MEMMAT: Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma and ATRT

Sponsor

Medical University of Vienna (Other)

Overall Status

Recruiting

CT.gov ID

NCT01356290

Collaborator

(none)

100

Enrollment

Locations

144

Anticipated Duration (Months)

4.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Medulloblastoma Recurrent Ependymoma Recurrent ATRT Recurrent	Drug: Bevacizumab Drug: Thalidomide Drug: Celecoxib Drug: Fenofibric acid Drug: Etoposide Drug: Cyclophosphamide Drug: Etoposide phosphate Drug: Cytarabine	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

3 Strata (medulloblastoma, ependymoma, ATRT)3 Strata (medulloblastoma, ependymoma, ATRT)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 1, 2014

Anticipated Primary Completion Date :

Apr 1, 2026

Anticipated Study Completion Date :

Apr 1, 2026

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Overall survival rate [8 years]
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
Progression free survival rate [8 years]
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.
Toxicity [8 years]
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.
Feasibility [6 years]
To evaluate the feasibility of achieving the prescribed drug doses given the reduced bone marrow tolerance after multiple relapses.
Quality of life [8 years]
Quality of Life (QoL) will be evaluated by a generic quality of life instrument for children (the KINDL®-questionnaire).
Prognostic factors [8 years]
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.
Angiogenic factors [8 years]
To evaluate serum markers for in-vitro correlative studies of tumor response.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 19 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611-2605
2	Dana-Farber Cancer Institute and Boston Children's Hospital	Boston	Massachusetts	United States	02215
3	Helen DeVos Children's Hospital	Grand Rapids	Michigan	United States	48503
4	Dell Children's Medical Group SFC-HEM/ONC	Austin	Texas	United States	78723
5	Medical University of Graz	Graz		Austria	8036
6	Medical University of Innsbruck	Innsbruck		Austria	6020
7	Kepler Universitätsklinikum Med Campus IV	Linz		Austria	4020
8	Salzburger Universitätsklinikum	Salzburg		Austria	5020
9	Medical University of Vienna	Vienna		Austria	1090
10	University Hospital Brno	Brno		Czechia	61300
11	Motol University Hospital Prague	Prague		Czechia	15006
12	University hospital Rigshospitalet	Copenhagen		Denmark	2100
13	Centre Oscar Lambret	Lille		France	59037
14	Centre Léon Bérard	Lyon		France	69373
15	Onkologisk-hematologisk seksjon Barneklinikken Haukeland universitetssjukehus	Bergen		Norway	5021
16	Hospital Infantil Universitario Nino Jesus	Madrid		Spain	28009
17	Sahlgrenska Universitetssjukhuset	Göteborg		Sweden	416 85
18	Universitetssjukhuset Linköping	Linköping		Sweden	581 85
19	Skånes universitetssjukhus	Lund		Sweden	221 85
20	Karolinska University Hospital	Stockholm		Sweden	SE-171 76
21	Norrlands Universitetssjukhus	Umeå		Sweden	901 85
22	Akademiska sjukhuset	Uppsala		Sweden	751 85