A Phase II Study of metronomic and targeted anti-angiogenesis therapy for children with recurrent/progressive medulloblastoma

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.

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