Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma and ATRT

Medulloblastoma Recurrent Clinical Trial

— MEMMAT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01356290
• Other study ID #: MUV-MEMMAT-01
• Status: Recruiting
• Phase: Phase 2
• Start date: April 2014
• Est. completion date: April 2026

Study information

• Verified date: January 2024
• Source: Medical University of Vienna
• Contact: Andreas Peyrl, MD
• Phone: +43 1 40400
• Email: andreas.peyrl[@]meduniwien.ac.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with relapsed medulloblastoma, ependymoma and ATRT have a very poor prognosis whether treated with conventional chemotherapy, high-dose chemotherapy with stem cell rescue, irradiation or combinations of these modalities. Antiangiogenetic therapy has emerged as new treatment option in solid malignancies. The frequent, metronomic schedule targets both proliferating tumor cells and endothelial cells, and minimizes toxicity. In this study the investigators will evaluate the use of biweekly intravenous bevacizumab in combination with five oral drugs (thalidomide, celecoxib, fenofibrate, and alternating cycles of daily low-dose oral etoposide and cyclophosphamide), augmented with alternating courses of intrathecal etoposide and cytarabine. The aim of the study is to extend therapy options for children with recurrent or progressive medulloblastoma, ependymoma and ATRT, for whom no known curative therapy exists, by prolonging survival while maintaining good quality of life. The primary objective of the MEMMAT trial is to evaluate the activity of this multidrug antiangiogenic approach in these heavily pretreated children and young adults. Additionally, progression-free survival (PFS), overall survival (OS), as well as feasibility and toxicity will be examined.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: April 2026
• Est. primary completion date: April 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 19 Years

Eligibility

Inclusion Criteria:

• Relapsed or progressive medulloblastoma, ependymoma or ATRT (at least one site of untreated recurrent disease)
• Histological confirmation of medulloblastoma, ependymoma or ATRT at diagnosis or relapse
• 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 parents

Exclusion Criteria:

• Active infection
• VP-shunt dependency
• Pregnancy or breast feeding
• Conventional chemotherapy, antiangiogenic treatment or complete irradiation of all disease for current relapse (surgery may be performed before antiangiogenic 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 controled 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

Related Conditions & MeSH terms

• ATRT Recurrent
• Ependymoma
• Ependymoma Recurrent
• Medulloblastoma
• Medulloblastoma Recurrent
• Recurrence

Intervention

Drug:
• Bevacizumab
10mg/kg, intravenous (iv), biweekly, 1 year
• Thalidomide
3mg/kg, oral, daily, 1 year
• Celecoxib
50-400mg, oral bid, daily, 1 year
• Fenofibric acid
90mg/m2, oral, daily, 1 year
• Etoposide
35-50 mg/m2, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year
• Cyclophosphamide
2.5mg/kg, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year
• Etoposide phosphate
0.5mg, intrathecal, day 1-5, every four weeks, alternating with intrathecal liposomal cytarabine, 1 year
• Cytarabine
16-30mg, intrathecal, twice weekly for two weeks out of every four weeks, alternating with intrathecal etoposide phosphate, 1 year

Locations

Country	Name	City	State
Austria	Medical University of Graz	Graz
Austria	Medical University of Innsbruck	Innsbruck
Austria	Kepler Universitätsklinikum Med Campus IV	Linz
Austria	Salzburger Universitätsklinikum	Salzburg
Austria	Medical University of Vienna	Vienna
Czechia	University Hospital Brno	Brno
Czechia	Motol University Hospital Prague	Prague
Denmark	University hospital Rigshospitalet	Copenhagen
France	Centre Oscar Lambret	Lille
France	Centre Léon Bérard	Lyon
Norway	Onkologisk-hematologisk seksjon Barneklinikken Haukeland universitetssjukehus	Bergen
Spain	Hospital Infantil Universitario Nino Jesus	Madrid
Sweden	Sahlgrenska Universitetssjukhuset	Göteborg
Sweden	Universitetssjukhuset Linköping	Linköping
Sweden	Skånes universitetssjukhus	Lund
Sweden	Karolinska University Hospital	Stockholm
Sweden	Norrlands Universitetssjukhus	Umeå
Sweden	Akademiska sjukhuset	Uppsala
United States	Dell Children's Medical Group SFC-HEM/ONC	Austin	Texas
United States	Dana-Farber Cancer Institute and Boston Children's Hospital	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Helen DeVos Children's Hospital	Grand Rapids	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Vienna

Countries where clinical trial is conducted

United States,  Austria,  Czechia,  Denmark,  France,  Norway,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy	Response rate (Complete remission, partial response, stable disease =[CR+PR+SD]/n) 6 months after start of antiangiogenic treatment	8 years
Secondary	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
Secondary	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
Secondary	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
Secondary	Feasibility	To evaluate the feasibility of achieving the prescribed drug doses given the reduced bone marrow tolerance after multiple relapses.	6 years
Secondary	Quality of life	Quality of Life (QoL) will be evaluated by a generic quality of life instrument for children (the KINDL®-questionnaire).	8 years
Secondary	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
Secondary	Angiogenic factors	To evaluate serum markers for in-vitro correlative studies of tumor response.	8 years