Lorrach, Germany

Treatment of Patients with Chronic Hepatitis B with Hepatitis B Immunoglobulins

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.

Prospective, Multicenter Cohort Study on Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease. The course of the disease is characterized by a slow destruction of bile ducts, and progressive cholestasis. Prognosis depends on the development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) has been established as standard therapy for PBC and improves patients' long-term outcome. However, UDCA is not a uniformly effective drug, and the prognosis of PBC patients insufficiently responding to treatment is markedly worse. For patients with suboptimal treatment response to UDCA obeticholic acid (OCA) as newly approved medication (OCALIVA®) is available as second line treatment. Due to the low prevalence and the slowly progressive course of the disease it is very difficult to investigate the prognosis of subgroups of PBC patients or to evaluate the effectivness of therapeutic interventions on clinical outcomes. Therefore, several national or international registries (UK-PBC Consortium or the Global PBC Study Group) were founded to better characterize the clinical course of PBC patients. Since in Germany a registry for PBC does not exist, the German PBC Cohort is being implemented as observational study to collect data on treatment progress and success in clinical routine that reflects real world conditions in Germany as closely as possible. The effectiveness and safety/tolerability of PBC treatment options (UDCA as standard therapy and second-line treatment options like OCALIVA in case of inadequate UDCA treatment response) will be evaluated. In approximatly 40 sites in Germany routine data is collected. There are no specifications for the diagnosis, therapy and monitoring of the PBC patients. The documentation of the routine data is carried out alongside with guideline recommended treatment intervals of the patients. Furthermore, a critical criterion for the German PBC Cohort study is the involvement of a sufficient number of gastroenterology specialized practices and outpatient clinics that have consciously not been selected based on the strict specifications of a clinical trial and which provide routine treatment for PBC patients. In addition, patient access is designed to be open. Data will be collected on patient groups that represent a majority of the PBC patients in Germany, but who are not being investigated in clinical trials.

Registry to Collect Data on Patients Undergoing Segmental Mandibular Defect Reconstruction Following Oral Squamous Cell Carcinoma Resection and Drugs-induced Osteonecrosis

Data will be prospectively collected from at least 300 patients with acquired segmental mandibular defects of 2 cm or larger following resection of tumors or necrotic/infected tissue, all of whom require mandibular reconstruction. The follow up (FU) will consist of standard of care (routine) procedures and data collection will be done at 3, 6, 12, 18 and up to 24 months after resection and/or reconstruction. The maximum FU for each patient within the registry will be 2 years after mandibular resection. Data collection will include confounding baseline data, tumor characteristics, neurological function, patient reported outcomes, quality of life as well as anticipated procedure-related adverse events (AEs). Available images will be collected and evaluated centrally to determine the location, positioning, osseointegration, bone quantity and quality of the transplants. Depending on the volume and quality of the collected data, different statistical analyses will be performed. Exploratory analyses will be conducted to find relationships between the different treatment modalities and their outcomes.

Northern Survey on Therapeutic Oxygen Prescription

CYSTEA-BONE Clinical Study

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

Evaluation of a Donor Testing Kit for the Prediction of AGVHD in Patient Receiving a Peripheral Blood Stem Cell Allograft

Acute Graft Versus Host Disease (aGVHD) is the most frequent complication in allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT). It affects up to 50% patients, among whom 15% to 25% develop severe forms, often lethal, yet impossible to predict even for donors with a Human Leukocyte Antigene (HLA) 10/10 compatibility. Global Overall Survival (OS) after transplantation is 40% to 60% only due to post transplant severe complications. There is a major medical need for a technology that would predict the risk of aGVHD and would allow the selection of a favourable donor among multiple Human Leukocyte Antigene (HLA)10/10 compatible donors. MT. Rubio and M. Bouillié at Pr Olivier Hermine's lab previously reported that enhanced early post-transplant invariant Natural Killer T (iNKT) cells reconstitution from donor cells was correlated to reduced risk of aGVHD, without impairment of the Graft Versus Leukemia (GVL) effect. They subsequently demonstrated that the expansion of donors CD4neg invariant Natural Killer T (iNKT) cells subpopulation was predictive of a reduced risk of aGVHD, and developed a method for predicting this risk based on the expansion factor of CD4neg invariant Natural Killer T (iNKT) cells in the peripheral blood stem cell (PBSC) graft. This invariant Natural Killer T (iNKT) cells functional test reaches its optimal predictive capacity with 94% sensitivity and 100% specificity in allo-HSCT performed with Human Leukocyte Antigene (HLA) 10/10 matched peripheral blood stem cell (PBSC) grafts for non-progressive hematological malignant diseases, in complete response, which represent the majority of the indications of allogeneic HSCT. Similar predictive value was also observed when the test was performed from donor's peripheral blood before G-CSF mobilization. It was not associated with an increased risk of relapse. This test could therefore allow to easily selecting the best donor if different siblings or unrelated donors are available before PBSC allo-HSCT.

Monitoring of Donor-specific Antibodies After Treatment with Immunoglobulins, Plasmapheresis and Rituximab in Lung Transplantation

This is an observational study to monitor the treatment of donor-specific antibodies in lung transplant recipients with detection of donor-specific antibodies. All consented subjects will be approached for participation. The study will evaluate the effectiveness of the treatment protocol of donor-specific antibodies with Immunoglobulins or combined treatment with Immunoglobulins, Plasmapheresis and Rituximab after lung transplantation.

INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies

Compared to adult cancers, most pediatric cancers carry a relatively low mutational burden. HDAC inhibition (HDACi) modifies T-cell regulation and can augment response to checkpoint inhibition by reducing the number of myeloid-derived suppressor cells and creating an immunogenic tumor microenvironment including induction of MHCI and neo-antigens. In vitro and in vivo models showed enhanced anti-tumor activity of the combination of checkpoint inhibition and HDACi compared to either agent alone. This provides a strong rationale to combine these drug classes. Checkpoint inhibition results in activation of tumor-associated T cells. It is now becoming increasingly evident that patients with tumors with a high number of tumor infiltrating T cells at baseline show an increased response rate. Additionally, recent clinical data on immune checkpoint inhibition (ICI) for melanoma patients detected tertiary lymphoid structures (TLS) as indicators of an activated adaptive immune response. Their presence has been linked to objective treatment responses in patients with different cancer entities receiving ICI. Furthermore, MYC- or NMYC-driven (referred to as MYC(N)) malignancies like very high-risk medulloblastomas or very high-risk neuroblastomas still have a dismal outcome. MYC is not only reported to upregulate PD-L1 and thereby a possible biomarker for checkpoint inhibition but also very compelling recent preclinical data strongly suggests that HDAC inhibitors are active against MYC amplified medulloblastoma in vitro and in vivo. In NMYC amplified neuroblastoma cell lines similar observations were made in vitro. In addition, it has been shown recently that the molecular MYC subgroup of atypical teratoid rhabdoid tumors (ATRT) exhibit a strong T-cell infiltrate in contrast to the SHH-ATRT subtype and are considered immunological "hot" tumors. Taken together, our results suggest that MYC(N)-driven tumors depend on HDAC and we hypothesize that MYC(N) status can serve as a biomarker for response prediction to a combinatorial treatment of checkpoint inhibition and HDAC inhibition. Pediatric patients aged 2-21 years with refractory/relapsed/progressive high-risk malignancies with a high mutational load (group A), with MYC(N) amplification or from the ATRT-MYC subgroup (group C) as well as patients with high TILs and/or TLS positive (group E) are eligible for this trial. Phase I determines the recommended phase 2 dose (RP2D) for the combination of the HDACi entinostat and the checkpoint inhibitor nivolumab for the age groups 6-11 and 12-21 years, respectively. Phase II investigates activity in 3 groups A, C, E for patients in the two age cohorts 2-11 and 12-21 years. The duration of treatment is 12 cycles (1 cycle = 28 days), preceded by 1 priming week. In addition, a comprehensive accompanying research program investigates PD biomarkers for immune checkpoint and HDAC inhibition. Clinical trials investigating the combination of nivolumab and entinostat in children have not been reported so far.