Manchester, United Kingdom, United Kingdom

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

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).

ITP Registry and Accompanying Biospecimen Collection

Immune thrombocytopenia (ITP) is a rare hematologic disorder that can lead to a greater risk of bleeding or a prolonged bleeding time due to an autoimmune-mediated deficiency of platelets. In recent years, new treatment options for patients with immune thrombocytopenia have emerged. The results of published clinical studies on ITP can only be used for broad patient care to a limited extent, as they are designed for a patient population with clearly defined inclusion and exclusion criteria. Real world data collected from this registry will help to better understand the diagnosis and therapy of ITP patients in everyday treatment and to more effectively direct individual patients to optimal therapy, thus improving their outcomes. By collecting biospecimens, this project will contribute new knowledge to the study of ITP through standardized, systematic, and high-quality collection and storage of patient samples and associated data. The registry collects clinical data from patients diagnosed with ITP at defined points in the course of the disease. The Data collection includes a range of clinical measures, disease-related factors, treatment/treatment course and outcomes, complications during treatment and Qol, fatigue scoring and survival data (up to 5 years). The data are collected prospectively. In addition, patients can be included retrospectively up to 12 months after the initial diagnosis if continuous documentation can be provided at the treatment centre. In both cases, a written declaration of consent is obligatory.

ASCT After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma

Objectives and Endpoints Primary Objective: To establish one of three study arms, R-CHOP/R-DHAP followed by ASCT (control arm A), R-CHOP+ibrutinib /R-DHAP followed by ASCT and ibrutinib maintenance experimental arm A+I), and R-CHOP+ibrutinib /R-DHAP followed by ibrutinib maintenance experimental arm I) as future standard based on the comparison of the investigator-assessed failure-free survival (FFS). Secondary Objectives: - To compare the efficacy of the three treatment arms in terms of secondary efficacy endpoints - To determine the safety and tolerability of ibrutinib during induction immuno-chemotherapy and during maintenance and to compare the safety profile of the three treatment arms in terms of secondary toxicity endpoints Primary Endpoint: FFS defined as time from start of treatment to stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause. Secondary Efficacy Endpoints: - Overall survival (OS) - Progression-free survival (PFS) from randomization, from end of induction immuno-chemotherapy in patients with CR or PR at end of induction immuno-chemotherapy, and from the staging 6 weeks after end of induction assessment (at month 6) - Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6) - PR to CR conversion rate during follow-up after end of induction immuno-chemotherapy Secondary Toxicity Endpoints: - Rates of AEs, SAEs, and SUSARs by CTC grade (Version 4.03) during induction immuno-chemotherapy and during periods of follow-up after response to immune-chemotherapy - Cumulative incidence rates of SPMs Exploratory Objectives: - To compare feasibility of ASCT in arm A+I vs. arm A - To compare minimal residual disease status between the three treatment groups - To determine the impact of ibrutinib during induction immuno-chemotherapy and during maintenance therapy on the minimal residual disease status - To determine the prognostic value of minimal residual disease status - To determine the prognostic value of positron emission tomography with fluorine 18-fluorodeoxyglucose - To determine clinical and biological prognostic and predictive factors - To determine the role of total body irradiation (TBI) in ASCT conditioning Exploratory Endpoints: - Rate of successful stem cell mobilisations (success: separation of at least 2x2x10(6) CD34-positive cells, including a back-up) - Rate of molecular remissions (MRD-negative patients) at midterm, at end of induction immuno-chemotherapy, and at staging time-points during follow-up in patients with remission after end of induction immuno-chemotherapy - Time to molecular remission from start of therapy - Time to molecular relapse for patients in clinical and molecular remission after end of induction immunochemotherapy - RD in FDG-PET negative or positive patients after induction and ASCT Exploratory objectives may be evaluated only in a subset of patients according to local standards and resources.

A Study of Milvexian in Participants After an Acute Ischemic Stroke or High-Risk Transient Ischemic Attack- LIBREXIA-STROKE