Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors (MEMMAT)

A Phase II Study of Metronomic and Targeted Anti-angiogenesis Therapy for Children With Recurrent/Progressive Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors

Patients with with recurrent or progressive medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor (ATRT), and CNS tumors of various histologies have a very poor prognosis whether treated with conventional chemotherapy, high-dose chemotherapy with stem cell rescue, irradiation or combinations of these modalities.

Antiangiogenesis therapy has emerged as a new treatment option in solid malignancies. The frequent delivery of low doses of chemotherapy, referred to as metronomic or antiangiogenic chemotherapy, targets endothelial cells while reducing the toxicity associated with standard dose chemotherapy.

The aim of the study is to extend therapy options for children with recurrent or progressive medulloblastoma, ependymoma, ATRT, and CNS tumors of various histologies, for whom no known curative therapy exists, by prolonging survival while maintaining good quality of life.

The study will be conducted in independent strata. Stratum I (recurrent medulloblastoma): recently completed (Peyrl, 2023). Stratum II (recurrent ependymoma), III (recurrent ATRT) and V (recurrent CNS tumors of various histologies, patients with exclusion criteria and adult patients): The primary objective is to determine the response rate defined as the percentage of patients with complete response (CR), partial response (PR), stable disease (SD) or lack of recurrence at 6 months after start of antiangiogenic treatment. Stratum IV (recurrent medulloblastoma): To determine whether temozolomide, irinotecan, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt can increase the response rate after 6 months of treatment, compared with etoposid, cyclophosphamide, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt. Additionally, PFS, OS, toxicity, QoL, performance status, predictive and prognostic markers will be examined.

In stratum II and III, the study will follow an open label, single arm phase 2 design, and an open label randomized two-arm phase 2 design in Stratum IV, and the exploratory Stratum V.

Study Overview

• Status: Recruiting
• Conditions: Medulloblastoma Recurrent; Ependymoma Recurrent; ATRT Recurrent; Rare CNS Tumor Recurrent
• Intervention / Treatment: Drug: Bevacizumab; Drug: Thalidomide; Drug: Celecoxib; Drug: Fenofibric acid; Drug: Etoposide; Drug: Cyclophosphamide; Drug: Etoposide phosphate; Drug: Cytarabine; Drug: Temozolomide (TMZ); Drug: Irinotecan

• Study Type: Interventional
• Enrollment (Estimated): 232
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Andreas Peyrl, MD; Phone Number: 32320 +43 1 40400; Email: andreas.peyrl@meduniwien.ac.at
• Study Contact Backup: Name: Amedeo A Azizi, MD; Phone Number: 32320 +43 1 40400; Email: amedeo.azizi@meduniwien.ac.at

Study Locations

• Austria
  • Graz, Austria, 8036
    • Recruiting
    • Medical University of Graz
    • Contact: Elisabeth Hulla-Gumbsch; Phone Number: 82686 +43 316 385; Email: elisabeth.hulla-gumbsch@klinikum-graz.at
    • Principal Investigator: Martin Benesch, MD
  • Innsbruck, Austria, 6020
    • Recruiting
    • Medical University of Innsbruck
    • Contact: Yvonne Ennemoser, MSc; Phone Number: 23605 +43 512 504; Email: yvonne.ennemoser@tirol-kliniken.at
    • Principal Investigator: Roman Crazzolara, MD
  • Linz, Austria, 4020
    • Recruiting
    • Kepler Universitätsklinikum Med Campus IV
    • Contact: Martina Winkler; Phone Number: 24302 +43 5 7680 84; Email: martina.winkler@gespag.at
    • Principal Investigator: Georg Ebetsberger, MD
  • Salzburg, Austria, 5020
    • Recruiting
    • Salzburger Universitätsklinikum
    • Principal Investigator: Agnes Gamper, MD
    • Contact: Neil Jones, MD; Phone Number: 759 +43 662 448257; Email: n.jones@salk.at
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna
    • Contact: Andreas Peyrl, MD; Phone Number: 32320 +43 1 40400; Email: andreas.peyrl@meduniwien.ac.at
    • Contact: Irene Slavc, MD; Phone Number: 32320 +43 1 40400; Email: irene.slavc@meduniwien.ac.at
    • Principal Investigator: Andreas Peyrl, MD
    • Sub-Investigator: Irene Slavc, MD
• Czechia
  • Brno, Czechia, 61300
    • Recruiting
    • University Hospital Brno
    • Contact: Alexandra Martincekova, MD; Phone Number: +420532234755; Email: Martincekova.Alexandra@fnbrno.cz
    • Principal Investigator: Jaroslav Sterba, MD
    • Sub-Investigator: Zdenek Pavelka, MD
  • Prague, Czechia, 15006
    • Recruiting
    • Motol University Hospital Prague
    • Contact: Klara Hruba; Phone Number: +42 0224436401; Email: klara.hruba@fnmotol.cz
    • Principal Investigator: David Sumerauer, MD
• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • University Hospital Rigshospitalet
    • Contact: Karsten Nysom, MD; Phone Number: +45 3545 0809; Email: karsten.nysom@regionh.dk
    • Principal Investigator: Karsten Nysom, MD
• France
  • Lille, France, 59037
    • Terminated
    • Centre Oscar Lambret
  • Lyon, France, 69373
    • Recruiting
    • Centre léon bérard
    • Contact: Pierre Leblond, MD; Phone Number: +33 4 78 78 28 28; Email: pierre.leblond@ihope.fr
    • Principal Investigator: Pierre Leblond, MD
• Norway
  • Bergen, Norway, 5021
    • Recruiting
    • Onkologisk-hematologisk seksjon Barneklinikken Haukeland universitetssjukehus
    • Contact: Ingrid Torsvik; Phone Number: +4755975147 +4705300; Email: ingrid.kristin.torsvik@helse-bergen.no
    • Principal Investigator: Ingrid Torsvik, MD
• Spain
  • Madrid, Spain, 28009
    • Recruiting
    • Hospital Infantil Universitario Nino Jesus
    • Contact: Alvaro Lassaletta, MD, PhD; Phone Number: 377 +34 915 035938; Email: alvaro.lassaletta@salud.madrid.org
    • Principal Investigator: Alvaro Lassaletta, MD, PhD
• Sweden
  • Gothenburg, Sweden, 416 85
    • Recruiting
    • Sahlgrenska Universitetssjukhuset
    • Contact: Karin Fritzson; Phone Number: +46 31 343 58 65; Email: karin.fritzson@vgregion.se
    • Contact: Anna Schröder- Håkansson; Phone Number: +46 31 343 58 65; Email: anna.schroder_hakansson@vgregion.se
    • Principal Investigator: Magnus Sabel, MD
    • Sub-Investigator: Birgitta Lannering, Prof
  • Linköping, Sweden, 581 85
    • Recruiting
    • Universitetssjukhuset Linköping
    • Contact: Birgitta Hellström; Phone Number: +46 10 103 13 54; Email: birgitta.hellstrom@regionostergotland.se
    • Contact: Pernilla Augustsson; Phone Number: +46 10-103 13 50; Email: pernilla.augustsson@regionostergotland.se
    • Principal Investigator: Irene Devenney, MD
  • Lund, Sweden, 221 85
    • Recruiting
    • Skanes universitetssjukhus
    • Contact: Yvonne Håkansson; Phone Number: +46 46-17 80 64; Email: Yvonne.Hakansson@skane.se
    • Contact: Simon Johansson; Phone Number: +46 46-17 80 64; Email: simon.johansson@skane.se
    • Principal Investigator: Helena Mörse, MD
  • Stockholm, Sweden, SE-171 76
    • Recruiting
    • Karolinska University Hospital
    • Contact: Carina Rinaldo; Phone Number: +46 8 517 701 51; Email: carina.rinaldo@karolinska.se
    • Contact: Yvonne Copeland; Phone Number: +46 8 517 724 84; Email: yvonne.copeland-wahlo@karolinska.se
    • Principal Investigator: Stefan Holm, MD
  • Umeå, Sweden, 901 85
    • Recruiting
    • Norrlands Universitetssjukhus
    • Contact: Marita Wikström-Larsson; Phone Number: +46 90-785 02 44; Email: Marita.Vikstrom.Larsson@vll.se
    • Principal Investigator: Mattias Mattsson
  • Uppsala, Sweden, 751 85
    • Recruiting
    • Akademiska Sjukhuset
    • Contact: Katarina Vallin; Phone Number: +46 18 611 34 94; Email: katarina.vallin@akademiska.se
    • Principal Investigator: Anders Öberg, MD
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Terminated
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Terminated
      • Dana-Farber Cancer Institute and Boston Children's Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 48503
      • Recruiting
      • Helen DeVos Children's Hospital
      • Contact: Rebecca Loret de Mola; Phone Number: 616-267-0334; Email: rebecca.loretdemola@helendevoschildrens.org
      • Principal Investigator: Rebecca Loret De Mola, MD
  • Texas
    • Austin, Texas, United States, 78723
      • Recruiting
      • Dell Children's Medical Group SFC-HEM/ONC
      • Contact: Ashley Ratcliffe; Phone Number: 512-628-1900; Email: aeRatcliff@ascension.org
      • Principal Investigator: Virginia Harrod, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 19 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria for patients Stratum I: Relapsed or progressive medulloblastoma - completed Stratum II: Relapsed or progressive ependymoma (at least one site of untreated recurrent disease) Stratum III: Relapsed or progressive ATRT (at least one site of untreated recurrent disease) Stratum IV: Relapsed or progressive medulloblastoma (at least one site of untreated recurrent disease) Stratum V: Relapsed or progressive CNS tumor of various histologies or patients with exclusion criteria or adult patients (explorative) Histological confirmation at diagnosis or relapse Stratum IV: Confirmation of the medulloblastoma group by methylation; IDAT (Intensity Data; raw data of methylation array) Female or male, aged from 0 to <20 years (at time of original diagnosis) 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 Karnofsky performance status ≥50. For infants and children less than 12 years of age, the Lansky play scale ≥50% will be used Written informed consent of patients and / or legal guardian

Exclusion criteria for patients VP- or subdural peritoneal shunt dependency (can be included in Stratum V) Prior treatment with temozolomide/irinotecan (can be included in Stratum V) Active infection, pregnancy or breast feeding Treatment for current relapse (surgery may be performed before MEMMAT treatment; patients with sites of disease not irradiated are still eligible for the protocol) Known hypersensitivity to any of the drugs in the protocol Active peptic ulcer Any significant cardiovascular disease not controlled by standard therapy e.g. systemic hypertension Anticipation of the need for major elective surgery during the course of the study treatment 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 Non-healing surgical wound A bone fracture that has not satisfactorily healed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Standard Arm (Stratum II, III, IV, V); Etoposid, cyclophosphamide, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt	Drug: Bevacizumab; 10mg/kg, intravenous (iv), biweekly, 1 year; Other Names: Avastin; Drug: Thalidomide; 3mg/kg, oral, daily, 1 year; Drug: Celecoxib; 50-400mg, oral bid, daily, 1 year; Drug: Fenofibric acid; 90mg/m2, oral, daily, 1 year; Drug: Etoposide; 35-50 mg/m2, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year; Drug: Cyclophosphamide; 2.5mg/kg, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year; Drug: Etoposide phosphate; 0.5mg, intrathecal, day 1-5, every four weeks, alternating with intrathecal liposomal cytarabine, 1 year; Drug: Cytarabine; 16-30mg, intrathecal, twice weekly for two weeks out of every four weeks, alternating with intrathecal etoposide phosphate, 1 year
Experimental: Experimental arm (Stratum IV); Temozolomide, irinotecan, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt	Drug: Bevacizumab; 10mg/kg, intravenous (iv), biweekly, 1 year; Other Names: Avastin; Drug: Thalidomide; 3mg/kg, oral, daily, 1 year; Drug: Celecoxib; 50-400mg, oral bid, daily, 1 year; Drug: Fenofibric acid; 90mg/m2, oral, daily, 1 year; Drug: Etoposide phosphate; 0.5mg, intrathecal, day 1-5, every four weeks, alternating with intrathecal liposomal cytarabine, 1 year; Drug: Cytarabine; 16-30mg, intrathecal, twice weekly for two weeks out of every four weeks, alternating with intrathecal etoposide phosphate, 1 year; Drug: Temozolomide (TMZ); Stratum IV; 150mg/m2, day 1-5 every four weeks; Drug: Irinotecan; Stratum IV; 50mg/m2, day 1-5 every four weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy	Response rate (Complete remission, partial response, stable disease =[CR+PR+SD]/n) 6 months after start of antiangiogenic treatment	8 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival rate	The percentage of patients in the study who are alive for a certain period of time (6, 12, 24, and 36 months) after start of treatment with an antiangiogenic multidrug-regime	8 years
Progression free survival rate	The percentage of patients in the study who are alive with a non-progressive disease for a certain period of time (6, 12, 24, and 36 months) after start of treatment with an antiangiogenic multidrug-regime.	8 years
Toxicity	To evaluate and document toxicities from chronic administration of these drugs at the doses prescribed in this protocol in patients with recurrent or progressive medulloblastoma. These will be descriptive in nature.	8 years
Feasibility	To evaluate the feasibility of achieving the prescribed drug doses given the reduced bone marrow tolerance after multiple relapses.	6 years
Quality of life	Quality of Life (QoL) will be evaluated by a generic quality of life instrument for children (the KINDL®-questionnaire).	8 years
Prognostic factors	To evaluate the influence of tumor biology(histologic subgroups, metastatic stage, age at first diagnosis [<3 years, >3 years]), age at start of antiangiogenic therapy, sex, duration of remission prior to antiangiogenic therapy, number of recurrences.	8 years
Angiogenic factors	To evaluate serum markers for in-vitro correlative studies of tumor response.	8 years

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Andreas Peyrl, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Slavc I, Mayr L, Stepien N, Gojo J, Aliotti Lippolis M, Azizi AA, Chocholous M, Baumgartner A, Hedrich CS, Holm S, Sehested A, Leblond P, Dieckmann K, Haberler C, Czech T, Kool M, Peyrl A. Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a "MEMMAT-like" Metronomic Antiangiogenic Approach. Cancers (Basel). 2022 Oct 19;14(20):5128. doi: 10.3390/cancers14205128.
• Peyrl A, Chocholous M, Sabel M, Lassaletta A, Sterba J, Leblond P, Nysom K, Torsvik I, Chi SN, Perwein T, Jones N, Holm S, Nyman P, Morse H, Oberg A, Weiler-Wichtl L, Leiss U, Haberler C, Schmook MT, Mayr L, Dieckmann K, Kool M, Gojo J, Azizi AA, Andre N, Kieran M, Slavc I. Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized Controlled Trial. JAMA Oncol. 2023 Dec 1;9(12):1688-1695. doi: 10.1001/jamaoncol.2023.4437.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Estimated): April 1, 2030
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: May 17, 2011
• First Submitted That Met QC Criteria: May 18, 2011
• First Posted (Estimated): May 19, 2011

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Children; Medulloblastoma; ATRT; Ependymoma; Relapse; antiangiogenic; metronomic; intraventricular; Rare CNS tumor
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Pathological Conditions, Signs and Symptoms; Recurrence; Ependymoma; Medulloblastoma; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Carboxylic Acids; Camptothecin; Alkaloids; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Dacarbazine; Triazenes; Imidazoles; Amides; Piperidines; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Benzene Derivatives; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Arabinonucleosides; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Isoindoles; Benzenesulfonamides; Sulfonamides; Sulfones; Pyrazoles; Temozolomide; Celecoxib; Bevacizumab; Irinotecan; Cyclophosphamide; Cytarabine; Etoposide; Thalidomide; etoposide phosphate; fenofibric acid
• Other Study ID Numbers: MUV-MEMMAT-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No