate; Days 29-85-141-197-253-309-365: Vincristine and Cyclophosphamide; Days 43-44-99-100-154-155-211-212-267-268-323-324-379-380: Cisplatin 2-day continuous infusion. Valproate: initial dose 30 mg/kg/day for two weeks in 2 divided doses (BID 15 mg/kg). Increasing weekly up to 40 - 50 - 60 mg/kg/day in 2 divided doses.
  • Conformal radiotherapy:
    Conformal radiotherapy: 59.4Gy (children <18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
  • VEC (Vincristine / Etoposide / Cyclophosphamide / ):
    D1: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D1-D3: Etoposide: 100 mg/m² infused over 60 minutes; D1: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; D22: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D22-D24: Etoposide: 100 mg/m² infused over 60 minutes; D22: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; D43: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D43-D45: Etoposide: 100 mg/m² infused over 60 minutes; D43: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes
  • Chemotherapy (Vincristine / Carboplatin / Methotrexate / Cyclophosphamide / Cisplatin / ):
    Days 1-57-113-169-225-281-337: Vincristine and Carboplatin; Days 15-71-127-183-239-295-351: Vincristine and Methotrexate; Days 29-85-141-197-253-309-365: Vincristine and Cyclophosphamide; Days 43-44-99-100-154-155-211-212-267-268-323-324-379-380: Cisplatin 2-day continuous infusion.
  • conformal radiotherapy +/- boost:
    Conformal radiotherapy: 59.4Gy (children <18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week. In case of persistent residue : Boost of radiation 8 Gy in 2 equivalent fractions

Quelle: ClinicalTrials.gov


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