Starý Tekov, Slovakia

Niraparib Maintenance Treatment in Patients With Newly Diagnosed Advanced Platinum- Sensitive, OC. The First Poland RWE Study.

Although over the last 2 decades the surgical management of ovarian cancer has improved with more chemotherapy options are available, however 5-year survival rates have remained relatively stable at 25 to 40% (36) The proposed real-life observation study can deliver valuable real-world information about niraparib patient outcomes and safety complementing the results of the PRIMA and PRIME clinical trials. This will also include establishing the importance of KELIM as a predictor of maintenance therapy choices. The multicenter design of the study will allow collection of data from a relatively large and representative group of patients within the Polish Drug program B.50. To this time, no study has been published about niraparib patient outcomes and safety in Poland. This study will also include evaluation of patient outcomes when initiating therapy up to 4, 8, 12 weeks after completion of platinum based chemotherapy. The population of patients included in the study will come from two programs: EAP and B.50. EAP is an early access program sponsored by GSK, which has been operating in Poland since 2021 Jan. The inclusion criteria for EAP contained the same measurable parameters as the B.50 drug program offers. The B.50 drug program is a ministerial program guaranteeing the Polish patients with advanced ovarian cancer access to approved medicines like maintenance treatment with PARP inhibitors, including niraparib. The B.50 and EAP inclusion criteria are in accordance with the study protocol. Primary Objective - Primary objectives will be to describe patient and disease characteristics for patients receiving niraparib treatment in Poland. - To quantify PFS: the primary PFS analysis will be based upon the Investigator's assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria, Appendix 2. The day considered as disease progression is the day of the CT examination on which progression was found according to RECIST 1.1 criteria - PFS measured from the time of the first dose of niraparib. - Primary objectives will also estimate safety and tolerability of niraparib treatment in Poland. Strict monitoring of safety profile (e.g. blood test is performed every 7 days during first month of treatment and after each changing of dose, blood pressure is performed every 7 days within the first two months then every month within the first year). Secondary Objectives - OS (Overall Survival) - Chemosensitivity based on KELIM as a surrogate marker for platinum sensitivity to assess for niraparib response as a standard procedure due to the B.50 drug program - Evaluation of outcomes of including patients in therapy up to 4, 8, 12 weeks after completion of platinum-based chemotherapy - TFST (Time to the First Subsequent Therapy) - DCR (Disease Control Rate). INVESTIGATIONAL PLAN Overall Study Design Patients who complete the Chemotherapy Treatment Period without progressive disease (CR, PR, NED) will start Maintenance Treatment with niraparib after Cycle 6 up to 12 weeks after completion of the chemotherapy. Prior to receiving oral maintenance treatment, patients must have a CBC that demonstrates adequate recovery from hematologic toxicity from chemotherapy: - Absolute neutrophil count ≥1,500 cells/μL - Platelet count ≥100,000 cells/μL - Hemoglobin ≥10 g/dl Number of Patients and Study Design We expect to enroll approximately 300 patients from about 10 sites. Treatment part of study. Part I- looking retrospectively at the time period JAN 2021-MAR 2023. The retrospective data will include patients who are enrolled in niraparib treatment: - under the EAP (started in JAN 2021, in continuation) - under the B.50 drug program, which began in January 2022 Of note, the retrospective multi-center observational study will involve about 30 patients treated with niraparib in EAP (FIGO III R0 after PDS included) and patients who were treated with niraparib before starting RWE (about 120 pts) (JAN 2021- MAR 2023) by the drug program B.50 which has been started to adapt on 1st of Jan, 2022. FIGO III PDS to R0 patients are included to this study. Part II- looking prospectively at the time period APR 2023 to DEC 2025. The prospective data will include patients who are enrolled in niraparib treatment under the B.50 drug program. The prospective multi-center observational study will involve about 150 patients with ovarian cancer (OC) who have been treated in about 10 OC gyn- oncocenters in Poland (OCgoC) (APR 2023- DEC 2025). Study follow up Part III- survival follow up after treatment part of study (from JAN 2026 - DEC 2026). Chemotherapy Treatment Period Not covered by the study protocol. Maintenance Treatment Period All the patients will be given a sequential number by the system. Additionally, each patient from the EAP will have individual number which was given to them. In the CRF there will be additional information that there is a patient in the EAP phase of the study. Patients who have responded to first-line chemotherapy (NED, CR, PR) and with recovery to baseline of any hematologic toxicities will enter the Maintenance Treatment Period. Oral niraparib will be dispensed to patients on Day 1 of every 28-day cycle beginning with Cycle 1 of the Maintenance Treatment Period for up to 3 years in the absence of PD, unacceptable toxicity, or patient withdrawal, or based on Investigator's decision. The recommended dose is 200 mg per day (2 capsules). Patients with a baseline body weight of ≥77 kg and baseline platelet count of ≥150,000 cells/μL will take 3 capsules of 100 mg strength (300 mg/day) at each dose administration. Dose modifications will not be based upon changes in the patient's actual body weight during their study participation. The inclusion criteria, the way of monitoring, both in a prospective and a retrospective cohort, will be followed by the B.50 drug program criteria. For that reason CA125 measurements necessary for KELIM as well as RECIST data are available in both cohorts during the whole period of time. Duration of Treatment Patients may continue niraparib treatment for up to 3 years according to the B.50 drug program.

Study to Investigate Comparative Efficacy, Safety and Immunogenicity Between AVT16 and Entyvio

The study will consist of a screening period, a treatment and assessment period and an End of Study visit. Eligibility for the study will be determined during a screening period. Subjects who meet the eligibility criteria will be randomised to either AVT16 or Entyvio.

RVU120 in Patients With Intermediate or High-risk, Primary or Secondary Myelofibrosis

The study schedule consists of a screening period up to 28 days, a 21-day treatment period, an end of treatment visit (30 days) and a 1-year follow-up where participants will be contacted every 3 months for assessment. Study duration for each participant will vary depending on the number of 21-day treatment cycles received. The study is open to participants aged ≥18 years with intermediate or high-risk, primary or secondary MF who have been previously treated, are ineligible for, or had a suboptimal response to JAK inhibitor therapy. Participants must have adequate organ function (kidney, liver) and no history of hematopoietic stem cell transplant. Participants may withdraw from the study at any time at their own request or may be withdrawn at any time at the discretion of the Investigator.

Safety and Efficacy of RVU120 Combined With Venetoclax for Treatment of Relapsed/Refractory AML

In Part 1 dose-escalation participants will receive escalating oral doses of RVU120 starting at 125 mg administered every other day on days 1-13, and escalating oral doses of venetoclax starting with 200 mg administered daily on days 1-14 of each 21-day cycle of treatment. The recommended doses for further study will be based on the observed safety, tolerance, PK and PD. In Part 2, it will be assessed whether the recommended dose level from Part 1 reaches the targetted response criteria, and if reached, Part 3 will be initiated to further evaluate the efficacy and safety of the recommended doses in a larger population.

A Phase 3 Study of Barzolvolimab in Participants With Chronic Spontaneous Urticaria

This is a global, multicenter, randomized, double-blind, parallel group, placebo-controlled phase 3 study investigating the efficacy, safety and tolerability of barzolvolimab in adult participants with Chronic Spontaneous Urticaria (CSU) who are symptomatic despite treatment with non-sedating second generation H1-antihistamines at 1-4 times the locally approved dose. There is a screening period of up to 4 weeks, followed by a 24-week placebo-controlled treatment period, a 28-week active treatment period where all participants receive barzolvolimab followed by a 16-week treatment free period. Approximately 915 adult participants (610 in the active arms and 305 in the placebo arm) will be randomly assigned to the treatment arms.

Study to Evaluate the Efficacy and Safety of Subcutaneous Sonelokimab Compared with Placebo in Adult Participants with Moderate to Severe Hidradenitis Suppurativa

A Study of Lebrikizumab in Adult Participants With Perennial Allergic Rhinitis (PREPARED-1)

Fecal Microbiota Transplantation (FMT) to Decolonize Antibiotic - Resistant Bacteria (ARB) - New Protocol

Fecal microbiota transplantation (FMT) was shown to be very efficient in treatment of relapsed and refractory Clostridium difficile infection and became a standard treatment. The investigators company produces and uses FMT not only in case of Clostridioides difficile colitis, but also in case of gut colonization with antibiotic-resistant bacteria and other indications as a clinical studies under Bioethical Committee approval. Company's flagship program to decolonize ARB is based on assumption that physiological gut flora may outcompete the pathogenic bacteria similarly as in case of Clostridium difficile and lead to loss of colonization. Patients colonized with ARB are characterized by poor diversity of gut microbiome (dysbiosis), which makes them vulnerable to further infections. In case of gut mucosa injury and severe immune suppression, these colonizing bacteria may cause severe systemic infections. During this interventional prospective, single arm, observational study, the investigators collect the information about the safety and effectiveness of FMT in gut decolonization with antibiotic-resistance bacteria (ARB) using their new treatment protocol and own full-spectrum, full-richness, full-viability anaerobic FMT. The project protocol is based on the intervention (fecal microbiota transplantation; FMT) in capsules (or colonoscopy if per os route is not possible) applied twice - on day 7th after procedure initiation and between day 9-14 within extended period, low dose (1/6th every day) application. All patient are premedicated with non-absorbable antibiotics on days 1-5 and a bowel cleansing on day 6 from the screening. After the end of the eradication procedure, the patient proceeds to the follow-up assessment stage and is observed up to 360 days with longitudinal samples collection.

A Study to Assess the Effect of Dexpramipexole in Adolescents and Adults With Severe Eosinophilic Asthma.

This is a multicenter, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and safety of dexpramipexole in adults and adolescents with severe, inadequately controlled asthma with eosinophilic phenotype on medium to high-dose inhaled corticosteroids (ICS )and at least one additional asthma controller medication with or without oral corticosteroids (OCS). Approximately 1400 participants will be randomized globally. Participants will receive dexpramipexole, or placebo, administered orally, over a 52-week treatment period. The study also includes a post-treatment follow-up period of 4 weeks.

Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)

MAINSTREAM is a prospective, multicentre, randomised, placebo-controlled, double-blind, parallel-group, investigator-initiated clinical trial. The study is powered to demonstrate the difference between the groups in the primary endpoint, which has been defined as the occurrence of a decrease in LVEF by ≥ 5% assessed by transthoracic echocardiography (TTE) within 24 months. Approximately 600 patients will be recruited in three tertiary supraregional Polish oncology centers. Of those patients, after an estimated dropout, during the single-blinded phase of drug uptitration to the target dose, 480 will be randomized in a 1:1 ratio into sacubitril/valsartan or matching placebo. In brief, patients with histologically confirmed, and phenotypically assessed breast cancer at an early stage, defined as stages I-III and oligometastatic IV stage, with a radical treatment plan, which includes surgery and the post- and/or pre-operative systemic treatment, will be included in the study. The patients must be classified in the 0-2 classes of the Eastern Cooperative Oncology Group. In the baseline echocardiography analysis, the LVEF must be ≥50% and the patients must be in the sinus rhythm. The patients who underwent prior therapy with anthracyclines and/or left-sided radiotherapy, suffered from myocardial infarction within the preceding 3 months prior to the study, or have symptomatic, clinically relevant heart failure, will be excluded from the study. Similarly, patients with contraindications, or prone to the adverse effects of the studied drug, which includes patients with symptomatic hypotension, hyperkalemia defined as K+ higher than 5.5 mmol/L and estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 on the screening visit, will also be considered ineligible to participate in this trial. Patients must not have been on treatment with ACE-I/ARB/ARNI at least in the 36 hours prior to study enrollment. According to the ESC guidelines on cardio-oncology, the inclusion and exclusion criteria for the trial define the vast majority of the studied population in the low- or moderate risk of cancer therapy-related cardiac dysfunction (CTRCD), however, the inclusion of patients at high risk of either anthracycline- or anti-HER-2-associated CTRCD, such as patients aged ≥80 years, is not impossible. No very high-risk patients will be considered eligible for enrollment. After assessment of the inclusion and exclusion criteria, and all examinations, including the echocardiography assessment, the patients will begin the single-blinded phase of treatment with sacubitril/valsartan during the screening visit. The MRI study may be performed according to the availability of the method in each participating facility. The initial dosing of the drug will be 49/51 mg twice daily, which should be uptitrated to the target dose of 97/103 mg twice daily at the Run-in-visit scheduled at 6-8 days from the initial evaluation and drug introduction, tolerance permitting. After further 6-8 days of single-blinded treatment with target dose of sacubitril/valsartan, providing satisfactory tolerance of the drug, the patients will undergo randomization at the Randomization visit. Providing the patient signed informed consent, is fully eligible for randomization, and underwent the single-blinded study treatment regimen with satisfactory tolerance, the patient will be randomized with the use of an electronic, centralized randomization system, blinded to the patient's characteristics, to either interventional group, which will be administered with sacubitril/valsartan, or the placebo group. The system will dynamically randomly allocate patients to the two groups in a 1:1 ratio. After randomization, the patients will follow treatment with either sacubitril/valsartan or a matching placebo, for a maximum of 24 months. During this period, three study visits are planned, at 3 months, 12 months, and 24 months from randomization. At each visit, the patients will be assessed for the medical presentation, undergo laboratory and imaging studies, and will be assessed for the presence of adverse events. In patients, who will be unable to tolerate the target dose of the study drug of 97/103 mg twice daily, the dose can be down-titrated to 49/51 mg twice daily at the investigator's discretion (after having considered whether there is any other concomitant medication that could act as a parallel contributor to the lower tolerance of the drug). If the dose of 49/51 mg twice daily cannot be tolerated, the dose could be temporarily lowered by half for a period of two weeks. However, if after that period the uptitration of the dose is impossible, the patients will have to be excluded from further participation in the trial. The physicians will be strongly encouraged to foster the continuation of the target dose of the study drug, based on their assessment of the patient's condition. The primary endpoint of the study has been defined as the occurrence of a reduction in LVEF by ≥ 5% assessed by TTE within 24 months. Among the secondary endpoints of the study, the clinical composite endpoint of death from any cause or hospitalization for heart failure and its components will be analysed, as well as the wide spectrum of echocardiographic, electrocardiographic, laboratory, and clinical outcomes, including the CTRCD resulting in the need to implement treatment consistent with the ESC guidelines on cardio-oncology. To maintain utmost objectivity, all examinations performed in relation to the study, including the echocardiographic, electrocardiographic, and magnetic resonance imaging analyses will be sent using 3D option ImageCom (TOMTEC Imaging Systems GmbH, Germany) - a multi-modality, vendor-neutral 3D/4D viewer - to the core laboratory where their results will be analysed by two independent investigators blinded to the patient's randomization status. Breast cancer treatment The patients should be treated according to the standard protocols of the participating centres, with the intention of radical treatment based on the surgical excision of cancer, with addition of either pre- or post-surgical chemo- and/or radiotherapy. The choice of the scheme of oncological treatment will be at the discretion of the treating oncologist and will be performed after analysis of the risk of recurrence, the potential response to a particular type of treatment, with consideration of possible drug-related adverse effects, and patient's co-morbidities and preferences. All decisions, including the scheme of therapy, will be performed in accordance with the recommendations of the Polish Society of Clinical Oncology. Pre-operative and post-operative chemotherapy with alkylating drugs, which include anthracyclines, usually in multi-drug regimens, will begin most commonly, with the initiation of anthracyclines (4 cycles or 3 cycles of EC). In routine perioperative treatment, trastuzumab will be administered̨ for 12 months, but shorter regimens (6 months) may be considered in individual situations, however, due to the cardiotoxic effects of trastuzumab, it will not be routinely given concomitantly with anthracyclines. As there are currently no data regarding the potential differences in the pharmacodynamics and pharmacokinetics, and consequently efficacy and safety of sacubitril/valsartan prophylactic treatment in patients with breast cancer and systemic therapy, there may be genetic biomarkers defining the disease susceptibility and prognosis, as well as the response to treatment. For each patient who gives informed consent to participate in the study, an additional blood sample will be taken at the first visit. After completion of the study, the subanalysis of the trial will be attempted based on the genetic profile aiming at defining the genetic pattern characterizing the response to sacubitril/valsartan for the prevention of cardiotoxicity caused by anthracyclines and/or anti-HER-2 targeted drugs. At the screening visit and completion of the study, the patient will undergo TTE, which according to the recent ESC Guidelines on cardio-oncology has been defined as the first-line modality in assessment of cardiac function in oncological patients. The assessment of LVEF with the use of 3D echocardiography will be preferred in all patients, although in selected cases a two-dimensional LVEF assessment will be accepted. In every patient, the assessment of global longitudinal strain will be recommended. The investigator performing the echocardiography will be blinded to the patient's randomization scheme. All images will be sent to the core laboratory. The quality of life will be assessed with the 36-Item Short Form Survey (SF-36) questionnaire at the screening visit and at the completion of the study. Laboratory tests The details of the blood tests performed during each study visit are presented in Table 4. All blood samples will be performed at fasting, on the day of the study visits, and analysed in the local laboratories of the three participating oncology centres. The blood sample for genetic testing in patients who sign an additional consent for genetic evaluation will be collected only on the screening visit and stored locally for the eventual transfer into the biobank of the Maria Sklodowska-Curie Institute - Oncology Centre (MSCI), Gliwice, Poland for further analyses. High-sensitivity cardiac troponin (with a preference to measure cardiac troponin T over troponin I due to previously described variability in the results of the latter), as well as N-terminal prohormone of brain natriuretic peptide (NT-proBNP), will be assessed using assays at the local laboratories of the participating oncology centres during study visits and at any time when deemed necessary by the physician-in-charge, or as supported by the local treatment protocols established by the participating centres and with reference to the ESC guidelines on cardio-oncology. The investigators will be blinded to the patients' randomization results. Intervention in case of HF development Based on the prior studies, it is estimated that approximately 20% of patients from the placebo arm and 10% of study drug arm might develop a certain degree of cardiotoxicity and require introduction of cardioprotective agents. The diagnosis of CTRCD should be based on the assessment of TTE and/or high-sensitivity cardiac troponin, as well as NT-proBNP. The intervention in case of development of either symptomatic, or asymptomatic CTRCD should be in line with current ESC guidelines on cardio-oncology and may include discontinuation or temporary interruption of chemotherapy, or continuation of treatment with thorough patient monitoring, while the study drug/placebo might be terminated or continued, depending on the severity of CTRCD.