German Clinical Trials Register

Acronym/abbreviation of the study

PTT2.0

URL of the study

http://pediatric-neurooncology.dkfz.de/index.php/de/diagnose/pediatric-targeted-therapy

Brief summary in lay language

The “Pediatric Targeted Therapy” program aims at the identification of drugable molecular targets in tumors in single cases. Most tumor cells harbour more than one tumor-propagating change, therefore a strategy employing several targeted therapies seems appropriate as well as very promising. We analyze formalin fixed parafin embedded (FFPE) tumor material and blood for druggable alterations.

Brief summary in scientific language

Although the therapy of pediatric malignant diseases has reached a rather favourable overall survival (OS) of around 80% overall, recurrences or progression of high-risk entities such as brain tumors, sarcomas etc. still have a very poor prognosis, with response rates down to below 20%. In most instances, a conventional chemotherapy is chosen as (adjuvant) therapy, without a patient-tailored approach. However, today´s knowledge on the molecular background of the recurrences or progressions is often ahead of the clinical reality, and molecular alterations that can be targeted specifically are known. In our preceding study "Pediatric Targeted Therapy" (PTT) we were able to show that we can detect targetable alterations in the routine diagnostic setting, influencing 41% of the cases in terms of therapeutic decision making. The INFORM Pilot-study showed that targetable alterations are detectable in ca. 50% of recurrences or progressive tumors by analysis of DNA-methylation, gene expression and DNA sequencing. For all cases not fulfilling the INFORM inclusion criteria (e.g. not an entity included in the study, no fresh frozen of the current manifestation available, no target lesion present) the PTT2.0 study is a diagnostic program that allows for a minimum of molecular work-up. The aim of the PTT2.0 study is to the transfer the previously exclusively IHC-based diagnostics into the molecular era, using DNA-methylation analysis and gene-panel sequencing (GPS; next generation sequencing of a defined set of genes). This should enable the confirmation and/or refinement of the histological diagnosis, possibly including first therapeutically usable information, as well as the exact detection of genetic alterations. Since we believe it to be unethical to withhold this information (although being on a research level by nature), the informed consent allows to pass on this information to the treating physician. The treating physician can then decide if she/he wants to use this information for further therapy. The patient can specifically opt out of being informed about genetic alterations potentially predisposing to cancer. Samples of childhood malignant recurrences or progressive tumors diagnosed in Germany or abroad will be analyzed using two complementary molecular screening methods: DNA-methylation analysis and GPS. Both can be done on formalin-fixed paraffin-embedded (FFPE) tissue, considerably facilitating the clinical feasibility. A blood sample is needed for technical reasons. We furthermore want to study if and how often the detection of molecular alterations influences clinical decision making, and how this impacts the clinical course of the patient. The clinical follow-up will be performed by sending a standardized questionnaire to the treating physician in regular intervals after completion of the molecular report. In summary, the PTT2.0 study will answer the question, in how many cases the molecular diagnostics applied can confirm and refine the diagnosis, in how many cases targetable alterations were detected, and finally how often and how successful the additional molecular information has influenced the therapeutic strategy.