Patients with with recurrent or progressive medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor (ATRT), and CNS tumors of various histologies have a very poor prognosis whether treated with conventional chemotherapy, high-dose chemotherapy with stem cell rescue, irradiation or combinations of these modalities. Antiangiogenesis therapy has emerged as a new treatment option in solid malignancies. The frequent delivery of low doses of chemotherapy, referred to as metronomic or antiangiogenic chemotherapy, targets endothelial cells while reducing the toxicity associated with standard dose chemotherapy. The aim of the study is to extend therapy options for children with recurrent or progressive medulloblastoma, ependymoma, ATRT, and CNS tumors of various histologies, for whom no known curative therapy exists, by prolonging survival while maintaining good quality of life. The study will be conducted in independent strata. Stratum I (recurrent medulloblastoma): recently completed (Peyrl, 2023). Stratum II (recurrent ependymoma), III (recurrent ATRT) and V (recurrent CNS tumors of various histologies, patients with exclusion criteria and adult patients): The primary objective is to determine the response rate defined as the percentage of patients with complete response (CR), partial response (PR), stable disease (SD) or lack of recurrence at 6 months after start of antiangiogenic treatment. Stratum IV (recurrent medulloblastoma): To determine whether temozolomide, irinotecan, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt can increase the response rate after 6 months of treatment, compared with etoposid, cyclophosphamide, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt. Additionally, PFS, OS, toxicity, QoL, performance status, predictive and prognostic markers will be examined. In stratum II and III, the study will follow an open label, single arm phase 2 design, and an open label randomized two-arm phase 2 design in Stratum IV, and the exploratory Stratum V.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
232
10mg/kg, intravenous (iv), biweekly, 1 year
3mg/kg, oral, daily, 1 year
50-400mg, oral bid, daily, 1 year
90mg/m2, oral, daily, 1 year
35-50 mg/m2, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year
2.5mg/kg, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year
0.5mg, intrathecal, day 1-5, every four weeks, alternating with intrathecal liposomal cytarabine, 1 year
16-30mg, intrathecal, twice weekly for two weeks out of every four weeks, alternating with intrathecal etoposide phosphate, 1 year
Stratum IV; 150mg/m2, day 1-5 every four weeks
Stratum IV; 50mg/m2, day 1-5 every four weeks
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
TERMINATEDDana-Farber Cancer Institute and Boston Children's Hospital
Boston, Massachusetts, United States
TERMINATEDHelen DeVos Children's Hospital
Grand Rapids, Michigan, United States
RECRUITINGDell Children's Medical Group SFC-HEM/ONC
Austin, Texas, United States
RECRUITINGMedical University of Graz
Graz, Austria
RECRUITINGMedical University of Innsbruck
Innsbruck, Austria
RECRUITINGKepler Universitätsklinikum Med Campus IV
Linz, Austria
RECRUITINGSalzburger Universitätsklinikum
Salzburg, Austria
RECRUITINGMedical University of Vienna
Vienna, Austria
RECRUITINGUniversity Hospital Brno
Brno, Czechia
RECRUITING...and 12 more locations
Efficacy
Response rate (Complete remission, partial response, stable disease =\[CR+PR+SD\]/n) 6 months after start of antiangiogenic treatment
Time frame: 8 years
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
Time frame: 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.
Time frame: 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.
Time frame: 8 years
Feasibility
To evaluate the feasibility of achieving the prescribed drug doses given the reduced bone marrow tolerance after multiple relapses.
Time frame: 6 years
Quality of life
Quality of Life (QoL) will be evaluated by a generic quality of life instrument for children (the KINDL®-questionnaire).
Time frame: 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.
Time frame: 8 years
Angiogenic factors
To evaluate serum markers for in-vitro correlative studies of tumor response.
Time frame: 8 years
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