Kazincbarcika, Hungary

PulseSelect™ PFA Global Registry

The PulseSelect™ PFA Global Registry is a prospective, global, multi-center, observational post-market registry. The purpose of this clinical study is to collect clinical performance and safety data in a broad patient population treated with the PulseSelect™ PFA system. The PulseSelect™ PFA System used in the study is market approved. The ablation procedure will be performed according to routine hospital practice. The follow up period is intended to align with standard practice and subjects will be followed for a minimum of 12 months post-procedure.

Iberdomide Vs. Iberdomide Plus Isatuximab Maintenance Therapy Post ASCT in Newly Diagnosed Multiple Myeloma

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial for a maintenance therapy, for patients who underwent an induction therapy and autologous stem cell transplantation in the GMMG-HD8/DSMM XIX trial. Investigational Medicinal Product: Iberdomid (oral), isatuximab (subcutaneous administration via a wearable injector system). Randomisation will be performed centrally by GMMG/DSMM offices after verification of the eligibility of the patient. At the time of study inclusion, randomization will be performed into arm A (iberdomide) or arm B (iberdomide + isatuximab). Randomization will be stratified by centrally assessed MRD negativity status (yes vs. no vs. unknown); assessed by NGF from BMA; sensitivity of 10^-5; independent of standard IMWG response) and number of HDM/ASCT (single vs. tandem). Patients randomized in arm A will receive 39 cycles of the drug iberdomide, a Cereblon E3 Ubiquitin Ligase Modulating Drug (CELMoD®) that shares structural similarities to the immunomodulatory compounds (IMiDs) such as thalidomide and lenalidomide. Each cycle will last for 29 days. Patients in arm B will receive the same the 39 cycles of iberdomide plus monoclonal anti-CD38 antibody isatuximab subcutaneously. In both arms, patients will receive 20 mg dexamethasone in cycle 1, on the same days as the isatuximab administration in Arm B. End of study will be after 36 months of the maintenance therapy. There is one primary objective: - Demonstration of superiority of iberdomide plus isatuximab compared to iberdomide with respect to bone marrow minimal residual disease (MRD) negativity rates (sensitivity 2x10^-6 via next-generation flow cytometry [NGF]) after two years of maintenance therapy. There is one key secondary objective: - PFS, defined as time from randomization to disease progression or death from any cause, whichever occurs first. Further secondary objectives are: - Rates of sustained MRD negativity (at sensitivity levels of 10-5 and 2x10^-6 via NGF from BMA) after 1, 2 and 3 years of maintenance therapy. - Conversion from MRD positive to negative (at sensitivity levels of 10^-5 and 2x10^-6 via NGF from BMA). - Rates of best overall response to treatment (BOR). - Rates of partial response (PR), very good partial response (VGPR), complete response (CR) and stringent complete response (sCR). - Time-to-next-treatment (TTNT). - PFS on subsequent line of therapy. - Overall survival (OS). - Improvement of IMWG response categories (PR, VGPR, CR, sCR). - Proportions of patients in both treatment arms maintaining BOR and CR from baseline. - Assessment of quality-of-life (QoL) via the EORTC-QLQC30, EORTC-QLQMY20, and EQ-5D-5L questionnaires.

Randomized Trial in Adult de Novo Ph Positive ALL With Chemotherapy, Imatinib or Ponatinib, Blinatumomab and SCT

Clinical Cohorts for Validation of New Digital Biomarkers

Atrial fibrillation (AF) and stroke are major health care problems in Europe. They are most often the clinical expression of atrial cardiomyopathy, which is under-recognised due to the lack of specific diagnostic tools. Multidisciplinary research and stratified approaches are urgently needed to prevent, diagnose, and treat AF and stroke and preempt the AF-related threat to healthy ageing in Europe. MAESTRIA is a European consortium of 18 clinicians, scientists and pharma industry partners who are at the forefront of research and medical care of AF and stroke patients funded by the EU Horizon 2020 programme (grant number 965286). The Atrial Fibrillation Network (AFNET) is one of the 18 partner institutions in this European consortium. MAESTRIA will create multi-parametric digital tools based on a new generation of biomarkers that integrate artificial intelligence (AI) processing and big data from cutting edge imaging, electrocardiography and omics technologies. It will develop novel biomarkers, diagnostic tools and personalized therapies for atrial cardiomyopathy. The MAESTRIA-AFNET 10 Study is an integral part of the MAESTRIA project. The study will collect relevant clinical parameters for AF from patients, this includes ECGs, cardiac CTs, MRIs and echocardiograms. Dedicated core labs will collect and homogenize the clinical data. For atrial arrhythmias (AA) and vascular stiffness index (VSI) recording, patients will be provided with a measuring bracelet for continuous monitoring of heart rhythm with a photoplethysmographic (PPG) sensor coupled with a smartphone app and the Preventicus Heartbeats® analytic service (Class IIa, CE marked), approved as consumer device. Preventicus is ISO 13485 certified.

Efficacy and Safety of Zanubrutinib Plus Tislelizumab Treatment with or Without Sonrotoclax for Patients with Richter Transformation

Richter Transformation (RT) remains one of the biggest challenges in the treatment and management of CLL. While considerable progress has been made in the treatment of CLL, the prognosis of CLL patients with malignant disease transformation still is very poor and reported median OS is between 6 to 8 months. Conventional approaches with chemo- and chemoimmunotherapy have largely failed to improve response rates in RT patients. However, as the established treatment approach for de-novo Diffuse Large B Cell Lymphoma (DLBCL) is chemoimmunotherapy with a combination of Rituximab, Cyclophosphamid, Hydroxydaunorubicin, Vincristin and Prednisolon (R-CHOP), this has become the most commonly used regimen for lack of alternative strategies, despite poor efficacy. Patients being fit enough for allogeneic transplantation are undergoing this procedure after induction with R-CHOP. However, the majority of patients are not suitable for transplantation and relapse quickly. Hence, there is urgent need to improve therapy of RT by testing new compounds and combinations for treatment of this disease. Based on the available preclinical and preliminary clinical data on checkpoint inhibition plus Bruton's tyrosine (BTK) inhibition, the current trial will systematically assess the safety and toxicity of tislelizumab, a programmed cell death protein 1 (PD-1) inhibitor, plus zanubrutinib, a BTK inhibitor in patients with RT.

A Phase-3-trial of Acalabrutinib, Obinutuzumab & Venetoclax Compared to Obinutuzumab and Venetoclax in Previously Untreated Patients with High Risk CLL

CLL is the most frequent leukemia in industrialized countries. International guidelines agree on diagnosis and management of this disease. The clinical course of CLL is highly variable and can be predicted by clinical staging (according to Rai and Binet) as well as genetic, serum markers and risk models. This study is designed for a randomized comparison of two different, non-chemotherapeutic and fixed-duration modalities for patients with high risk chronic lymphocytic leukemia (CLL) and addresses a high medical need, since high risk-CLL represents a so far incurable, aggressive cancer. The high risk-group of CLL patients can be identified by molecular characteristics, allowing the inclusion of a clearly described group of patients: 17p-deletion, TP53-mutation and/or complex karyotype.TP53 defects are the strongest prognostic factors for non-response to chemotherapy. Patients harboring TP53 defects should be treated with chemotherapy-free regimens. Complex karyotype (CKT), defined as the presence of three or more chromosomal aberrations in two or more metaphases is associated with a poorer outcome in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). In CLL, CKT is one of several well established adverse prognostic factors, comparable to 17p-deletion, TP53-mutation or unmutated IGHV status. Depending on age and prior exposure to chemotherapy, 10-30% of patients with CLL exhibit CKT. A broad body of evidence has suggested a predictive prognostic value of CKT. Despite considerable advances with chemoimmunotherapy in the treatment of frontline as well as relapsed/refractory (r/r) CLL, outcome of patients with CKT remains poor. To date, a randomized comparison to optimize the treatment of patients with high risk disease defined as either the presence of TP53 aberrations or CKT, by novel agents has not been performed. Patients with high risk CLL (TP53-defects and/or CKT) have a poor outcome with chemoimmunotherapy and do not benefit to the same extent from approved regimen such as continuous treatment of ibrutinib or 12 months treatment with obinutuzumab plus venetoclax. Monotherapy with BTK-inhibitor is less effective in those patients as compared with patients without high risk disease. Venetoclax combined with the anti-CD20 monoclonal antibody obinutuzumab offers a highly effective fixed-duration treatment option with a manageable toxicity profile. The recent results of the CLL14 study define a new standard of a fixed 12-months treatment with obinutuzumab and venetoclax in previously untreated patients yielding a major benefit also for patients with high risk disease as compared to chemoimmunotherapy. However, high risk patients appear to progress earlier than low risk patients and the therapy is not clearly curative so far. Acalabrutinib is a second generation, selective BTK inhibitor which has shown promising overall response rates in patients with relapsed CLL or patients intolerant to ibrutinib. The development of acalabrutinib focussed on minimization of off-target activity. Results of a three-arm study investigating the combination of acalabrutinib plus obinutuzumab versus acalabrutinib alone versus chlorambucil plus obinutuzumab (NCT02475681) showed a substantial improvement of PFS for the combination arm and the monotherapy versus the standard chemoimmunotherapy regimen. The addition of a BTK-inhibitor, such as acalabrutinib to obinutuzumab and venetoclax has the potential to result in a better outcome, because synergistic effects have been reported between BTK inhibitors and B-cell lymphoma 2 (BCL-2) inhibitors or for BCL-2 inhibitors and monoclonal antibodies. Synergistic effects, which are expected to reduce early progressions or insufficient responses, are in particular important for this high risk population. The triple combination of acalabrutinib, obinutuzumab (or rituximab) and venetoclax has been investigated in a phase 1 b- study and had a tolerable safety profile with minimal to no drug-drug interactions, results of a phase 2 trial studying the same combination showed that the triple combination was highly active with 78% undetectable MRD levels in the bone marrow . Currently, the GCLLSG conducts phase 2 studies, investigating a triple combination consisting of BTK- and Bcl2-inhibitors and monoclonal antibodies (CLL2GIVe: NCT02758665; CLL2BAAG: NCT03787264) and a large phase 3 trial with one experimental arm with a triple combination (CLL13, NCT02950051) but results are not yet published. Acalabrutinib, venetoclax and obinutuzumab is now being studied in a registrational phase 3 trial CL-311 (NCT03836261) against the current standard of chemoimmunotherapy (fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR) in patients without 17p-deletion or TP53-mutation. Acalabrutinib is indicated in Germany as monotherapy or in combination with obinutuzumab for the treatment of adult patients with treatment-naive chronic lymphocytic leukemia (CLL) and as monotherapy for the treatment of adult patients with relapsed chronic lymphocytic leukemia (CLL).

Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL

This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR) in subjects with previously untreated CLL without del(17p) or TP53. Subjects will be randomized in a 1:1:1 ratio into 3 arms through a block stratified randomization procedure. The study includes screening (35 days), treatment (from randomization until study drug discontinuation) and follow-up phase.

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.

Study to evaLuate the effIcacy and Safety of abeLacimab in High-risk Patients With Atrial Fibrillation Who Have Been Deemed Unsuitable for Oral antiCoagulation (LILAC-TIMI 76)

Acalabrutinib in Combination With R-miniCHOP in Older Adults With Untreated Diffuse Large B-Cell Lymphoma