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

Conditions

ATRT Recurrent, Ependymoma Recurrent, Medulloblastoma Recurrent, Rare CNS Tumor Recurrent

Keywords

Medulloblastoma, Ependymoma, ATRT, Relapse, Children, antiangiogenic, metronomic, intraventricular, Rare CNS tumor

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.

Andreas Peyrl, Monika Chocholous, Magnus Sabel, Álvaro Lassaletta, Jaroslav Štěrba et al. (27 authors)

JAMA Oncology2023-10-2636 citations

10.1001/jamaoncol.2023.4437

Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a “MEMMAT-like” Metronomic Antiangiogenic Approach

Irene Slavc, Lisa Mayr, Natalia Stepien, Johannes Gojo, Maria Aliotti Lippolis et al. (17 authors)

Cancers2022-10-1940 citations

10.3390/cancers14205128

Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol

Pierre Leblond, Maura Massimino, Martin English, Timothy Ritzmann, Lorenza Gandola et al. (11 authors)

Frontiers in Neurology2022-06-0231 citations

10.3389/fneur.2022.887544

MBCL-43. RECURRENT MEDULLOBLASTOMA – LONG-TERM SURVIVAL WITH A “MEMMAT” BASED ANTIANGIOGENIC APPROACH

Irene Slavc, Andreas Peyrl, Johannes Gojo, Stefan Holm, Klas Blomgren et al. (8 authors)

Neuro-Oncology2020-12-016 citations

10.1093/neuonc/noaa222.516

INNV-36. A METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY MAY PROLONG SURVIVAL FOR PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND ATYPICAL TERATOID RHABDOID TUMOR

Irene Slavc, Andreas Peyrl, Monika Chocholous, Amedeo A. Azizi, Dominik Reisinger et al. (8 authors)

Neuro-Oncology2018-11-01

10.1093/neuonc/noy148.607

P05.32 Update on a metronomic antiangiogenic combination therapy for recurrent atypical teratoid rhabdoid tumor

Irene Slavc, Andreas Peyrl, Monika Chocholous, Thomas Czech, Karin Dieckmann et al. (6 authors)

Neuro-Oncology2018-09-01

10.1093/neuonc/noy139.358

MBCL-27. RESPONSE OF RECURRENT MALIGNANT CHILDHOOD CNS TUMORS TO A MEMMAT BASED METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY VARIES DEPENDENT ON TUMOR TYPE: EXPERIENCE IN 71 PATIENTS

Irene Slavc, Andreas Peyrl, Monika Chocholous, Dominik Reisinger, Lisa Mayr et al. (9 authors)

Neuro-Oncology2018-06-014 citations

10.1093/neuonc/noy059.423

OS02.5 Prolonged survival of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor treated with an antiangiogenic metronomic combination therapy

Irene Slavc, Andreas Peyrl, Amedeo A. Azizi, Johannes Gojo, Thomas Czech et al. (9 authors)

Neuro-Oncology2017-04-01

10.1093/neuonc/nox036.011

ANGI-14UPDATE ON A METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY FOR RECURRENT MEDULLOBLASTOMA AND ATYPICAL TERATOID RHABDOID TUMOR

Irene Slavc, Andreas Peyrl, Monika Chocholous, Johannes Gojo, Moritz Rauch et al. (7 authors)

Neuro-Oncology2015-11-01

10.1093/neuonc/nov207.14

Interventions

DRUGBevacizumab

10mg/kg, intravenous (iv), biweekly, 2 years

DRUGThalidomide

3mg/kg, oral, daily, 2 years

DRUGCelecoxib

50-400mg, oral bid, daily, 2 years

DRUGFenofibric acid

90mg/m2, oral, daily, 2 years

DRUGEtoposide

35-50 mg/m2, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year

DRUGCyclophosphamide

2.5mg/kg, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year

DRUGCytarabine

16-30mg, intraventricular twice weekly for two weeks out of every four weeks, alternating with intraventricular etoposide phosphate, 2 years

DRUGTemozolomide (TMZ)

Stratum IV; 150mg/m2, day 1-5 every four weeks, 1 year

DRUGIrinotecan

Stratum IV; 50mg/m2, day 1-5 every four weeks, 1 year

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

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;

Eligibility

Sex/Gender

ALL

Age

No minimum to 19 Years

Healthy volunteers

No

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 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 * Written informed consent of patients and / or legal guardian

Design outcomes

Primary

Measure	Time frame	Description
Efficacy	8 years	Response rate (Complete remission, partial response, stable disease =\[CR+PR+SD\]/n) 6 months after start of antiangiogenic treatment

Secondary

Measure	Time frame	Description
Overall survival rate	8 years	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
Progression free survival rate	8 years	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.
Toxicity	8 years	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.
Feasibility	6 years	To evaluate the feasibility of achieving the prescribed drug doses given the reduced bone marrow tolerance after multiple relapses.
Quality of life	8 years	Quality of Life (QoL) will be evaluated by a generic quality of life instrument for children (the KINDL®-questionnaire).
Prognostic factors	8 years	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.
Angiogenic factors	8 years	To evaluate serum markers for in-vitro correlative studies of tumor response.

Countries

Austria, Czechia, Denmark, France, Norway, Spain, Sweden, United States

Contacts

CONTACTAndreas Peyrl, MD

andreas.peyrl@meduniwien.ac.at+43 1 40400

CONTACTJohannes A Gojo, MD, PhD

johannes.gojo@meduniwien.ac.at+43 1 40400

PRINCIPAL_INVESTIGATORAndreas Peyrl, MD

Medical University of Vienna

STUDY_DIRECTORAmedeo A Azizi, MD