Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors

ConditionsMedulloblastoma Recurrent Ependymoma Recurrent ATRT Recurrent Rare CNS Tumor Recurrent

Trial statusRecruiting

Trial phasePhase 2

Trial typeInterventional

Biological sexAll

AgeUp to 19

SponsorMedical University of Vienna

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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)

Disqualifiers

Histological confirmation at diagnosis or relapse Stratum IV: 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 <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

Trial design

Design model

Parallel

Treatments tested in this trial

Bevacizumab
Drug
10mg/kg, intravenous (iv), biweekly, 2 years
Thalidomide
Drug
3mg/kg, oral, daily, 2 years
Celecoxib
Drug
50-400mg, oral bid, daily, 2 years
Fenofibric acid
Drug
90mg/m2, oral, daily, 2 years
Etoposide
Drug
35-50 mg/m2, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year
Cyclophosphamide
Drug
2.5mg/kg, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year
Etoposide
Drug
0.5mg, intraventricular, day 1-5, every four weeks, alternating with intraventricular cytarabine, 2 years
Cytarabine
Drug
16-30mg, intraventricular twice weekly for two weeks out of every four weeks, alternating with intraventricular etoposide phosphate, 2 years
Temozolomide (TMZ)
Drug
Stratum IV; 150mg/m2, day 1-5 every four weeks, 1 year
Irinotecan
Drug
Stratum IV; 50mg/m2, day 1-5 every four weeks, 1 year

Treatment groups

232 Participants

are divided into 2 treatment groups

Group A: Standard Arm (Stratum II, III, IV, V)Other 7 interventions

Group B: Experimental arm (Stratum IV)Experimental treatment 8 interventions

Trial outcomes

Primary outcomes

Efficacy

Response rate (Complete remission, partial response, stable disease =\[CR+PR+SD\]/n) 6 months after start of antiangiogenic treatment

Time frame

8 years

Secondary outcomes

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