Praha 10 - Strasnice, Czech Republic

Expression-linked and R-ISS-adapted Stratification for First Line Therapy in Multiple Myeloma Patients

Multiple myeloma is a malignant disease of the BM characterized by clonal expansion of plasma cells. Current guidelines recommend that newly diagnosed transplant-eligible patients with multiple myeloma (NDMMTE) shall undergo several cycles of induction, followed by one or two cycles high-dose melphalan followed by autologous stem cell transfusion (ASCT). With the introduction of new drugs, the prognosis of multiple myeloma patients has considerably improved over time. Currently, induction therapy schemes usually consist of an immunomodulator (thalidomide or lenalidomide), a CD38 targeting antibody, a proteasome inhibitor, and dexamethasone. The induction therapy is then followed by stem cell mobilization and subsequently one or two cycles of high-dose melphalan-chemotherapy based on the initial cytogenetic findings of the malignant plasma cells and the initial stage of the disease. Current guidelines recommend two cycles of high-dose melphalan therapy followed by autologous stem cell transplantation in case of the following initial findings: presence of cytogenetic: (4;14), (14;16), (14;20) translocations or deletion 17p (del 17p), determined by fluorescence in situ hybridization (FISH). In addition, initial stage of R-ISS stage III leads also to the recommendation of two rounds of high-dose melphalan. Furthermore, if the patient does not achieve partial response as described by International Myeloma Working Group (IMWG) recommendations after the first cycles of high-dose melphalan, a second cycle of high-dose melphalan therapy should be administered. Later, patients treated outside clinical trials receive either 2-3 cycles of consolidation therapy and finally take lenalidomide (usually 10 or 15 mg on a daily basis) or proceed directly to a lenalidomide based maintenance therapy till progression or intolerable toxicity. Essentially, all NDMMTE patients undergo at least one cycle of high-dose chemotherapy, which is associated with high morbidity including acute toxicities like cytopenia, infection, and long-term effects such as myelodysplastic disease (MDS) and secondary malignancies and rarely death. Based on preliminary data and published reports, exposure to high-doses of the genotoxic agent melphalan might render the residual malignant myeloma cells into more aggressive clones, accelerating relapse by potentially altering stroma. Finally, exposure to melphalan is well known to increase the possibility of secondary malignant disease development. In MM patients, high-dose melphalan therapy improves OS and PFS if patients from all risk groups are taken in consideration. Yet, it remains to be answered, whether also low risk patients have an additional benefit from high-dose melphalan therapy or whether for these patients, a less toxic regime would be similarly sufficient with regard to PFS and OS. The challenging question will be whether the effect of melphalan on initial disease control might be outpaced by the negative effects as described above. Hence, the sponsor will explore whether treatment with high-dose melphalan might represent an overtreatment for certain subpopulation myeloma patients. These patients might be adequately treated without need of high-dose melphalan as part of the first line treatment. We, therefore, propose to use a personalized approach to evaluate whether patients with a low-risk profile (R-ISS stage I, characterized by low tumor burden and absence of adverse cytogenetic findings or elevated LDH) and with a gene expression profile indicating a standard risk of relapse (please see below) might be sufficiently treated with an intensified induction course without subsequent upfront high-dose melphalan chemotherapy. Personalized therapy can be achieved by considering gene expression analysis of the malignant BM cells together with the diagnostic work-up. We have a standardized CE-certified gene expression array, the MMprofilerTM, allowing accurate prediction of high-risk disease based on the SKY92 risk signature, calculating a risk score based on the expression of 92 genes from the malignant plasma cells. Its prognostic superiority has been analyzed in multiple retrospective analyses, totaling over 3,000 MM patients. This enables us to better define the aggressiveness of the disease and NDMMTE patient's 'individual' risk for disease progression within this research initiative and to define appropriate clinical strategies. As an ultimate goal of this study, the sponsor aims to combine the outcome of gene expression array with the revised international staging system (R-ISS) to achieve a more personalized treatment. For patients with R-ISS stage I and the absence of high-risk disease as determined by the SKY92 signature (GEP-SR), the sponsor proposes a therapeutic approach without a requirement for high-dose chemotherapy as part of first-line therapy. This study would provide personalized treatment for myeloma patients, which could dramatically reduce toxicity, cost of therapy and lower the probability to develop a malignant clone (by about 25%) in all NDMMTE, and simultaneously improving the outcome of overall survival (OS) and progression-free survival (PFS).

International Cooperative Treatment Protocol for Children and Adolescents With Lymphoblastic Lymphoma

The trial LBL 2018 is a collaborative prospective, multi-national, multi-center, randomized clinical trial for the treatment of children and adolescents with newly diagnosed lymphoblastic lymphoma. The LBL 2018 trial will be open for the qualified centers of following participating study Groups (core study cohort): AIEOP (Italy), BFM (Austria, Czech Republic, Germany, Switzerland), BSPHO (Belgium), CoALL (Germany), DCOG (The Netherlands), NOPHO (Denmark, Finland, Norway, Sweden), PPLLSG (Poland), SEHOP (Spain) and SFCE (France). HKPHOSG (Hong Kong), HPOG (Hungary), ISPHO (Israel), NSPHO (Moscow), SHOP (Portugal) and SPS (Slovak Republic) start patient recruitment into the extended study cohort (without randomization). Over the trial period study groups may switch from the extended study cohort to the core study cohort. Primary objectives: - Randomization R1, all patients eligible: To examine, whether the cumulative incidence of relapses with involvement of the CNS (CNS relapse, pCICR) can be decreased by a modified induction therapy including dexamethasone (experimental arm) instead of prednisone (standard arm) - Randomization R2, only patients with high risk LBL eligible: to examine, whether the probability of event-free survival (pEFS) in these patients can be improved by receiving an intensified treatment arm versus a standard treatment arm (as used in the EURO-LB 02) Patients are stratified into 3 different risk groups according to CNS status, immunophenotype, genetic markers and stage of disease at diagnosis: high risk group (HR), standard risk group I/II (SR I/II) and standard risk group (SR). Patients in the risk groups SR I/II and SR are randomized (R1) in two arms after a cytoreductive prephase with prednisone. Patients in standard arm receive the standard induction phase with prednisone. Patients in the experimental arm receive an induction phase with dexamethasone instead of prednisone. In SR group, induction phase is followed by the consolidation phase, the non-HR extra-compartment phase with HD-MTX (high-dose methotrexate), the reintensification phase and the maintenance therapy for the total therapy duration of 24 months. In SR I/II group, patients receive no reintensification phase. The Induction phase is followed by the consolidation phase, the non-HR extra-compartment phase and the maintenance therapy for the total therapy duration of 24 months. Patients in the HR group are eligible for randomization (R1) as outlined above. In addition high risk patients are eligible for second randomization (R2) at the end of induction phase. In the standard arm, HR-patients receive the consolidation phase and the non-HR extra-compartment phase. In the experimental arm, HR-patients receive a consolidation phase including two additional doses of PEG asparaginase and the HR-intensified extra-compartment phase consisting of two high risk courses alternating with two HD-MTX courses. Either phase is followed by the reintensification phase and the maintenance therapy for the total therapy duration of 24 months. Patients with involvement of the CNS (CNS positive) are stratified to the high risk group (HR) and are eligible for both randomizations (R1 and R2). Additionally, patients with CNS involvement (CNS positive) receive intensified intrathecal therapy. Intrathecal therapy consists of TIT (triple intrathecal therapy) after diagnosis of CNS involvement. TIT is administered twice weekly until clearance of blasts in the cerebrospinal fluid is achieved. Further intrathecal therapy is provided at the same points of time as for patients without CNS involvement, but TIT instead of MTX IT. In addition, patients receive four additional doses of TIT during maintenance. Cranial irradiation is omitted for patients with CNS involvement.

Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia

In Waldenström's macroglobulinemia (WM) chemotherapy induces only low CR/VGPR rates and response duration is limited. In addition, WM patients are often elderly, partly not tolerating chemotherapy related toxicities. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity and favorable toxicity profile in indolent B-NHL such as CLL, Venetoclax was approved for the treatment of this diseases by the FDA and the European Medicines Agency (EMA). First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment or patients carrying CXCR4 mutations. Ibrutinib itself has high activity and a relatively low toxicity profile in WM, but has also major disadvantages: the main disadvantage is the need to apply this drug continuously. Furthermore, Ibrutinib efficacy depends largely on the genotype with a substantial drop in major responses and PFS in the presence of CXCR4 mutations and non-mutated MYD88. In particular the need of continuous treatment for Ibrutinib has prevented that Ibrutinib has become the standard of care outcompeting conventional Rituximab/chemotherapy. This is reflected in current guidelines such as the NCCN and the ESMO guidelines, which still see immunochemotherapy as a backbone of treatment, largely because of the advantage of a timely fixed application. Data in CLL in the relapsed as well as in the first line setting have convincingly shown that in contrast to Ibrutinib Venetoclax is highly efficient also when used in a timely defined application scheme over 12 months in combination with the anti-CD20 antibody Rituximab. Data documented deep responses including molecular responses and a highly significant advantage over immunochemotherapy in large international Phase III trials, changing the standard of care in this disease. Based on this the hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes compared to chemotherapy and Rituximab (DRC) in patients with treatment naïve WM, regardless of the genotype. A first indication for this assumption in the proposed trial will allow the performance of confirmatory phase 3 trials that might change the standard of care in WM. This study is an International phase II explorative, multicenter, open label, and randomized trial. The study will consist of an open labeled, stratified 1:1 randomization between Arm A and Arm B for de novo WM patients in need of treatment (phase II). Stratification factors are MYD88 and CXCR4 status (positive vs. negative). A stratified central block randomization will be used. The central randomization service will be used to avoid predictability of the treatment arm. The primary goal of this study is to explore the efficacy of Venetoclax plus Rituximab versus Dexamethasone/Cyclophosphamide/Rituximab in the treatment of de novo WM patients (Arm A vs. Arm B). 80 patients are planned to be recruited for this study at approcimately 30 sites in Germany, Greece and France.

Escalated Single Platelet Inhibition for One Month Plus NOAC in Patients With Atrial Fibrillation and ACS Undergoing PCI

Niraparib vs Niraparib Plus Bevacizumab in Patients With Platinum/Taxane-based Chemotherapy in Advanced Ovarian Cancer

Eligible patients will be those patients with newly diagnosed, histologically confirmed, advanced (FIGO stage III/IV, except FIGO stage IIIA2 without nodal involvement) invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer, who have either undergone upfront primary surgery or plan to undergo chemotherapy with interval debulking surgery (IDS). In addition, patients should not have any medical contraindications that would exclude treatment with bevacizumab and/or niraparib. All eligible patients will receive the first cycle of chemotherapy (carboplatin area under curve [AUC] 5 and paclitaxel 175 mg/m²) as part of Study Run-In-Period (cycle 1). In parallel, central laboratory will determine the breast cancer (BRCA) status in tumor tissue (tBRCA). All patients with a valid central tBRCA test result will be randomized prior to day 1 of cycle 2 in a 1:1 ratio in the following treatment arms: Arm 1: Patients will receive further 5 cycles of carboplatin and paclitaxel q21d followed by niraparib once daily for up to a total of 3 years Arm 2: Patients will receive further 5 cycles of carboplatin and paclitaxel plus bevacizumab q21d followed by bevacizumab q21d (for up to 1 year) and niraparib once daily for up to a total of 3 years. The study aims to investigate, if the treatment strategy of carboplatin / paclitaxel / bevacizumab / niraparib is superior to the treatment of carboplatin / paclitaxel / niraparib-Inhibitor in an all-comer population.

Ultrasound-facilitated, Catheter-directed, Thrombolysis in Intermediate-high Risk Pulmonary Embolism

This study will assess whether ultrasound-facilitated, catheter-directed thrombolysis and standard anticoagulation are associated with a significant reduction in the composite outcome of pulmonary embolism (PE)-related mortality, cardiorespiratory decompensation or collapse, or nonfatal symptomatic and objectively confirmed recurrence of PE compared to anticoagulation alone within seven days of randomization The HI-PEITHO study has been designed to address the important gaps in clinical evidence by comparing the clinical benefit of the ultrasound-facilitated local delivery of a low dose thrombolytic agent and anticoagulation with those of anticoagulation alone in patients with intermediate-high risk PE at a higher estimated risk of early decompensation based on clinical parameters at presentation. This study has a focus on improving the safety of thrombolysis and advancing the concept of intermediate-high risk and the PE severity criteria, to better identify patients who may clinically benefit from thrombolysis. The results of this study will contribute further evidence to the existing data on the treatment and outcomes of acute, intermediate-high risk PE and provide controlled data related to catheter-based interventions. Data will be entered by the site into an electronic database. The database will include data checks to compare data entered into the database against predefined rules for ranges and consistency with other data fields in the database. Site monitoring will take place with source data verification to assess the accuracy and completeness of registry data by comparing the data to medical records and study assessments.

Optimizer System With ODOCOR II CCM™ Leads

Design A prospective, multi-center, single arm open label study, 12-month study of 400 ODOCOR II CCM™ leads in 200 subjects . Method Subjects shall be enrolled that have been diagnosed with NYHA Class III-IV heart failure and left ventricular ejection fraction (25-45% inclusive). Eligible subjects will receive the Optimizer IPG device implant with 2 ODOCOR II CCM leads. Subjects will return for follow-up visits at 2-weeks, 6 months and 12 months following the device implant. Endpoints Primary Safety endpoint The primary safety endpoint is the incidence of lead-related complication free rate at 12 months post-index implantation procedure compared to the incidence previously described in the literature for pacing therapy leads. Secondary Safety endpoint The secondary safety endpoint is an assessment of the lead-related "observations" occurring during the 12-month study. Primary Efficacy endpoint The total amount of CCM delivered to the cardiac tissue of the right ventricle (measured by CCM percentage) will be measured over a period of 12 months. Secondary Efficacy endpoint Change in QOL, as measured by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ), from baseline to 12 months following index implantation procedure. Additional Endpoints Handling characteristics of the lead will be evaluated by the implanting physician. Ease of insertion, lead visibility on x-ray, and the ability to visualize the helix deployment will be assessed via a questionnaire administered at the completion of an implant procedure. Patients, sites Four hundred (400) ODOCOR II CCM leads will be implanted in 200 eligible subjects from up to 40 sites in Europe. Duration The total investigation is expected to last approximately 3 years , including enrollment and follow-up periods.

Lead EvaluAtion for Defibrillation and Reliability (LEADR) / Lead Evaluation for Defibrillation and Reliability in Left Bundle Branch Area Pacing (LEADR LBBAP)

The LEADR and LEADR LBBAP studies will enroll subjects who are indicated to receive an implantable single or dual chamber ICD, or CRT-D, and who meet all of the inclusion criteria and none of the exclusion criteria. Subjects will receive an investigational Next Generation ICD Lead. Subjects in the LEADR study will be followed for at least 18 months following Next Generation ICD Lead implantation in a septal (non-LBBAP) or apical implant location. Enrollment in the LEADR study has been completed (675 subjects enrolled). Subjects in the LEADR LBBAP study will be followed for at least 3 months (ICD-indicated subjects) or 6 months (CRT-indicated subjects) following Next Generation ICD Lead implantation in an LBBAP implant location.

Intersectoral Platform (SÜP) of the National Pandemic Cohort Network (NAPKON)

The intersectoral platform is part of the National Pandemic Cohort Network (NAPKON), which, together and in interaction with other components of the National Research Network of University Medicine on COVID-19 (NUM), provides the essential basis for the successful understanding and thus combating pandemics using the example of coronavirus disease 2019 (COVID-19). NAPKON represents a sustainable, integrative and comprehensive concept that provides benefits for society as a whole in defending against and coping with pandemics, especially at the level of public health care, in hospital and patient management and from the individual patient's perspective. The intersectoral platform records data and biomaterial of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-infected patients through a network of university clinics, hospitals at all levels of care, general practitioners and specialist practices with appropriate study experience and infrastructure. The longitudinal phenotyping programme tracks patients for up to one year and collects detailed and harmonized clinical data as well as biomaterial. Follow-up data is enriched by patient-reported outcomes (PROM) and recruitment is intensified by focusing on hot-spot regions. Mobile study teams are used to reach, among others, long-term care and rehabilitation facilities, thus mapping all structural elements of the German care network. The primary aim of the intersectoral platform is to provide a comprehensive and harmonized collection of data and biomaterial for researchers from national consortia, pharmaceutical companies and for participation in international research collaborations for the purpose of studying COVID-19 disease and future pandemics.

EMPOWERYOU: Examining an Internet-based Prevention Program for Primary Caregivers

Given that childhood victimization leads to an increased vulnerability for subsequent revictimization in adolescence, findings highlight a strong need for evidence-based prevention programs targeting children with a history of child maltreatment as a high-risk population of revictimization. However, evidence-based programs for foster parents that aim to prevent revictimization of the child, while addressing the needs of the caregivers are scarce. In order to develop and tailor such services to foster parents (and youth in care) with maltreatment experiences, we developed a consumer-informed conceptual model in a prior project (EMPOWERYOU SP3) that outlines the key mediators which may impact upon the risk of revictimization and how we plan to address these with different intervention components. Thus, in subproject 3 the conceptual model and the online-intervention components were developed, involving the participants themselves as well as relevant stakeholders. The usability of the online-intervention and the feasibility of the clinical trial (EMPOWERYOU SP4) was piloted in subproject 3 (March 2021 - September 2021). In subproject 4, we will conduct a factorial study to tear apart the main effects of each intervention component on the mediator and outcome of interest, including potential interaction effects. This will help optimizing the intervention approach. The full online-intervention comprises five content modules and a coach, who is supporting the caregiver with up to four phone-calls (50 minutes each) and short message service (SMS) or e-mail reminders. Caregivers have two weeks to work through one module. Every caregiver will receive the first two basic modules on parental self-care and child´s self-worth and emotional regulation. This allows us to offer some level of support in all conditions including the condition with the lowest component level across all factors. Based on the MOST principles, this study will use a 2 x 2 x 2 x 2 full factorial design by randomly allocating families with equal probability to one of 16 experimental conditions. However, this factorial experiment does not represent a 16-arm randomized controlled trial (RCT). The ultimate goal is to choose from a set of four intervention components with two levels each (on/off) the one(s) that best reduce and prevent (re-)victimization. The following intervention components have been selected (three content components, one engagement/adherence component): 1. Component: "Watch out!" (on/off): Improving relationship-related risk detection and self-protective behavior 2. Component: "You are safe here" (on/off): Improving relationship-related safety and facilitating solid relationships 3. Component: "Who am I and where do I belong?" (on/off): Supporting the child constructing an identity 4. Component: "My Coach" (on/off): Professional support of the caregiver in form of up to four phone calls with a coach (i.e., one call per module 1&2 (combined), 3, 4, and 5). The primary research objectives are: 1. To examine the efficacy of selected candidate components on primary outcome, the risk of re-victimization, at follow-up (i.e., 3 months post intervention; approx. 24 weeks after baseline) 2. To examine the efficacy of selected candidate components on secondary outcomes (risk-taking behavior and functional behavior in relationships with caregiver, siblings, peers, and others) at post-test (i.e., 1 week post intervention; approx. 12 weeks after baseline) The secondary objectives are: 1. To test enduring effects of selected components on secondary outcomes at 3-month follow-up 2. To test mediating effects of theory-driven factors on the relationship between selected components on secondary outcomes 3. To explore whether there are any interaction effects between components on primary or secondary outcomes 4. To conduct exploratory analyses of potential moderators Based on the conceptual model described above, this study will examine the following hypotheses related to the main effects of intervention components: 1. Component "Watch out!" - Relationship-related risks: We hypothesize that receiving this component will result in better detection of risk signals in relationships and less risk-taking cognitions. This will lead to less relationship-related risk-taking behavior which in turn will result in reductions of re-victimization experiences and others secondary outcomes. 2. Component "You are safe here" - Relationship-related safety: We hypothesize that receiving this component will result in better detection of safety signals in relationships and more emotional security. This will lead to more functional relationship behavior which in turn will result in reductions of (re-)victimization experiences and other secondary outcomes. 3. Component "Who am I and where do I belong?" - Constructing identity: We hypothesize that receiving this component will increase parental support in the child´s constructing of identity. This will lead to a more positive self-appraisal and in turn to less risk-taking and more functional relationship behavior, which in turn will result in reductions of (re-)victimization experiences and other secondary outcomes. 4. Component "My Coach" - Professional support: We hypothesize that professional support from a parent coach who is facilitating each component, will result in higher program adherence/engagement which will yield larger intervention effects on primary and secondary outcomes than without professional support. 5. We hypothesize that there will be an interaction effect between the relationship risk and relationship safety components. When both components will be present, the effect will be larger compared to only one of them present. 6. We hypothesize that there will be an interaction effect between each component and the professional support component, such that with professional support, the effects of each component will be larger than without professional support via greater adherence/engagement of the caregiver.