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Protocol Synopsis

The INFORM Registry

Although current treatment of childhood malignancies results in overall cure rates in the order of 75% with modern multi-modal protocols, relapse from high risk disease remains a tremendous clinical problem. Only a small proportion of patients with relapses (about 10%) can be cured. This medical need will be addressed with the INFORM registry „INdividualized Therapy FORelapsed Malignancies in Childhood“. The INFORM consortium is comprised of leading pediatric oncologists from the study groups of the Society for Pediatric Oncology and Hematology (GPOH) or the respective national coordinator in case of international patients and renowned scientists in the field of high-content genomics research.

Concept

The concept of the INFORM registry is to biologically characterize tumor samples (collected through routine standard of care biopsies) for all pediatric patients with relapsed or refractory high risk disease of the 12 most common but also selected rare entities for which no further standard of care therapy is available. State-of-the-art next-generation sequencing technologies will be applied to get a “fingerprint” of each individual tumor. An expert panel of experienced pediatric oncologists, biologists, bioinformaticians and pharmacologists classifies and weighs the aberrations/targets found for each single patient according to clinical relevance. These molecular targets shall be available in less than 4 weeks and will be entered in the central database. No therapy recommendation will be given within this registry study. The treating physician has access to the molecular information/targets of their patients and carries the full responsibility as to whether and in which way they use these data for therapy decision-making.

Aims

The intention of the INFORM registry is to establish the technical, structural and information basis for a future clinical trial (AMG) for personalized pediatric oncology. The primary objectives of the INFORM registry are: To establish the logistics (tissue sample submission, analysis and classification); to establish an individualized risk management support (working group with experts in drug interaction) and access modes for targeted compounds; and to establish a database for the documentation of sequencing results, identified clinically relevant targets, clinical courses, and therapies / single experimental treatments (Einzelheilversuche). Secondary objectives of the INFORM registry are the descriptive and exploratory analyses of registered patients regarding response rates, progression free and overall survival as well as to collect fresh tumor tissue for establishment of in vitro and in vivo based tumor models.

Eligible Patients

Inclusion criteria for the registry population are relapsed/progressive or refractory diagnoses of ALL-HR, ALL Post-SCT, AML, rhabdoid tumor, ependymoma, medulloblastoma, Ewing’s-sarcoma, high-grade glioma (including diffuse intrinsic pontine glioma), high-risk neuroblastoma, non-hodgkin lymphoma, osteosarcoma, soft tissue sarcoma and rare tumor diseases in case of no established curative treatment.

The patients should be 1 to 40 years old and treated according to a protocol of the Society for Pediatric Oncology and Hematology (GPOH) or an equivalent protocol as their first-line protocol, except in case of specific primary soft tissue sarcoma or diffuse intrinsic pontine glioma indications. .

Although patients can be included up to the age of 40 years, they must have had their primary diagnosis below the age of 21 years. Exceptionally, “other” pediatric refractory or progressive/relapsed entities including rare tumor diseases may be registered following consultation with the INFORM trial office (and in case of rare tumor diseases with the GPOH STEP registry) before enrollment. The collection of tumor samples is carried out as part of routine standard of care of the patients. 260 patients in Germany plus additional international patients shall be included over a time period of two years. Patients can be enrolled from GPOH centers in Germany and international partners of the INFORM consortium. For details, please see In-/Exclusion criteria.

Process Synopsis

Patients with clinical indications of refractory/relapsed/progressive malignant disease and who receive a biopsy (solid tumors) or bone marrow aspiration (leukemia) as part of their standard of care treatment at their local Pediatric Oncology Center are eligible for INFORM. Before enrollment, the GPOH study group of the respective entity or the respective national coordinator will be consulted to confirm eligibility. Informed consent will be obtained before enrollment in the INFORM registry by the local treating physician and the patient will be registered in the central database (MARVIN) through remote data entry (RDE) system. Accompanied with a shipment form generated by MARVIN (see below), samples and matching non-malignant material (corresponding normal cells, e.g. blood) will be submitted to the Central Pathology Lab. After sequencing/molecular analysis, raw data will be subjected to bioinformatic processing and biological filtering, resulting in up to 5 prioritized targets that will be technically verified with an independent method by the Central Pathology Lab. An expert panel consisting of molecular biologists, pediatric oncologists including the coordinator of the respective disease entity (or the respective national coordinator in case of international patients) and pharmacologists will review and prioritize the identified targets. Thereafter, the Central Pathology Lab will report all verified targets to the data review board which, after interdisciplinary discussion, will deposit the targets in the central database. The central database is linked to the INFORM website which contains regularly updated information on molecular targets and a list of targeted drugs including information on dosing, administration, side effects, toxicities, pharmacology, and drug interactions. The treating physician has password secured access to their patients’ data deposited in the central database. They may use the molecular target information for clinical decision-making on an individual basis. The coordinator of the disease entity (or the respective national coordinator) will be available for recommendations for the use of specific drugs in context with disease-specific backbone therapies and has password secured access to the data of all patients within the respective entity. Clinical follow-up of all patients will be deposited in the central database.

Patient Registration and Shipment of Material

For details, please read the manual carefully – incomplete submissions will significantly delay the process! 

After receiving informed consent, it is mandatory to register a patient in the central MARVIN database before tissue shipment.

INFORM shipment forms, provided with an INFORM patient ID will be automatically generated upon registration of a patient in MARVIN. Only after registration and with these forms, tissue can be shipped to the Central Pathology Laboratory in Heidelberg. 

Tissue shipped without INFORM patient ID and/or no previous registration in MARVIN cannot be processed.

Important Note

Data of all registered patients will be deposited in the registry database. Routine biopsy or puncture and histopathological confirmation are part of standard of care treatment. Sequencing of tumor material is not part of the diagnostic procedure. The registry does not give treatment recommendations. The treating physician has password secured access to their own patients and may retrieve their patients’ identified targets from the database. It is within the responsibility of the treating physician, whether or not they want to use the information from the registry database for individual clinical treatment decision-making. The treating physician carries full responsibility for treatment. The treating physician will collect clinical information about the course of his registered patients in the INFORM database whether or not deposited biological information was used for clinical decision-making.

For additional information regarding sample shipment, please contact the Central Pathology Laboratory in Heidelberg: 

 For all other additional information regarding the INFORM registry, please contact the NCT Clinical Trial Center in Heidelberg:

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