Nedands, Australia

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.

Study of Standard Intensive Chemotherapy Versus Intensive Chemotherapy with CPX-351 in Adult Patients with Newly Diagnosed AML and Intermediate- or Adverse Genetics

Transcranial Direct Current Stimulation to Enhance Training Effectiveness in Chronic Post-Stroke Aphasia

Intensive speech-language therapy (SLT) can promote recovery from chronic post-stroke aphasia, but effect sizes are moderate. This highlights the pressing need to explore adjunct strategies, such as transcranial direct current stimulation (tDCS), to enhance training effectiveness. Recently, the investigators provided evidence from a single-center randomized controlled trial (RCT) suggesting that anodal-tDCS of the left primary motor cortex (M1) improves naming and communication ability in chronic post-stroke aphasia, with medium-to-large effect sizes. However, prior to integration into clinical routine, a multi-center RCT with adequate power, duration, and outcomes relevant to everyday life is required, which is the goal of the present study. After trial completion, a workshop with relevant stakeholders will ensure transfer into best-practice guidelines.

Electrical Stimulation in Traumatic Brain Injury (TBI) Induced Aphasia

Acupuncture for Relief of Gag Reflex

Patients undergoing elective transesophageal echocardiography (TEE) often report discomfort because of active gagging reflex, which sometimes preclude the performance of TEE and requires additional medication. According to existing literature, needling of acupoint CV24 effectively prevents gagging during dental procedures. We are going to use this phenomenon in patients scheduled to TEE in order to reduce discomfort during insertion of TEE probe and reduce the need for additional sedative medication. Within this investigation the patients will be randomly assigned to receive either verum acupuncture of CV24 and P6 acupoints or placebo procedure immediately before TEE examination. As outcome the incidence and intensity of gagging, total dose of additional sedative medication and hemodynamic parameters will be recorded.

Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

Patients are stratified into 4 early risk groups for therapy during the consolidation phase (T/early SR, T/early non-SR, pB/early non-HR, pB/early HR) and 5 risk groups for post-consolidation therapy (T/non-HR, T/HR, pB/SR, pB/MR, pB/HR). Risk stratification is based on immunophenotypic lineage, genetics of leukemic cells and treatment response on the basis of cytomorphology and methods for detection minimal residual disease. The trial includes four randomized study questions testing experimental treatments on top of the risk-stratified standard chemotherapy backbone: Primary study questions: Randomization R-eHR: Early High-risk (early HR) pB-ALL defined by genetics and/or inadequate treatment response over the course of induction: Can the probability of event-free survival (pEFS) from time of randomization be improved by additional therapy with the proteasome inhibitor bortezomib during an extended consolidation treatment phase compared with standard extended consolidation? Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or inadequate treatment response by the end of consolidation: Can the pEFS from time of randomization be improved by a treatment concept including two cycles of post-consolidation immunotherapy with blinatumomab (15 µg/m²/d for 28 days per cycle) plus 4 doses intrathecal Methotrexate replacing two conventional highly intensive chemotherapy courses? Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics and intermediate MRD response: Can the probability of disease-free survival (pDFS) from time of randomization be improved by additional therapy with one cycle of post-reintensification immunotherapy with blinatumomab (15 µg/m²/d for 28 days)? Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients defined by treatment response over the course of induction: Can the pEFS from time of randomization be improved by the extension of the standard of care consolidation phase by 14 days with an increase of the consolidation cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by 50%? Secondary study questions: All randomizations: Can the overall survival be improved by the treatment in the experimental arm? All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm? Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with bortezomib? Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with blinatumomab? Randomization R-HR: What is the proportion of patients with insufficient MRD response to blinatumomab as defined in the protocol as compared to the MRD response after the HR-2' block in the control arm? Randomization R-HR: Can the MRD load after the first treatment cycle (HR 2'/blinatumomab) and the second cycle (HR-3'/blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy? Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the blinatumomab cycle compared to 4 weeks of standard maintenance therapy? Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase? Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009? A small subgroup of patients at very high relapse risk is eligible for allogeneic hematopoietic stem cell transplantation after the intensified consolidation therapy phase. Patients with T-ALL and hyperleukocytosis (>=100,000/µL) and patients with CNS involvement at diagnosis (CNS3 status) are eligible for cranial irradiation with 12 Gy if age at time of irradiation is at least 4 years.

Pulmonary Hemodynamics During Exercise - Research Network

The FOrMe Registry (The German Focal Segmental Glomerulosclerosis and Minimal Change Disease Registry)

Idiopathic Nephrotic Syndrome is characterized by proteinuria, volume retention, hyperlipidemia, hypoalbuminemia. As Minimal Change Disease (MCD) represents by far the most prevalent underlying diagnosis in children older than 1 year, a kidney biopsy is usually deferred in these cases. In adolescence and adults, a kidney biopsy is crucial for the diagnosis because MCD and FSGS account for only 10-15 and 12-35 percent of all cases of nephrotic syndrome respectively. Pathomechanisms as well as optimal treatment remain elusive as systematic trials are scarce and hampered by low incidence and heterogenicity of the clinical presentation. To bridge this informational gap, the investigators identified the need for a German registry of pediatric and adult patients with idiopathic nephrotic syndrome (in children) and biopsy-proven MCD/FSGS (in adults). The registry will record clinical data of participants regarding basic demographics, initial presentation, hereditary traits, disease course and treatment modalities as well as quality of life, concomitant diseases, and comedication. During the initial visit and to a lesser intent on follow-up visits, biomaterials (blood, urine, DNA, feces, tissue) will be collected and stored in a state-of-the art biobank. This material will be available to collaborators to support research on idiopathic nephrotic syndrome and MCD/FSGS. By the time of completion, the registry will provide data on clinical courses and outcome of approximately 500 patients that can easily be correlated with biomaterials giving insight into risk factors, prognostic parameters, and association with comorbidities. Tissue sections of all patients that undergo kidney biopsy (all adult and some pediatric patients) will be digitalized, annotated, and analyzed by a panel of nephropathologists. Histopathologic features will be individually assessed and scored according to a set of descriptors that was developed and is used by the American NEPTUNE (Nephrotic Syndrome Study Network).

Trial to Evaluate Efficacy and Safety of Bortezomib in Patients with Severe Autoimmune Encephalitis

Autoimmune encephalitis is characterized by autoantibodies against neuronal surface antigens like the NMDA (N-methyl-D-aspartate) receptor or LGI1 (Leucin-rich glioma inactivated protein 1). So far, no specific therapy exists for this disease. Actual treatment includes combination therapies aiming for a reduction of pathogenic antibodies and containing the autoimmune process. In first line, patients are treated with plasmapheresis and cortisone. In second line, Rituximab and/or cyclophosphamide are administered. The response to these treatments are, however, often delayed and insufficient. Therefore, we need a specific therapy aiming at the antibody-producing plasma cells. Bortezomib is a proteasome inhibitor which interferes with NF-kB (nuclear factor kB) and the ubiquitin proteasome signaling pathway. Bortezomib acts preferably on cells with high protein synthesis - like plasma cells - and induces cell death in these cells. Bortezomib is used since more than a decade in chemotherapy of the multiple myeloma. Additionally, it is reported for systemic autoimmune diseases like lupus erythematodes that bortezomib leads to a depletion of plasma cells and therefore reduces the number of pathogenic antibodies and improves clinical outcome. The therapeutic potential of bortezomib for NMDAR encephalitis is described in a first case series with 5 patients.

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