Metronomic and Targeted Anti-angiogenesis Therapy for Children With Recurrent/Progressive Medulloblastoma

Patients with relapsed medulloblastoma 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 liposomal cytarabine. The aim of the study is to extend therapy options for children with recurrent or progressive medulloblastoma, 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.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Site-responsible Investigators:

Contacts:

Eligibility Criteria

Inclusion Criteria:

  -  Relapsed or progressive medulloblastoma (at least one site of untreated recurrent
     disease)

  -  Histological confirmation of medulloblastoma 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