SIOPEATRT01

Author:  Julia Dobke, erstellt am 2022/05/04, Last modification:  2022/05/11

SIOPEATRT01

An international prospective umbrella trial for children with Atypical Teratoid/Rhabdoid Tumours (ATRT) including A randomized phase III study evaluating the non-inferiority of three courses of highdose chemotherapy (HDCT) compared to focal radiotherapy (RT) as consolidation therapy

Disease

Patients with ATRT of any site and any stage

Type

Prospective, open label multicentre, international, umbrella trial including a randomized phase III study evaluating the non-inferiority of 3 courses of high-dose chemotherapy compared to focal radiotherapy plus standard chemotherapy as a consolidation measure following conventional chemotherapy in children with ATRT ranging from 12-35 months at the time of consolidation (Radiotherapy vs. High Dose Chemotherapy). 

Problem / Objectives

Randomized Part A
To test the non-inferiority, as evaluated by 2-year overall survival (OS), of three courses of HDCT compared to focal RT plus conventional chemotherapy as consolidation therapy following conventional chemotherapy in children with ATRT aged 12-35 months at consolidation therapy.

Part B (not randomized)
To assess the efficacy, as evaluated by OS, of three courses of HDCT as a consolidation measure following conventional-type chemotherapy in children with ATRT aged < 12 months or with contraindications to RT at the time of HDCT and not eligible for randomization within Part A of this protocol, compared to historical controls.

Part C (not randomized)
To assess the efficacy, as evaluated by overall survival, of RT as a consolidation measure combined with conventional-type chemotherapy in children aged >= 36 months with ATRT or contraindications to HDCT and ineligibility for Part A, compared to historical controls.

Therapy / Study arms

All patients start with a tumor-operation, or tumor-biopsy, or tumor-staging followed by a
Common induction chemotherapy:
Patients will receive at least four, and up to six courses of chemotherapy as used in the EU-RHAB protocol: DOX (Doxorubicin) - ICE (Ifosfamide, Carboplatin,Etoposide) - VCA (Vincristine,
Cyclophosphamide, Actinomycin D) + intraventricular methotrexate (MTX).

Part A
Arm RT Conventional chemotherapy
a) Patients will receive a total of 12 courses of DOX (3), ICE (5), VCA (4) + intraventricular MTX (4-6)
b) Radiotherapy to the primary tumour bed will be administered after a minimum of 4 courses of chemotherapy, or as soon as possible thereafter, according to the age (at least 12 months at RT) and clinical condition of the patient.

Arm HDCT Experimental Arm HDCT
Patients will receive a minimum of three and a maximum of six courses of DOX (2), ICE (2), VCA (2) + intraventricular MTX (4-6), followed by three courses of High Dose Chemotherapy, at least 28 days apart, each consisting of: Carboplatin, Thiotepa and Autologous stem cell reinfusion on day 0

Part B
Children under 12 month are not eligible for radiotherapy of the brain. They can´t take part in Part A.
After Induction therapy they will receive 1-2 courses EU-Rhab Therapy and in the case of chemosensitivity followed by 3 courses High Dose Chemotherapy with stemcell rescue (see Part A).

Part C
Part C is for all children from age 36 month and older, who are eligible for radiotherapy.
After the common inductiontherapy they will receive focal or craniospinal radiation followed by 9 courses of Stabdard-EU-Rhab therapy.

Inclusion Criteria

General inclusion criteria

  • Age at diagnosis from birth to 18 years
  • Pathology compatible with ATRT and INI1 loss or SMARCB1 or SMARCA4 deficiency confirmed by local pathology lab
  • Written informed consent and/or assent for study participation according to national legislation
  • Patient agrees to use effective contraception whilst on treatment (patients of childbearing potential)

Specific inclusion criteria Part A

  • Enrolled in the umbrella trial
  • Received 3 courses of induction chemotherapy according to protocol and following induction in SD or better
  • Expected age 12-35 months at time of consolidation therapy (RT or HDCT)
  • Written informed consent and/or assent for randomization according to national legislation
  • Central review of pathology confirmed ATRT
  • MRI (magnetic resonance imaging) and CSF examination after 3 courses of chemotherapy and, if applicable, later showing SD or better (central review national or regional centre)
  • Alanine transaminase (ALT) or aspartate transaminase (AST) <=3.0 of upper limit of normal (ULN) and bilirubin <1.5 x ULN
  • Creatinine <= 1.5 x ULN and measured glomerular filtration rate (GFR) defined age-related values according to national standard methods.
  • Ejection fraction (EF) > 50 % or fractional shortening (FS) > 29 % by echocardiography
Exclusion Criteria

Part A

  • Previous or concomitant tumour directed chemotherapy, RT or targeted therapy, other than within the SIOPE ATRT01 trial
  • Metastatic disease at primary diagnosis
  • At time of inclusion Diarrhoea grade 3 or worse according to the CTCAE v5.0, if uncontrolled despite optimal supportive therapy
  • History or presence of clinically significant cardiac disease, including, but not limited to, any of the following, if uncontrolled despite optimal supportive care: a. Sustained ventricular tachyarrhythmia, b. Any ventricular fibrillation or torsade de pointes,
  • At time of inclusion bradycardia defined as persistent heart rate < 50/minute if uncontrolled despite optimal supportive therapy; Screening electrocardiogram (ECG) with a QTcB) > 450msec minute if uncontrolled despite optimal supportive therapy
  • Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs
  • Any contraindication to any planned chemotherapy drug according to summary of medical product chart (SmPC)
  • Known active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunedeficiency virus (HIV) infection
  • Participation in another interventional therapeutic clinical trial
  • Patients on coumarin-derivative anticoagulants
  • History of thrombosis or sinusoidal obstruction syndrome (SOS)
  • Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
  • Neutropenia (absolute neutrophil count (ANC) <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
  • Synchronous multifocal rhabdoid tumours
  • Hypersensitivity to the active compounds or other excipients contained in one of the investigational medical products listed in the SmPC.
Recruitment 152 patients (76 in each arm) shall be randomized
Status Start in 2021, planned recruitment time ca. 5 years
EudraCT 2018-00332529
Entry Study Register
Principal Investigator Prof. Dr. Dr. med. Michael Frühwald
E-Mail michael-fruehwald@uk-augsburg.de
Contact

Studienleitung

Univ. Prof. Dr. Dr. med. Michael C. Frühwald Universitätsklinikum Augsburg Kinderklinik Augsburg / Mutter-Kind-Zentrum Schwaben / Schwäbisches Kinderkrebszentrum Stenglinstr. 2 81656 Augsburg Telefon +49 (821) 400-9201 Fax +49 (821) 400-179201 michael.fruehwald@uk-augsburg.de

Participants GPOH, France, Denmark, United Kingdom
Weitere Informationen Sponsor: GPOH gGmbH