Ransbach-baumbach, Germany

HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that introducing targeted therapy using a biomarker driven approach for treatment stratification may improve the outcome of children with R/R acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that allows for the investigation of multiple IMPs and generate pivotal safety and efficacy evidence within the sub-protocols to establish and define the benefits and risks of new treatments for children with R/R leukemia. Sub-Protocol D within HEM-iSMART, is a phase I/II, multicenter, international, open-label clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with actionable alterations in the RAS-RAF-MAPK pathway will be eligible for sub-protocol D including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del.

A Phase 1/2 Study of VX-522 in Participants With Cystic Fibrosis (CF)

A Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 As Monotherapy and Combination Therapy in Subjects with BRAF V600 Mutant Solid Tumors

CATCH: Implementation of Genomics-guided Precision Medicine in Metastatic Breast Cancer

Study Flow CATCH has the goal to implement personalized oncology workflows into the clinic. The clinical precision oncology core backbone encompasses a streamlined diagnostic end-to-end pipeline: Patient screening and enrolment: Metastatic breast cancer (mBC) patients at initial diagnosis of locally-advanced-/ distant metastasis and any other clinical progress are screened for eligibility. The treating physician has to obtain written informed consent prior to enrolment. Collection of biomaterial: Fresh-frozen tumor tissue from progressive prognostic-relevant metastatic lesions is collected during standard-of-care routine procedures at study entry. Consecutive biopsies can be offered at progress. Blood samples are taken at baseline (V1) to account for germline controls and can be sequentially repeated at 3-monthly intervals for monitoring of therapy response. Processing and analyses of patient samples: Biomaterials are centrally processed (standard histology/IHC and pathology review for tumor content; analyte extraction, QC according to standardized, quality-controlled, accredited workflows (DIN EN ISO/IEC 17025). Analyte extraction on fresh-frozen tissue encompasses DNA, RNA and protein isolation. Molecular profiling (Sequencing): Genomic profiling (DIN EN ISO/IEC 17025) is centrally processed to ensure standardization and encompasses whole-genome sequencing (WGS) on fresh-frozen tissue biopsies or whole-exome sequencing (WES) on FFPE specimens (in case of unsuccessful biopsy sampling on recent lesion due to low tumor cell content) complemented by RNA-sequencing. Clinical bioinformatics /Data curation: Tumor- and treatment-relevant genomic aberrations together with standard clinical as well as histopathological parameters are analyzed and put into the clinical context to delineate biomarkers and actionable alterations as well as to tackle the underlying biology of treatment-resistance. Molecular Tumor Board (MTB): Molecular data and conclusive biomarker profiles are discussed by clinicians, bioinformaticians, molecular biologists, human geneticists and pathologists in a weekly interdisciplinary MTB established at NCT Heidelberg. Treatment-relevant biomarkers and actionable drug targets are validated independently. Therapeutic options are prioritized within a molecular report. Therapy Implementation: Patients will be informed in detail by the treating physician to discuss potential genetically-tailored treatment options. The major goal is to offer patients further interventional clinical trials and drive assignment towards genomics-guided matched biomarker / drug combinations. Follow-up / Documentation Schedule: Clinical documentation is conducted by authorized study personal at study entry in a certified electronic case report form (eCRF) and subsequently every 3 months for at least 3 years, at any staging interval or cancer-specific therapy change to generate a comprehensive patient registry. To ascertain comprehensive follow-up, only patients will be enrolled who will be treated locally at the involved trial sites. Molecular data will be systematically collected to drive translational exploratory research projects. The following data are collected and stored (baseline and follow-up assessments) - patient identifier /demographics (including sex, age at diagnosis, family history) - cancer type / medical history / characteristics diagnosis (including date of diagnosis) - clinical outcome / longitudinal disease assessments: relapse and progression - genomic and transcriptomic data - ECOG status - sample information (e.g. specimen type, tumor histological type, anatomical location, tissue analyses) - health-related Quality-of-Life (QoL) / Patient-Reported Outcomes (PROs) Translational scientific companion programs: Excess biomaterial not needed for the diagnostic precision oncology approach can be used for exploratory research (e.g. ex vivo approaches, liquid biopsies, immunophenotyping). Results / Outcome Evaluation:Molecular data will be analysed and interpreted on complementary levels. Biomarkers and molecular aberrations such as mutations, amplifications and aberrant gene expression are evaluated for their tumor-relevance and clinical potential to assign patients for specific clinical trials with targeted treatment approaches.

Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Participants With Beta (β)-Thalassemia

Prospective, Multicenter Cohort Study on Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease. The course of the disease is characterized by a slow destruction of bile ducts, and progressive cholestasis. Prognosis depends on the development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) has been established as standard therapy for PBC and improves patients' long-term outcome. However, UDCA is not a uniformly effective drug, and the prognosis of PBC patients insufficiently responding to treatment is markedly worse. For patients with suboptimal treatment response to UDCA obeticholic acid (OCA) as newly approved medication (OCALIVA®) is available as second line treatment. Due to the low prevalence and the slowly progressive course of the disease it is very difficult to investigate the prognosis of subgroups of PBC patients or to evaluate the effectivness of therapeutic interventions on clinical outcomes. Therefore, several national or international registries (UK-PBC Consortium or the Global PBC Study Group) were founded to better characterize the clinical course of PBC patients. Since in Germany a registry for PBC does not exist, the German PBC Cohort is being implemented as observational study to collect data on treatment progress and success in clinical routine that reflects real world conditions in Germany as closely as possible. The effectiveness and safety/tolerability of PBC treatment options (UDCA as standard therapy and second-line treatment options like OCALIVA in case of inadequate UDCA treatment response) will be evaluated. In approximatly 40 sites in Germany routine data is collected. There are no specifications for the diagnosis, therapy and monitoring of the PBC patients. The documentation of the routine data is carried out alongside with guideline recommended treatment intervals of the patients. Furthermore, a critical criterion for the German PBC Cohort study is the involvement of a sufficient number of gastroenterology specialized practices and outpatient clinics that have consciously not been selected based on the strict specifications of a clinical trial and which provide routine treatment for PBC patients. In addition, patient access is designed to be open. Data will be collected on patient groups that represent a majority of the PBC patients in Germany, but who are not being investigated in clinical trials.

Optimal Detection of Atrial Fibrillation in TIA

Transient ischemic attacks (TIA) are a common neurologic emergency. Clinical management guidelines recommend oral anticoagulation for TIA patients suffering from atrial fibrillation (AF). Therefore, a diagnosis of AF in TIA patients has a major impact on the choice of adequate secondary stroke prevention. However, detection of paroxysmal AF in patients with TIA can be challenging. AF remains undetected in a relevant proportion of stroke and TIA patients using current routine diagnostic procedures. The actual prevalence of AF in TIA patients is unknown. Although the detection of AF has identical consequences for preventive therapy in patients with ischemic stroke and TIA, the management setting and diagnostic pathways frequently differ substantially between both manifestations. So far, only limited data exist on AF detection after TIA specifically, and the best method for diagnosis of AF has not been established. The usefulness of prolonged rhythm monitoring using event recorders or non-invasive continuous ECG in TIA patients has not been determined. While the use of an AF detection tool in TIA patients is desirable, an adequate use of resources of AF detection technologies in unselected TIA patients may be needed for this large scale health care problem. Identifying TIA patients that are at increased risk of suffering from AF using clinical and blood-based biomarkers and therefore most likely to benefit from such diagnostic procedures would be useful. The primary research question of the trial is whether prolonged ECG recording (intervention) significantly increases the rate of detection of pAF compared to 24 h ECG monitoring (control) 6 months after start of monitoring in patients with recent TIA. The co-primary question of the trial is whether 28 d non-invasive continuous ECG monitoring is non-inferior to ECG recording using an implanted event recorder for AF detection. The ODEA-TIA trial is an investigator initiated prospective, multicentre, randomized, open study with blinded outcome assessment comparing different diagnostic methods for detection of paroxysmal AF in patients with recent TIA. The primary endpoint is the rate of AF detection during the 6 months after randomization. Approximately 40 centers in Europe (e.g. UK, Germany, and Spain) will participate in this trial. Patients with a recent TIA fulfilling the eligibility criteria (see below) will be randomized in a 1:1:1 fashion between 24 h arrhythmia monitoring (control arm) and the two procedures for prolonged ECG monitoring (interventional arms). That means we have two interventional arms, patients receiving either continuous 28d non-invasive ECG monitoring or ECG event recording using a subcutaneously implanted event recorder.