Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors (MEMMAT)
Brief Summary
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.
Detailed Description
N/A
Intervention / Treatment
Study Design
Treatment
Randomized
Parallel Assignment
5 Strata: Stratum I: medulloblastoma - 40 patients -completed (see Peyrl et al, 2023, JAMA Oncology); Stratum II: ependymoma - 30 patients; Stratum III: ATRT - 30 patients); Stratum IV: medulloblastoma - randomized, 132 patients; Stratum V: Rare CNS tumors and patients with exclusion criteria - exploratory
None (Open Label)
Arm Groups
Other: Standard Arm (Stratum II, III, IV, V)
Etoposid, cyclophosphamide, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt
Experimental: Experimental arm (Stratum IV)
Temozolomide, irinotecan, bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide ivt, cytarabine ivt
Eligibility Criteria
Inclusion criteria for patients
Stratum I: Relapsed or progressive medulloblastoma - completed
Stratum II: Relapsed or progressive ependymoma (at least one site of untreated recurrent disease)
Stratum III: Relapsed or progressive ATRT (at least one site of untreated recurrent disease)
Stratum IV: Relapsed or progressive medulloblastoma (at least one site of untreated recurrent disease)
Stratum V: Relapsed or progressive CNS tumor of various histologies or patients with exclusion criteria or adult patients (explorative) Histological confirmation at diagnosis or relapse
Stratum VI: Confirmation of the medulloblastoma group by methylation; IDAT (Intensity Data; raw data of methylation array) 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 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 legal guardian
Exclusion criteria for patients VP- or subdural peritoneal shunt dependency (can be included in Stratum V)
Prior treatment with temozolomide/irinotecan (can be included in Stratum V)
Active infection, pregnancy or breast feeding
Treatment for current relapse (surgery may be performed before MEMMAT 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 controlled 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
Outcome Measures
Efficacy
Response rate (Complete remission, partial response, stable disease =[CR+PR+SD]/n) 6 months after start of antiangiogenic treatment
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
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
Where is this study conducted?
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