Kazimdirik, Turkey

AXONE-Acute II: Acute Assessment of a Micro Multipolar Lead for Enhanced Cardiac Resynchronisation Therapy

ALFAOMEGA Master Observational Trial

AlfaOmega is an observational study that will follow a stage-mixed cohort of at least 500 patients through their course of treatments, until death or a minimum of 5 years. Patients will be longitudinally sampled and matched clinical data (including imaging) will be collected. Via a multi-tiered informed consensus process, AlphaOmega will also allow to develop companion diagnostics for molecular enrichment strategies in AIRC-driven proof-of-concept trials. To achieve the required level of 'experimental precision', patients will enter AlphaOmega at two different 'therapeutic checkpoints': i) prior to a surgical event or ii) prior to a systemic treatment. In the latter case patients with no previous lines of therapy for metastatic disease will be privileged. To optimize the enrollment of patients, the longitudinal collection of data/samples and their logistic management, AlphaOmega has been designed as a flexible infrastructure organized in TIERS for the stepwise comprehension of the biological processes that drive tumor evolution, and precisely: - TIER1, Monitoring: the ability to follow CRC evolution under standard of care treatments and to define new evolution-linked biomarkers. This will be achieved through the collection of clinical data, imaging data, FFPE tissue and frozen plasma/PBMC. - TIER2, Modelling: the ability to develop pertinent experimental models to study evolutionary mechanisms and define evolution-targeting therapeutic strategies. This will be achieved through the collection of Fresh Tissue, Whole Blood, Stools, Buccal Swabs and other fluids. - TIER3, Linking: the ability to access data and samples of patients enrolled in proof-of-concept trials to prove the efficacy and study/understand resistance mechanisms of evolution-targeting therapies. This will be achieved by introducing the connection in the trial protocol.

First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia

This Phase 1/2, first-in-human (FIH), open-label, dose-escalation and dose-validation/expansion study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML). The dose-escalation part of the study (Phase 1a) will determine the maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D). The dose-validation/expansion part of the study (Phase 1b) will determine the safety, tolerability, and minimal biologically effective dose of ziftomenib in dosing cohorts which have demonstrated early biological activity and have been determined to be safe in the dose-escalation phase. The Phase 2 portion of the study will determine the safety, tolerability, and anti-leukemia activity of ziftomenib in patients with NPM1-m AML.

A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation

Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib to identify the MTD and RP2D. Participants will be enrolled in one of six dose-escalation arms: Arm A: Participants not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers or fluconazole. Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis. Arm C: Participants receiving revumenib and cobicistat. Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis. Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers. Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis. In Phase 2, participants will be enrolled in 3 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of revumenib: - Cohort 2A: Participants with KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL) - Cohort 2B: Participants with KMT2A AML - Cohort 2C: Participants with NPM1m AML

Immunotherapy, Chemotherapy, Radiotherapy and Surgery for Synchronous Oligo-metastatic NSCLC

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer-related mortality worldwide. Even with adjustment for age NSCLC is responsible for almost 20% of cancer-related deaths. Recent years have brought tremendous progress in the understanding of the disease, its underlying biology and the development of effective therapies. Traditionally, NSCLC has been treated with surgery, platinum-based chemotherapy or radiotherapy alone or in combination, depending on tumour stage, tolerability of expected side effects and prognosis. Various strategies are currently being pursued in order to increase the patient population that may benefit from immunotherapy and to further improve the outcome of patients with NSCLC. The CHESS clinical trial is for patients with NSCLC that has progressed to a small number of other parts of the body (oligo-metastatic) and has not been previously treated, or after surgical resection of a single metastasis (central nervous system or adrenal). The trial aims to reduce the risk of systemic progression and thereby improve progression free survival. Participants will receive induction treatment consisting of immunotherapy combined with platinum-based doublet chemotherapy and stereotactic body radiotherapy (SBRT) that will be given to all oligo-metastatic locations. SBRT started early and concurrently with immunotherapy aims at enhancing a postulated immune effect and simultaneously effectively control the macro-metastases. Preclinical data have shown a strong immune-enhancing effect of radiotherapy, especially when delivered to small volumes, in high-single fraction doses and over a short period of time. Consequently, stereotactic body radiotherapy (SBRT) is currently being intensively investigated as a partner for systemic immunotherapy. Earlier clinical studies generated proof-of-principle data for the synergistic effects of combined radiotherapy and immunotherapy. Chemotherapy and high-dose radiotherapy are well known triggers of immunogenic cell death and are therefore highly promising partners for combination with immunotherapy. The sub-group of patients with "oligometastatic" disease was originally described by Hellman and Weichselbaum in 1995. In line with this concept, the current NCCN and ESMO guidelines describe that Stage IV NSCLC patients presenting with solitary metastases can be treated with curative intent using local surgery and/or radiotherapy. Local treatment for oligo-metastatic NSCLC has been adopted rapidly in the oncological community and one reason is the progress made in the fields of surgery and radiotherapy, both becoming less toxic (minimally invasive surgery) and simultaneously less toxic and more effective (precision radiotherapy), respectively. SBRT allows treatment of small peripheral primaries and metastases at virtually all anatomical locations with a favourable therapeutic ratio of local tumour control rates >90% and low rates of toxicity. Simultaneously, minimally invasive surgery for early and locally advanced NSCLC today achieves excellent local tumour control with low rates of toxicity. Patients with a limited number of metastases - oligometastatic disease - are currently treated with combined radical local treatment for all active lesions (locoregional primary and metastases) and their prognosis is better as compared to patients who receive systemic treatment only for widespread metastatic disease. However, the majority of patients still develop systemic disease progression indicating the urgent clinical need for more effective systemic treatment to control subclinical disease. All CHESS trial participants will receive induction treatment with the immunotherapy drug durvalumab, standard platinum-chemotherapy and radiation therapy of the lung cancer metastases (SBRT). Durvalumab is a human monoclonal antibody carefully engineered to attach to immune cells to stimulate their activity against cancer cells. There are now several approved antibodies for the treatment of cancer or other diseases. Standard platinum-chemotherapy includes treatment with carboplatin and paclitaxel. After three months of induction treatment the status of the lung cancer will be restaged. If the primary lung cancer is stable or has not increased in size it will be surgically removed if possible or, alternatively, treated with radiation therapy. Treatment with durvalumab will continue until the disease relapses or for a maximum of one year from the start of induction treatment. If the lung cancer has increased in size at the time of the three month restaging all trial treatment will stop and the study doctor will discuss other treatment options that are available. The efficacy, safety and tolerability of combining immunotherapy with standard platinum-chemotherapy and SBRT will be evaluated in the CHESS clinical trial. Encouraged by the positive results of the POSEIDON trial, we amended the CHESS protocol to include a second cohort of additional 47 patients who will receive tremelimumab, in addition to the protocol treatment of the original CHESS protocol (e.g., durvalumab, platinum-based doublet chemotherapy, and SRBT to the oligo-metastatic lesions, followed by definitive local treatment for patients that have not progressed at the time of restaging). Objectives and endpoints, patient selection and statistical assumption remain the same as for cohort 1 in the original protocol.

HER2-PREDICT: Translational Study of Tumor Samples From Patients Treated With Trastuzumab Deruxtecan (T-DXd; DS-8201a)

A Study of JNJ 73763989+JNJ 56136379+Nucleos(t)Ide Analog (NA) Regimen Compared to NA Alone in e Antigen Negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection

Hepatitis B virus (HBV) is a small deoxyribonucleic acid (DNA) virus that infects the liver and can cause either acute or chronic infection. It consists of a so-called nucleocapsid in which viral DNA is packed with hepatitis B core protein (HBc) and membranous envelope containing hepatitis B surface antigen (HBsAg). Chronic HBV infection may lead to serious illnesses like cirrhosis and hepatocellular carcinoma (HCC). Oral treatment with NAs is effective at suppressing viral DNA formation and lowering virus concentration in blood to levels below lower limit of quantification (LLOQ). JNJ-73763989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic HBV infection via ribonucleic acid interference mechanism but rarely lead to functional cure defined as sustained loss of HBs Ag and HBV DNA in serum. JNJ-56136379 is an orally administered capsid assembly modulator that is being developed for treatment of chronic HBV infection. The aim of study is to evaluate efficacy of 48-week study intervention with JNJ-3989+JNJ-6379+NA regimen compared to NA alone, assessed by HBsAg seroclearance at Week 72 (i.e., 24 weeks after completion of all study interventions at Week 48) without restarting NA treatment in HBeAg negative virologically suppressed chronic hepatitis B (CHB) infected participants who received NA treatment for at least 2 years prior to screening. The study will be 2.3 years and will be conducted in 3 phases: a screening phase (4 weeks), a study intervention phase (48 weeks), and a follow-up phase (48 weeks). Safety will be evaluated by AEs including AEs of special interest to any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical examinations.

Real-time Ultrasound Imaging as Feedback for Deep Cervical Extensors Activation

Participants will be randomly allocated into two exercise groups: "DCE exercise without RUSI feedback (DCE)" and "DCE exercise with RUSI feedback (DCE+RUSI)". Participants assigned to DCE will perform an exercise known to selectively activate the semispinalis cervicis muscles. By the other hand, participants in the DCE+RUSI group will perform the same exercise as the DCE group to selectively activate the semispinalis cervicis muscle but receiving RUSI feedback about correct performance. In both groups, a total of 10 sets of 10 repetitions will be performed with one minute of rest between each set. Ultrasound measurement will be used to asses the antero-posterior dimension (thickness) of the DCE both at rest and during contraction at the level of C4 at baseline, immediately after the DCE exercise activation protocol and one-week follow-up in order to evaluate retention capacity. All participants will be asked to not perform any other cervical motor control exercise or exercise using RUSI feedback until the last time point assessment will be finished. All participants will be asked to avoid any exercises or treatments for neck pain between sessions. All ultrasound images will be analysed off-line using Image J software. Thickness and percent thickness change will be measured. The percent thickness change will be calculated by using the following equation: thickness contracted - thickness rest / thickness rest.

A Study of Tildrakizumab in Pediatric Subjects With Chronic Plaque Psoriasis

Spanish Registry of Patients With IgM Monoclonal Gammopathies