Neoplasms

All Conditions

Digestive System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Rare Diseases

Osteosarcoma

Neuroblastoma

Sarcoma

Liver Neoplasms

Wilms Tumor

Sarcoma, Ewing

Rhabdomyosarcoma

Neoplasms, Germ Cell and Embryonal

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Myosarcoma

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Syndrome

Neoplastic Syndromes, Hereditary

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Genetic Diseases, Inborn

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Soft Tissue Sarcoma

Germ Cells Tumors

Wilms' Tumor

Ewing Sarcoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

LTLD will be administered intravenously in combination with MR-HIFU ablation on day 1 of every 21 day cycle. There will be two potential dose escalation of LTLD with highest dose not to exceed the adult recommended MTD. Patients may receive up to a total of 6 cycles.

LTLD at dose determined from Part A will be administered intravenously on day 1 of every 21 day cycle. MR-HIFU induced MHT will follow immediately post LTLD infusion for one hour to target area with target temperatures of 40-45°C. Patients may receive up to a total of 6 cycles

Magnetic resonance (MR)-high intensity focused ultrasound (HIFU) provides precise controlled delivery of heat by focusing ultrasound energy inside a lesion using an external applicator that is completely non-invasive and non-ionizing.

Magnetic resonance high intensity focused ultrasound

A heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors.

Lyso-thermosensitive liposomal doxorubicin

AeRang Kim, MD, PhD

This study is looking to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lyso-thermosensitive liposomal doxorubicin (LTLD) administered in combination with MR-HIFU in children with relapsed/refractory solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, and germ cell tumors.

This is phase 1 trial of LTLD with MR-HIFU induced heating in children and young adults with relapsed/refractory solid tumors.

Part A of the trial will be a traditional dose escalation study to determine the pediatric MTD/RP2D of LTLD combined with MR-HIFU ablation which allows for release of doxorubicin in the ablation zone and peri-ablation margins.

Part B of the trial will combine LTLD at the MTD/RP2D with MR-HIFU induced mild hyperthermia (MHT) in an expanded cohort.

A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin and MR-HIFU for Pediatric Refractory Solid Tumors

A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) and Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) for Relapsed or Refractory Solid Tumors in Children, Adolescents, and Young Adults

To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of LTLD administered in combination with MR-HIFU ablation in children with relapsed/refractory solid tumors by examining blood samples collected from participants

To define and describe the toxicities of LTLD administered in combination with MR-HIFU as measured by reportable adverse events of participants as per the CTCAE v 4.0

Analyze blood samples of participants to characterize the pharmacokinetic properties of LTLD administered in combination with MR-HIFU

To determine the feasibility of LTLD administered at the recommended dose in combination with MR-HIFU induced mild hyperthermia (MHT) as determined by patient outcomes and adverse events

To preliminarily determine the antitumor activity of LTLD with MR-HIFU within the confines of a phase 1 study by examining the response of target lesions using RECIST criteria v1.1

To determine changes in symptoms and quality of life in children treated with LTLD and MR-HIFU by administering the Symptom Distress Scale and Peds QL v4.0 to participants

To determine the changes in immune markers in children treated with LTLD and MR-HIFU by examining blood samples from participants

AeRang Kim

MD, PhD

Antirheumatic Agents

Irinotecan

Etoposide

Cyclophosphamide

Temozolomide

Vincristine

Melphalan

Ifosfamide

Etoposide phosphate

Busulfan

Vinblastine

Isophosphamide mustard

Patients in Arm A receive

* VDC-IE x2: Intensified induction phase:

  * 4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
* Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Patients in Arm B receive

* VDC-IE \& TEMIRI: Intensified induction phase:

  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
  * 4 cycles of TEMIRI (Temozolomide-Irinotecan) association
* Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Patients in Arm C receive

* VDC-IE x2: Intensified induction phase:

  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Patients in Arm D receive

* VDC-IE \& TEMIRI: Intensified induction phase:

  * 4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
  * 4 cycles of TEMIRI (Temozolomide-Irinotecan) association
* Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
* Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
* Maintenance phase

  * 1st year : VC (Vincristine Cyclophosphamide) association
  * 2nd year : Cyclophosphamide po 25 mg/m²

Week 1, 5, 9 and week 13:

* Vincristine, IV, D1, 1.5mg/m²
* Doxorubicine, IV, D1-D2, 37.5mg/m²
* Cyclophosphamide, IV, D1, 1.2g/m²

Week 3, 7, 11 and week 15:

* Ifosfamide, IV, D15 to D19, 1.8g/m²/d
* Etoposide, IV, D15 to D19, 100mg/m²/d

VDC-IE x2

Week 1 and week 5:

* Vincristine, IV, D1, 1.5mg/m²
* Doxorubicine, IV, D1-D2, 37.5mg/m²
* Cyclophosphamide, IV, D1, 1.2g/m²

Week 3, and week 7:

* Ifosfamide, IV, D15 to D19, 1.8g/m²/d
* Etoposide, IV, D15 to D19, 100mg/m²/d

VDC-IE

Week 9, 12, 15 and week 18:

* Temozolomide, PO, D1 to D5, 150mg/m²/d
* Irinotecan, IV, D1 to D5, 50mg/m²/d

TEMIRI

After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC:

* Busulfan, IV, D-5 to D-2, dosa according to the weight
* Melphalan, IV, D-1, 140 mg/m²

Peripheral Blood Stem Cell infusion:

- PBSC infusion, D0, at least 3.10\^6 CD34/kg

Consolidation BuMel

\* 1st year : VC

* Vinblastine, IV, 3mg/m², once a week (except during radiotherapy: 1mg/m², 3 times a week)
* Cyclophosphamide, PO, 25mg/m² continuously

Maintenance

Surgical excision of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy. Radiotherapy can be added

Local treatment by surgery

Radiotherapy of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy

Local treatment by radiotherapy

Valérie LAURENCE, MD

Nadège CORRADINI, MD

Ewing's sarcoma and related tumours (ESFT) are rare tumours, with a peak incidence in the second decade of life. They start most often from bone, and are characterized by a specific translocation involving the so-called EWS gene. In one patient out of three, the staging procedures detect metastatic tumours at the diagnosis, most commonly in lungs, bones, and bone marrow.

ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local treatment, and consolidation chemotherapy.

The primary metastatic dissemination is the most important prognostic factor, as the survival rate is around 70-75% for localized tumours, in contrast with less than 50% for patients with primary metastatic disease.

Among primary metastatic patients, bone involvement and / or bone marrow strike markedly the prognosis of these patients. While the long-term survival of patients with isolated pleural pulmonary metastases is approximately 50%, whereas it is only from 0 to 25% in patients with bone marrow involvement.

In 1999, the Intergroup EURO EWING built a new study protocol for patients with Ewing tumours. For the patients with primary extrapulmonary metastatic Ewing tumours (R3 patients), the protocol proposed a heavy induction chemotherapy, in order to propose a consolidation with high dose chemotherapy to a higher rate of patients. The high-dose Busulfan Melphalan chemotherapy (BuMel) was based on Busulfan (600 mg/m²) and Melphalan (140 mg/m²), with autologous peripheral blood stem cell (PBSC) support.

Of note, for the full population of patients with metastatic disease, the 3-year EFS rate was 27% (SD 3%), and the OS rate was 34% (SD 4%), with a median follow-up of 3.9 years after diagnosis, and a median survival time of 1.6 years.

Ewing's sarcoma and related tumours (ESFT) are rare tumours, with a peak incidence in the second decade of life. They start most often from bone, and are characterized by a specific translocation involving the so-called EWS gene. The gene rearrangement results in the production of a transcription factor, in the majority EWS-FLI1 transcription.

In one patient out of three, the staging procedures detect metastatic tumours at the diagnosis; metastases involve most commonly lungs, bones, and bone marrow.

Therefore, in addition to local imaging, the initial extension assessment of any Ewing tumour includes at least a chest CT scan, and a bone marrow extensive evaluation, comprising bone marrow punctures into several different sectors, bone marrow biopsies, and a bone imaging evaluation. The FDG-PET scan is more sensible than bone scan and conventional imaging as MRI in detection of bone metastases. It is more and more widely used in the bone metastasis search in Ewing tumours and seems useful to complement the search of extra-osseous metastases (outside the lungs), including that of bone marrow metastases. The full-body MRI is still under evaluation for the disease extension evaluation.

ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local treatment, and consolidation chemotherapy. The local treatment may combine surgery and / or radiotherapy, according to the tumour site and size, and to the tumour response. ESFT chemotherapy is based on alkylating agents (ifosfamide and / or cyclophosphamide), etoposide, anthracyclines, vincristine, and actinomycin.

The primary metastatic dissemination is the most important prognostic factor, as the survival rate is around 70-75% for localized tumours, in contrast with less than 50% for patients with primary metastatic disease. Among primary metastatic patients, bone involvement and / or bone marrow strike markedly the prognosis of these patients. While the long-term survival of patients with isolated pleural pulmonary metastases is approximately 50%, whereas it is only from 0 to 25% in patients with bone marrow involvement.

In 1999, the Intergroup EURO EWING built a new study protocol for patients with Ewing tumours, localized or metastatic and below 50 years of age. For the patients with primary extrapulmonary metastatic Ewing tumours (R3 patients), the protocol proposed a heavy induction chemotherapy, in order to propose a consolidation with high dose chemotherapy to a higher rate of patients. The high-dose BuMel chemotherapy was based on Busulfan (600 mg/m²) and Melphalan (140 mg/m²), with autologous peripheral blood stem cell (PBSC) support.

The study enrolled 281 patients with primary dissemination and skeletal metastases, with or without bone marrow involvement and with or without additional pulmonary metastases or metastases to other sites. In contrast to the distribution in the entire group of patients with Ewing tumours, the primary site in this subgroup was extremity in only 31% patients, pelvis/abdomen in 45%, and axial/other in 24% patients. The overall survival at 3 years was 28% (SD 4%) in the group with primary tumour in the abdomen or pelvis, versus 39% (SD 6%) for each of the two other groups. Of note, for the full population of patients with metastatic disease, the 3-year EFS rate was 27% (SD 3%), and the OS rate was 34% (SD 4%), with a median follow-up of 3.9 years after diagnosis, and a median survival time of 1.6 years.

First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years

CombinaiR3 - First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years

Sponsor will share de-identified data sets. Documents generated under the project will be disseminated in accordance with Institut Curie policies.

EFS is defined as the time from inclusion date to the first documentation of progression, distant disease, second cancer or death (or last news for patients free of event). The event free survival is estimated by Kaplan-Meier method.

Number of patients with complete response (CR) / partial response (PR) eligible for consolidation phase

Number of patients eligible for consolidation phase have good response after induction phase :

* complete remission on primary tumour and on metastatic sites or
* very good disease response defined by:

  * complete or partial response according to RECIST 1.1 criteria on primary lesion
  * complete or very good partial response (\> 90 %) in case of RECIST 1.1 criteria on metastatic sites AND
  * complete metabolic response in case of metastatic visceral and/or bone/bone marrow lesions, or very good partial response according to investigator's judgment AND
  * in case of bone marrow involvement, bone marrow free of disease on at least one biopsy and two punctures at different sites at RE1 (evaluation after 4 cycles VDC-IE), RE2 (evaluation after 2x4 cycles VDC-IE or 4 cycles VDC-IE+4 cycles TEMIRI), or at the latest RE3 evaluation (evaluation after local treatment).

The overall survival (OS) is estimated by Kaplan-Meier method.

Number of patients with treatment-related adverse events using the NCI CTCAE version 4.03 to graduate the severity of adverse events

Number of patients with treatment-related toxicities on laboratory data using the NCI CTCAE version 4.03 to graduate the severity of toxicities

Efficacy assessed by primary tumour uptake (Standardized Uptake Value max at 18F-FDG PET)

Efficacy assessed by metabolic tumour volume (MTV at 18F-FDG PET)

sample collected : primary tumour and metastatic site (if possible)

Investigation whether the cells from metastatic material harbour a unique transcriptomic signature compared to primary tumour cells : quantification of EWS-ETS transcript and EWS-ETS gene using Polymerase Chain Reaction (PCR) methods to determine the genomic EWS-ETS translocation loci

UNICANCER

Institut Curie

Blood and Lymph Conditions

Nervous System Diseases

Leukemia

Central Nervous System Neoplasms

Nervous System Neoplasms

Cohort 1 : High risk Neuroblastoma, High risk Rhabdomyosarcoma, High risk Ewing Sarcoma Family Tumor, High risk Osteosarcoma, High risk Leukaemia (secondary acute myeloid leukaemia or biphenotypic acute leukaemia) Cohort 2 : Extracerebral and cerebral high risk tumor, High risk Leukaemia (leukaemia with high MRD) Sampling on blood, bone marrow and cerebrospinal fluid

Cohort 3 : Intermediate or low risk tumors : Neuroblastoma, Rhabdomyosarcoma, Ewing Sarcoma Family Tumor, Osteosarcoma Sampling on blood, bone marrow and cerebrospinal fluid

biological sampling during treatment and follow-up

Sampling on blood, bone marrow and cerebrospinal fluid

Gudrun SCHLEIERMACHER, MD

Cécile Simondi

Catherine DEVOLDERE, MD

Isabelle PELLIER, MD

Sebastien KLEIN, MD

Stéphane DUCASSOU, MD

Liana-Stéphania CARAUSU, MD

Marianna DEPARIS, MD

Justyna KANOLD, MD

Claire BRIANDET, MD

Cécile PERRET, MD

Anne-Sophie DEFACHELLESTHOMASSIN, MD

Christophe PIGUET, MD

Yves BERTRAND, MD

Carole COZE, MD

Laure SAUMET, MD

Estelle THEBAUD, MD

Pierre-Simon ROHRLICH, MD

Arnaud PETIT, MD

André BARUCHEL, MD

Frédéric MILLOT, MD

Claire PLUCHART, MD

Sophie TAQUE, MD

Pascale SCHNEIDER, MD

Claire Berger, MD

Catherine PAILLARD, MD

Marion GAMBART, MD

Pascale BLOUIN, MD

Pascal CHASTAGNER, MD

Claudia PASQUALINI, MD

Methodology:

Prospective, multicentric, open, non-randomised, non-therapeutic, interventional study

To identify and characterise:

* meaningful molecular genetic alterations,
* meaningful immunological features of high risk childhood, adolescents and young adult cancers, at diagnosis, during patient treatment and follow-up (time dimension).

Biological Characterisation of High Risk CHildhood Cancer in Children, Adolescents and Young Adults (MICCHADO)

Molecular and Immunological Characterisation of High Risk CHildhood Cancer At DiagnOsis, Treatment and Follow-up - Biological Evaluation in Children, Adolescents and Young Adults -

Identification of molecular genetic alterations based on molecular characterisation of tumor at diagnosis, during patient treatment and follow-up (time dimension)

Identification and characterisation of the tumor microenvironment and the host's immunological profile, at diagnosis and during patient treatment

Comparison between genetic variations identified at diagnosis and those identified on circulating tumor DNA during treatment, FU and/or relapse

To characterise biomarkers, based on molecular analyses of tumour samples from diagnosis, for prognostic and predictive purposes.

To characterise the tumour microenvironment and the host's immunological profile, for prognostic and predictive purposes.

To identify potential prognostic and predictive biomarkers on samples collected during patient's treatment and follow-up, based on changes on circulating tumour DNA (ctDNA), detected by molecular biology techniques, and on immunological findings

To compare molecular and immunological findings at diagnosis and during treatment (data integration)

To investigate the impact of the tumour microenvironment and host's immunological profile on the disease staging at diagnosis, by comparing patients with metastatic to patients with localised disease

Formaldehyde

The group include all the patients with histological confirmed diagnosis of Ewing's Sarcoma who received chemotherapic treatment with temozolomide and irinotecan. In this group the MGMT methylation evaluation will be done

The MGMT methylation will be evaluated by extracting DNA from fresh and Formalin Fixed paraffin Embedded (FFPE) tumor samples

MGMT methylation evaluation

Emanuela Palmerini, MD

This is a biological study in patients with advanced Ewing Sarcoma who received, according, clinical practice, temozolomide and irinotecan The O6-methylguanine-DNA methyltransferase (MGMT) methylation status, will be correlated with the disease clinical data and with the disease response

This is a biological study in patients with advanced Ewing Sarcoma who received, according, clinical practice, temozolomide and irinotecan.

The MGMT methylation status will be correlated with the disease clinical data and with the disease response also in term of metabolic activity (if data will be available) The MGMT methylation analysis will be performed extracting from fresh tumor sample, the DNA on the basis of the standard protocols.

Fresh and Formaline Fixed Paraffin Embeded tumor samples

Assessment of MGMT Promoter Methylation in Advanced Ewing Sarcoma Treated With Temozolomide and Irinotecan

Assessment of MGMT Promoter Methylation and Clinical Benefit From Temozolomide-based Therapy in Ewing Sarcoma Patients

Amplification the methylation-specific Polymerase Chain Reaction products will be electrophoresed on a 2% agarose gel and will visualized with UV light

Correlation with level of MGMT methylation with tumor response

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin and MR-HIFU for Pediatric Refractory Solid Tumors	NCT02536183	Pediatric Cance... Solid Tumors Rhabdomyosarcom... Ewing Sarcoma Soft Tissue Sar... Osteosarcoma Neuroblastoma Wilms Tumor Hepatic Tumor Germ Cell Tumor...	Magnetic resona... Lyso-thermosens...	- 30 Years	Children's National Research Institute
A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin and MR-HIFU for Pediatric Refractory Solid Tumors	NCT02536183	Pediatric Cance... Solid Tumors Rhabdomyosarcom... Ewing Sarcoma Soft Tissue Sar... Osteosarcoma Neuroblastoma Wilms Tumor Hepatic Tumor Germ Cell Tumor...	Magnetic resona... Lyso-thermosens...	- 30 Years	Children's National Research Institute
First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years	NCT03011528	Ewing Sarcoma F...	VDC-IE x2 VDC-IE TEMIRI Consolidation B... Maintenance Local treatment... Local treatment...	2 Years - 50 Years	Institut Curie
Biological Characterisation of High Risk CHildhood Cancer in Children, Adolescents and Young Adults (MICCHADO)	NCT03496402	Neuroblastoma Rhabdomyosarcom... Ewing Sarcoma F... Osteosarcoma Leukemia Central Nervous...	Sampling on blo...	1 Year - 25 Years	Institut Curie
Assessment of MGMT Promoter Methylation in Advanced Ewing Sarcoma Treated With Temozolomide and Irinotecan	NCT03542097	Ewing Sarcoma F...	MGMT methylatio...	-	Istituto Ortopedico Rizzoli

Spots Global Cancer Trial Database for ewing sarcoma family of tumors