Clinical trial • Phase II • Oncology|Neurology

CYCLOPHOSPHAMIDE for Medulloblastoma | Ependymoma | Atypical teratoid rhabdoid tumor (ATRT) | Rare central nervous system (CNS) tumours

Phase II trial of CYCLOPHOSPHAMIDE for Medulloblastoma | Ependymoma | Atypical teratoid rhabdoid tumor (ATRT) | Rare central nervous system (CNS) tumours.

Overview

Trial Therapeutic Area
Oncology|Neurology
Trial Disease
Medulloblastoma | Ependymoma | Atypical teratoid rhabdoid tumor (ATRT) | Rare central nervous system (CNS) tumours
Trial Stage
Phase II
Drug Modality
Small molecule|Monoclonal antibody
Paediatric Trial
Yes

Key dates

Initial CTIS Submission Date
03-09-2024
First CTIS Authorization Date
09-10-2024

Trial design

Stratum IV comparison described in objectives: temozolomide, irinotecan, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt versus etoposide, cyclophosphamide, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt (dose and schedule not specified in the summary)-controlled Phase II trial in Austria, Spain, Denmark and others.

Comparator
Stratum IV comparison described in objectives: temozolomide, irinotecan, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt versus etoposide, cyclophosphamide, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt (dose and schedule not specified in the summary)
Biomarker Stratified
True: Methylation-based medulloblastoma group (IDAT raw data of methylation array) used for Stratum IV confirmation
Target Sample Size
100

Eligibility

Recruits 100 paediatric patients.

Pregnancy Exclusion
Pregnancy or breast feeding
Vulnerable Population
The trial enrolls children (inclusion: "Female or male, aged from 0 to <20 years (at time of original diagnosis)"). Informed consent is required from patients and/or parents (inclusion: "Written informed consent of patients and / or parents"). Age-specific information and consent/assent documents are provided (multiple subject information and informed consent forms for children, adolescents and parents in several languages are listed in the application documents), and performance scales differ by age (Lansky for <12 years, Karnofsky for ≥12 years).

Inclusion criteria

  • {"criterion_text":"- Stratum I: Relapsed or progressive medulloblastoma (at least one site of untreated recurrent disease) - completed"}
  • {"criterion_text":"- Stratum IV: Confirmation of the medulloblastoma group by methylation; IDAT (raw data of methylation array)"}
  • {"criterion_text":"- Stratum V: Relapsed or progressive CNS tumor of various histologies or patients with exclusion criteria or adult patients (explorative)"}
  • {"criterion_text":"- Stratum II: Relapsed or progressive ependymoma (at least one site of untreated recurrent disease)"}
  • {"criterion_text":"- Stratum III: Relapsed or progressive ATRT (at least one site of untreated recurrent disease)"}
  • {"criterion_text":"- Histological confirmation of medulloblastoma/ependymoma/ATRT at diagnosis or relapse"}
  • {"criterion_text":"- Female or male, aged from 0 to <20 years (at time of original diagnosis)"}
  • {"criterion_text":"- Participants must have normal organ and bone marrow function (ALT <5x institutional upper limit of normal, creatinine <1.5x institutional upper limit of normal for age, WBC >1000/mm3, platelets > 20,000/mm3. Patients with values less than WBC 2000/mm3 or platelets 50,000/mm3 will require initiation of treatment with etoposide and cyclophosphamide at a lower starting dose as defined within the protocol."}
  • {"criterion_text":"- Karnofsky performance status ≥50. For infants and children less than 12 years of age, the Lansky play scale ≥50% will be used"}
  • {"criterion_text":"- Written informed consent of patients and / or parents"}
  • {"criterion_text":"- Stratum IV: Relapsed or progressive medulloblastoma (at least one site of untreated recurrent disease)"}

Exclusion criteria

  • {"criterion_text":"- Active infection"}
  • {"criterion_text":"- Anticipation of the need for major elective surgery during the course of the study treatment"}
  • {"criterion_text":"- Any disease or condition that contraindicates the use of the study medication/treatment or places the patient at an unacceptable risk of experiencing treatment-related complications"}
  • {"criterion_text":"- Stratum IV: Prior treatment with temozolomide/irinotecan (can be included in Stratum V)"}
  • {"criterion_text":"- Previously non-irradiated patients should be evaluated for radiotherapy"}
  • {"criterion_text":"- Non-healing surgical wound"}
  • {"criterion_text":"- A bone fracture that has not satisfactorily healed"}
  • {"criterion_text":"- VP- or subduroperitoneal shunt dependency (can be included in Stratum V)"}
  • {"criterion_text":"- Pregnancy or breast feeding"}
  • {"criterion_text":"- Treatment for current relapse (surgery may be performed before antiangiogenic treatment; patients with sites of disease not irradiated are still eligible for the protocol)"}
  • {"criterion_text":"- Known hypersensitivity to any of the drugs in the protocol"}
  • {"criterion_text":"- Active peptic ulcer"}
  • {"criterion_text":"- Any significant cardiovascular disease not controlled by standard therapy e.g. systemic hypertension"}

Endpoints

Primary endpoints

  • {"endpoint_text":"- π: probability for response, lack of recurrence after gross total resection. Stratum II+III: H0: π≤15% study therapy is considered as ineffective (type I error rate α=0.05, two sided). H1: π≥35% study therapy is considered as effective (type II error rate β=0.10 in Stratum I, β=0.20 in Stratum II+III). Stratum IV: H0: π1≤ π2 study therapy is considered as equal or inferior (type I error rate α=0.025, one sided). H1: π1>π2 study therapy is consididered as superior (type II error rate β=0.20)","definition_or_measurement_approach":"Response probability defined as percentage of patients with CR, PR, SD or lack of recurrence at 6 months after start of antiangiogenic treatment; hypothesis testing specified per stratum with stated null/alternative (H0/H1), alpha and beta error rates."}

Secondary endpoints

  • {"endpoint_text":"- Kaplan Meier survival estimates of overall survival rates after 6, 12, 24, and 36 months with 95% confidence intervals will be evaluated and compared to historical samples","definition_or_measurement_approach":"Overall survival estimated by Kaplan-Meier at 6, 12, 24 and 36 months with 95% CIs; comparison to historical data."}
  • {"endpoint_text":"- Kaplan Meier estimates of progression free survival after 6, 12, 24, and 36 months with 95% confidence intervals will be evaluated and compared to historical samples","definition_or_measurement_approach":"Progression-free survival estimated by Kaplan-Meier at 6, 12, 24 and 36 months with 95% CIs; comparison to historical data."}
  • {"endpoint_text":"- The number and relative frequency of toxicities (CTCAE Version 5.0 grade 3, 4 and 5) will be evaluated every 12 weeks.","definition_or_measurement_approach":"Toxicities graded using CTCAE v5.0; counts and relative frequencies for grade 3–5 events assessed every 12 weeks."}
  • {"endpoint_text":"- Performance status will be compared from the start of therapy and every 12 weeks","definition_or_measurement_approach":"Performance status measured using Karnofsky (≥12 years) or Lansky (<12 years) and compared from baseline every 12 weeks."}
  • {"endpoint_text":"- Subscale-scores and total scores of the KINDL assessments at the start of therapy, after 6 months 12 months, 18 months and 24 months of therapy will be evaluated. PRO will be evaluated every two weeks.","definition_or_measurement_approach":"Health-related quality of life using KINDL questionnaires (age-specific versions) at baseline and specified timepoints; patient-reported outcomes (PRO) collected every two weeks."}
  • {"endpoint_text":"- The aforementioned variables will be evaluated comparing their influence on response rate, overall survival rate, progression free survival rate, toxicity, quality of life and performance status by multivariate cox-regression","definition_or_measurement_approach":"Multivariate Cox regression will be used to evaluate influence of variables on response, OS, PFS, toxicity, QoL and performance status."}
  • {"endpoint_text":"- Examination of predictive and prognostic factors will be descriptive.","definition_or_measurement_approach":"Evaluation of predictive/prognostic factors (including tumor biology markers) described descriptively."}

Recruitment

Planned Sample Size
100
Recruitment Window Months
184
Consent Approach
Written informed consent is required from patients and/or parents (inclusion: "Written informed consent of patients and / or parents"). Age-specific consent/assent processes are used with multiple subject information and informed consent forms for children, adolescents and parents; documents are provided in multiple languages (English, German, Spanish, French, Swedish, Norwegian, Czech, Danish as indicated by the listed ICF/document titles). Performance-status assessments use Lansky for children <12 years and Karnofsky for those ≥12 years.

Geography

Total Number Of Sites
24
Total Number Of Participants
100

Austria

Earliest CTIS Part Ii Submission Date
19-09-2024
Latest Decision Or Authorization Date
14-10-2024
Processing Time Days
25
Number Of Sites
4
Number Of Participants
22

Sites

Site Name
Medical University Of Graz
Department Name
Klinische Abteilung für Pädiatrische Hämatologie/Onkologie
Principal Investigator Name
Martin Benesch
Principal Investigator Email
martin.benesch@medunigraz.at
Contact Person Name
Martin Benesch
Contact Person Email
martin.benesch@medunigraz.at
Site Name
Medizinische Universitaet Innsbruck
Department Name
Department für Kinder- und Jugendheilkunde
Principal Investigator Name
Roman Crazzolara
Principal Investigator Email
roman.crazzolara@i-med.ac.at
Contact Person Name
Roman Crazzolara
Contact Person Email
roman.crazzolara@i-med.ac.at
Site Name
Johannes Kepler University Linz
Department Name
Universitätsklinik für Kinder –u. Jugendheilkunde, MedCampus IV
Principal Investigator Name
Barbara Winkler
Principal Investigator Email
barbara.winkler@keplerklinikum.at
Contact Person Name
Barbara Winkler
Site Name
Medical University Of Vienna
Department Name
Division of Neonatology, Intensive Care Medicine and Neuropediatrics
Principal Investigator Name
Andreas Peyrl
Principal Investigator Email
andreas.peyrl@meduniwien.ac.at
Contact Person Name
Andreas Peyrl
Contact Person Email
andreas.peyrl@meduniwien.ac.at

Spain

Earliest CTIS Part Ii Submission Date
19-09-2024
Latest Decision Or Authorization Date
11-10-2024
Processing Time Days
22
Number Of Sites
1
Number Of Participants
15

Sites

Site Name
Hospital Infantil Universitario Nino Jesus
Department Name
Department of Pediatric Hematology and Oncology
Principal Investigator Name
Alvaro Lassaleta
Principal Investigator Email
alvaro.lassaletta@salud.madrid.org
Contact Person Name
Alvaro Lassaleta

Denmark

Earliest CTIS Part Ii Submission Date
19-09-2024
Latest Decision Or Authorization Date
10-10-2024
Processing Time Days
21
Number Of Sites
4
Number Of Participants
8

Sites

Site Name
Rigshospitalet
Department Name
Department of Paediatric and Adolescent Medicine
Principal Investigator Name
Karsten Nysom
Principal Investigator Email
karsten.nysom@regionh.dk
Contact Person Name
Karsten Nysom
Contact Person Email
karsten.nysom@regionh.dk
Site Name
Region Midtjylland
Department Name
Department of Paediatric and Adolescent Medicine
Principal Investigator Name
Ines Kristensen
Principal Investigator Email
INEKRI@rm.dk
Contact Person Name
Ines Kristensen
Contact Person Email
INEKRI@rm.dk
Site Name
Aalborg University Hospital
Department Name
Department of Paediatric and Adolescent Medicine
Principal Investigator Name
Marianne Olsen
Principal Investigator Email
marianne.olsen@rn.dk
Contact Person Name
Marianne Olsen
Contact Person Email
marianne.olsen@rn.dk
Site Name
Odense University Hospital
Department Name
The Hans Christian Andersen Childrens Hospital
Principal Investigator Name
Michael Callesen
Principal Investigator Email
michael.callesen@rsyd.dk
Contact Person Name
Michael Callesen
Contact Person Email
michael.callesen@rsyd.dk

Czechia

Earliest CTIS Part Ii Submission Date
19-09-2024
Latest Decision Or Authorization Date
11-10-2024
Processing Time Days
22
Number Of Sites
1
Number Of Participants
10

Sites

Site Name
Fakultni Nemocnice Brno
Department Name
Pediatric Oncology Departmen
Principal Investigator Name
Jaroslav Sterba
Principal Investigator Email
Sterba.Jaroslav@fnbrno.cz
Contact Person Name
Jaroslav Sterba
Contact Person Email
Sterba.Jaroslav@fnbrno.cz

Norway

Earliest CTIS Part Ii Submission Date
19-09-2024
Latest Decision Or Authorization Date
09-10-2024
Processing Time Days
20
Number Of Sites
3
Number Of Participants
5

Sites

Site Name
Helse Bergen HF
Department Name
Onkologisk-hematologisk seksjon
Principal Investigator Name
Ingrid Torsvik
Principal Investigator Email
ingrid.kristin.torsvik@helse-bergen.no
Contact Person Name
Ingrid Torsvik
Site Name
St. Olavs Hospital HF
Department Name
Dep. Pediatric oncology and hematology
Principal Investigator Name
Maguns Hjort
Principal Investigator Email
Magnus.Aasved.Hjort@stolav.no
Contact Person Name
Maguns Hjort
Contact Person Email
Magnus.Aasved.Hjort@stolav.no
Site Name
Oslo University Hospital HF
Department Name
Department of pediatric oncology and hematology
Principal Investigator Name
Thale Maehre Torjussen
Principal Investigator Email
uxtato@ous-hf.no
Contact Person Name
Thale Maehre Torjussen
Contact Person Email
uxtato@ous-hf.no

Sweden

Earliest CTIS Part Ii Submission Date
19-09-2024
Latest Decision Or Authorization Date
11-10-2024
Processing Time Days
22
Number Of Sites
7
Number Of Participants
20

Sites

Site Name
Queen Silvia Childrens Hospital - Sahlgrenska University Hospital - Vaestra Goetalandsregionen
Department Name
Childhood cancer centre (ward 322)
Principal Investigator Name
Magnus Sabel
Principal Investigator Email
magnus.sabel@vgregion.se
Contact Person Name
Magnus Sabel
Contact Person Email
magnus.sabel@vgregion.se
Site Name
Region Oestergoetland
Department Name
Department of Health, Medicine and Caring Sciences (HMV)
Principal Investigator Name
Per Nyman
Principal Investigator Email
per.nyman@regionostergotland.se
Contact Person Name
Per Nyman
Site Name
Region Skane Skanes Universitetssjukhus
Department Name
Childhood Cancer Research Unit
Principal Investigator Name
Helena Mörse
Principal Investigator Email
helena.morse@skane.se
Contact Person Name
Helena Mörse
Contact Person Email
helena.morse@skane.se
Site Name
Region Vaesterbotten
Department Name
Department of Oncology and Hematology
Principal Investigator Name
Magnus Borssén
Principal Investigator Email
magnus.borssen@regionvasterbotten.se
Contact Person Name
Magnus Borssén
Site Name
Karolinska University Hospital
Department Name
Astrid Lindgren Children's Hospital
Principal Investigator Name
Kleopatra Georgantzi
Principal Investigator Email
kleopatra.georgantzi@regionstockholm.se
Contact Person Name
Kleopatra Georgantzi
Site Name
Uppsala University Hospital
Department Name
Department of Women's and Children's Health
Principal Investigator Name
Anders Öberg
Principal Investigator Email
anders.oberg@akademiska.se
Contact Person Name
Anders Öberg
Contact Person Email
anders.oberg@akademiska.se
Site Name
Additional Swedish site (listed)

France

Earliest CTIS Part Ii Submission Date
19-09-2024
Latest Decision Or Authorization Date
11-10-2024
Processing Time Days
22
Number Of Sites
4
Number Of Participants
20

Sites

Site Name
Centre Leon Berard
Department Name
Centre Leon Berad
Principal Investigator Name
Pierre Leblond
Principal Investigator Email
pierre.leblond@ihope.fr
Contact Person Name
Pierre Leblond
Contact Person Email
pierre.leblond@ihope.fr
Site Name
Centre Oscar Lambret
Department Name
Department of Oncology, Pediatric unit
Principal Investigator Name
Hélène Sudour-Bonnange
Principal Investigator Email
h-sudour@o-lambret.fr
Contact Person Name
Hélène Sudour-Bonnange
Contact Person Email
h-sudour@o-lambret.fr
Site Name
Les Hopitaux Universitaires De Strasbourg
Department Name
Department of pediatric oncology and hematology
Principal Investigator Name
Natacha Entz-Werle
Principal Investigator Email
natache.entz-werle@chru-strassbourg.fr
Contact Person Name
Natacha Entz-Werle
Site Name
Centre Hospitalier Regional De Marseille
Department Name
Service d'imunologie, hématologie et oncologie pédiatrique
Principal Investigator Name
Nicolas Andre
Principal Investigator Email
nicolas.andre@ap-hm.fr
Contact Person Name
Nicolas Andre
Contact Person Email
nicolas.andre@ap-hm.fr

Sponsor

Primary sponsor

Full Name
Medical University Of Vienna
Organisation Type
Educational Institution
Country Of Registered Address
Austria

Investigational products

Investigational Product Name
Cyclophosphamide Injection 1 g.
Active Substance
CYCLOPHOSPHAMIDE
Modality
Small molecule
Routes Of Administration
ORAL
Route
ORAL
Authorisation Status
2
Maximum Dose
36 g
Investigational Product Name
Lipcor 200 mg-Kapseln
Active Substance
FENOFIBRATE
Modality
Small molecule
Routes Of Administration
ORAL
Route
ORAL
Authorisation Status
2
Maximum Dose
65 gm/m2
Investigational Product Name
Temozolomide Accord 100 mg hard capsules.
Active Substance
TEMOZOLOMIDE
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
ORAL USE
Authorisation Status
2
Maximum Dose
9000 mg/m2 (total)
Investigational Product Name
Thalidomide 50 mg capsules, hard
Active Substance
THALIDOMIDE
Modality
Small molecule
Routes Of Administration
ORAL
Route
ORAL
Authorisation Status
2
Maximum Dose
2100 mg/kg (total) [as provided]
Investigational Product Name
Eto-GRY® 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung
Active Substance
ETOPOSIDE
Modality
Small molecule
Routes Of Administration
I.T. BOLUS INJECTION TO THE INTRATHECAL SPACE
Route
I.T. BOLUS INJECTION TO THE INTRATHECAL SPACE
Authorisation Status
2
Maximum Dose
60 g
Investigational Product Name
Temozolomide Accord 20 mg hard capsules.
Active Substance
TEMOZOLOMIDE
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
ORAL USE
Authorisation Status
2
Maximum Dose
9000 mg/m2 (total)
Investigational Product Name
Avastin 25 mg/ml concentrate for solution for infusion.
Active Substance
BEVACIZUMAB
Modality
Monoclonal antibody
Routes Of Administration
INTRAVENOUS INFUSION
Route
INTRAVENOUS INFUSION
Authorisation Status
2
Maximum Dose
520 mg/kg (total) [as provided in product record]
Investigational Product Name
Cytarabine 100 mg/ml Solution for Injection
Active Substance
CYTARABINE
Modality
Small molecule
Routes Of Administration
I.T. BOLUS INJECTION TO THE INTRATHECAL SPACE
Route
I.T. BOLUS INJECTION TO THE INTRATHECAL SPACE
Authorisation Status
2
Maximum Dose
2.8 g
Investigational Product Name
CELEBREX® 200 mg Hartkapseln
Active Substance
CELECOXIB
Modality
Small molecule
Routes Of Administration
ORAL
Route
ORAL
Authorisation Status
2
Maximum Dose
582 g (total) [as provided]
Investigational Product Name
Etoposid Ebewe 20 mg/ml - Konzentrat zur Herstellung einer Infusionslösung
Active Substance
ETOPOSIDE
Modality
Small molecule
Routes Of Administration
ORAL
Route
ORAL
Authorisation Status
2
Maximum Dose
9.1 gm/m2
Investigational Product Name
ARA-cell® 40 mg Injektion 20 mg/ml Injektionslösung / Konzentrat zur Herstellung einer Infusionslösung
Active Substance
CYTARABINE
Modality
Small molecule
Routes Of Administration
I.T. BOLUS INJECTION TO THE INTRATHECAL SPACE
Route
I.T. BOLUS INJECTION TO THE INTRATHECAL SPACE
Authorisation Status
2
Maximum Dose
1440 mg
Investigational Product Name
Irinotecan 20 mg/ml Concentrate for Solution for Infusion
Active Substance
IRINOTECAN HYDROCHLORIDE TRIHYDRATE
Modality
Small molecule
Routes Of Administration
INTRAVENOUS USE
Route
INTRAVENOUS USE
Authorisation Status
2
Maximum Dose
3000 mg/m2 (total)
Combination Treatment
Yes

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