INdividualized Therapy FOr Relapsed Malignancies in Childhood (INFORM)

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. In addition to meanwhile established INFORM analyses, a standardized high-throughput drug sensitivity screening platform will be set up to directly test efficacy of drugs on viable tumor cells of the individual patient. Sensitivity and resistance profiles will be further validated in vitro and in vivo in patient derived tumor model systems. Through prospective collection and analyses of liquid biopsy specimens, plasma and cerebrospinal fluid (for brain tumors only), the project will address the question whether tumor derived circulating genetic information is suitable for molecular diagnostics and/or target identification. Within a research program of the DKTK network (proteomic platform) additional protein profiles (proteomics) will be generated for selected samples. Results will be integrated with sequencing data from standard INFORM pipelines to address the question whether proteomic information may serve as an informative additional layer of information to guide personalized patient treatment in the future. 

Clinical studies

The INFORM register provides a solid database for the development of clinical studies. For example, we examine the frequency of mutations for which “intelligent” drugs are available. Together with independent experts, we select the molecular changes for which one or two of these drugs are best suited. In future clinical studies, it will then be examined whether, regardless of the type of cancer, individualized therapy achieves better results than standard chemotherapy for patients with these molecular changes.

Why children?

Of course, we hope first and foremost to be able to improve the survival chances of the young patients. This is made easier by the fact that pediatric oncologists throughout Germany, but also internationally, have always worked closely together. This is the only way to make such a comprehensive study possible, in which more than fifty centers in Germany alone are working together to treat the children. We also now know that childhood tumors have about a hundred times fewer mutations than most adult cancers. This makes the task of identifying the tumor-causing mutations and combining them with the “right” intelligent drug much easier. The experience we gain in the course of the INFORM study will be of great benefit in planning similar studies in adult cancer patients.

The concept

The concept of the INFORM program is to biologically characterize tumor specimens from routine biopsies of pediatric patients with relapsed or refractory high-risk disease for which no other standard therapy exists, regardless of histological diagnosis. State-of-the-art sequencing technologies are used to gain a "fingerprint" of each individual tumor. An expert panel – consisting of experienced pediatric oncologists, bioinformaticians, biologists and pharmacologists - classifies and assesses the changes and targets that could be found in each patient in terms of their clinical relevance. These molecular targets should be available in less than 4 weeks and entered into a centralized database. This study registry does not provide a therapy recommendation. The attending physician has access to his patient's molecular information / targets and is fully responsible for whether and how the data is used for a therapy decision. The goal is to include 260 patients from Germany and other international patients over a period of 2 years.

The purpose of the INFORM registry is to establish a technical, structural and genetic information base for future clinical trials (AMG) in the field of personalized pediatric oncology.

If you have any questions, please contact: INFORM_info(at)DKFZ.de

Registration

New patients will be registered via a remote data entry system by their local pediatric oncologist. No analyses can be done without this electronic registration. Patients can be enrolled from GPOH centers in Germany and international partners of the INFORM consortium. The treating physician will have 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.

Ethics committee

The INFORM registry received a positive opinion from the Heidelberg University ethics committee.

Funding

The INFORM registry is financially supported by the German Cancer Consortium (DKTK), the German Cancer Aid (DKH), the German Childhood Cancer Foundation (DKS), the German Cancer Research Center (DKFZ) and “Ein Herz für Kinder”.

Study participation

Patients (and / or parents) are informed by their attending child oncologist via the INFORM registry and sign the consent form. After reviewing the inclusion and exclusion criteria, the treating oncologist can electronically register the patient with the INFORM register. Without this electronic application, no examinations can be performed. Only a pediatric oncologist can register a patient with the INFORM register.

What happens to any genetic changes found?

A panel of experts (experienced children's oncologists, bioinformaticians, biologists, pharmacologists) classify the changes found according to clinical relevance for each individual patient. The register does not provide any therapy recommendations, only the molecular information. The pediatric oncologist has access to the acquired biological information of the patient and can decide independently whether and how it is used for the therapeutic decision.

Please direct your inquiries to the following contact: INFORM_info(at)dkfz.de

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-sarcoma, high grade glioma, high risk neuroblastoma, non-hodgkin lymphoma, osteosarcoma, soft tissue sarcoma, nephroblastoma, retinoblastoma, malignant endocrine tumor or germ cell tumor. Patients with primary diagnosis high-grade glioma (incl. DIPG), primary diagnosis soft tissue sarcoma or ETMR, for which no curative treatment is established, may also be enrolled. 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) before enrollment.

The patients should be 0 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 diagnosis specified above.

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. The collection of tumor and blood samples as well as cerebrospinal fluid (for brain tumors only) is carried out as part of routine standard of care of the patients. 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 INFORM sample processing laboratory/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 INFORM sample processing laboratory. 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 INFORM sample processing laboratory 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 country. 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 INFORM sample processing 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 INFORM sample processing laboratory in Heidelberg: 

• +49 6221-56-4650

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

• +49 6221-56-6913 / 7294

• Drug Sensitive Profiling - Shipment of tumor tissue
• In- and exclusion criteria
• Overview diagnostics pipeline
• Registration and Shipment Manual International
• Registration and Shipment Manual Germany