Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma and ATRT

Study Overview
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Brief Summary
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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.

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

Conditions
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Medulloblastoma Recurrent, Ependymoma Recurrent, ATRT Recurrent

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Thalidomide
* Drug: Celecoxib
* Drug: Fenofibric acid
* Drug: Etoposide
* Drug: Cyclophosphamide
* Drug: Etoposide phosphate
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 3 Strata (medulloblastoma - 40 patients; ependymoma - 30 patients; ATRT - 30 patients)
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Bevacizumab|10mg/kg, intravenous (iv), biweekly, 1 year|
|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|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medulloblastoma, Ependymoma, ATRT, Relapse, Children, antiangiogenic, metronomic, intraventricular