Trial record 2 of 8 for:    chemotherapy and ependymoma | Open Studies

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by Centre Leon Berard
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard
ClinicalTrials.gov Identifier:
NCT02265770
First received: September 29, 2014
Last updated: June 24, 2015
Last verified: June 2015
  Purpose

The overall aim of this project is to improve the outcome of patients diagnosed with ependymoma by improving and harmonising the staging and the standard of care of this patient population and to improve the investigators understanding of the underlying biology thereby informing future treatment.

The program will evaluate new strategies for diagnosis (centralized reviews of pathology and imaging) and new therapeutic strategies in order to develop treatment recommendations.

Patients will be stratified into different treatment subgroups according to their age, the tumour location and the outcome of the initial surgery. Each subgroup will be studied in a specific randomised study to evaluate the proposed therapeutic strategies.

Stratum 1:

The aim of the stratum 1 is to evaluate the clinical impact of 16-week chemotherapy regimen with VEC-CDDP following surgical resection and conformal radiotherapy in terms of progression free survival in patients who are > 12 months and < 22 years at diagnosis, with completely removed intra cranial Ependymoma.

Stratum 2:

This stratum is designed as a phase II trial for patients who are > 12 months and < 22 years at diagnosis, with residual disease to investigate the possible activity of HD-MTX by giving to all patients the benefit of VEC chemotherapy whilst randomising half of patients to receive additional HD-MTX.

Patients will receive conformal radiotherapy (cRT). For patients who remain with a residual inoperable disease after induction chemotherapy and cRT, an 8 Gy boost of radiotherapy to the residual tumour will be delivered immediately after the end of the cRT.

Stratum 3 This stratum is designed as a phase II trial to evaluate the benefit of postoperative dose intense chemotherapy administered alone or in combination with valproate in children <12 months of age or those not eligible to receive radiotherapy .


Condition Intervention Phase
Childhood Ependymoma
Drug: 16 weeks of VEC + CDDP
Drug: VEC + HD-MTX
Drug: Chemotherapy + Valproate
Radiation: Conformal radiotherapy
Drug: VEC
Drug: Chemotherapy
Radiation: conformal radiotherapy +/- boost
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An International Clinical Program for the Diagnosis and Treatment of Children, Adolescents and Young Adults With Ependymoma

Resource links provided by NLM:


Further study details as provided by Centre Leon Berard:

Primary Outcome Measures:
  • Gross Total Resection rate [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Overall program, depends on the stratum (from 0.5 years to 3 years)

  • 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 ] [ Designated as safety issue: No ]
  • Number of treatment responders [ Time Frame: 15 months after final patient inclusion ] [ Designated as safety issue: No ]
    Objective response to chemotherapy is measured based on SIOP-E Neuro Imaging guidelines.


Secondary Outcome Measures:
  • Number of participants undergoing a second-look surgery [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Quality of Survival [ Time Frame: from date of randomization up to 5 years after the end of treatment ] [ Designated as safety issue: No ]
    Questionnaire

  • Evaluation of neuropsychological morbidity [ Time Frame: from date of randomization up to 5 years after the end of treatment ] [ Designated as safety issue: No ]
    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)

  • Comparison of neuroendocrine morbidity [ Time Frame: from date of randomization up to 5 years after the end of treatment ] [ Designated as safety issue: No ]
    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)

  • 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 ] [ Designated as safety issue: Yes ]
    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)

  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 480
Study Start Date: April 2015
Estimated Study Completion Date: August 2026
Estimated Primary Completion Date: June 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stratum 1 arm A
Conformal radiotherapy followed by 16 weeks of VEC + CDDP.
Drug: 16 weeks of VEC + CDDP
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.
Other Names:
  • Vincristine
  • Etoposide
  • Cyclophosphamide
  • Cisplatin
Radiation: Conformal radiotherapy
Conformal radiotherapy: 59.4Gy (children <18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
Active Comparator: Stratum 1 arm B
Conformal radiotherapy.
Radiation: Conformal radiotherapy
Conformal radiotherapy: 59.4Gy (children <18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
Experimental: Stratum 2 arm A
VEC + HD-MTX followed by conformal radiotherapy +/- boost
Drug: VEC + HD-MTX
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.
Other Names:
  • Vincristine
  • Etoposide
  • Cyclophosphamide
  • Methotrexate
Radiation: 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

Active Comparator: Stratum 2 arm B
VEC followed by conformal radiotherapy +/- boost
Drug: VEC
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
Other Names:
  • Vincristine
  • Etoposide
  • Cyclophosphamide
Radiation: 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

Experimental: Stratum 3 arm A
Chemotherapy + Valproate.
Drug: Chemotherapy + 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.

Other Names:
  • Vincristine
  • Carboplatin
  • Methotrexate
  • Cyclophosphamide
  • Cisplatin
  • Valproate
Active Comparator: Stratum 3 arm B
Chemotherapy
Drug: Chemotherapy
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.
Other Names:
  • Vincristine
  • Carboplatin
  • Methotrexate
  • Cyclophosphamide
  • Cisplatin

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.

  Eligibility

Ages Eligible for Study:   up to 22 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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: cellular, papillary, clear-cell and tanycytic 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. 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
  • Age ≥ 22 years
  • 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
  • Pregnancy and breast feeding

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02265770

Contacts
Contact: Didier FRAPPAZ, MD +33 4 78 78 28 81 didier.frappaz@lyon.unicancer.fr

  Show 37 Study Locations
Sponsors and Collaborators
Centre Leon Berard
Investigators
Principal Investigator: Didier FRAPPAZ, MD IHOP
  More Information

No publications provided

Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT02265770     History of Changes
Other Study ID Numbers: SIOP Ependymoma II (ET-13-002), 2013-002766-39, VHP358
Study First Received: September 29, 2014
Last Updated: June 24, 2015
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé

Additional relevant MeSH terms:
Ependymoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Carboplatin
Cisplatin
Cyclophosphamide
Etoposide
Etoposide phosphate
Methotrexate
Valproic Acid
Vincristine
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Alkylating Agents
Anticonvulsants
Antimanic Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 30, 2015