Eschweiler

This non-interventional study aims to provide information on real-world effectiveness, safety and tolerability, management of adverse events, QoL and patient compliance of patients with HR+/HER2- early breast cancer at high risk of recurrence treated with ribociclib in combination with an aromatase inhibitor (AI) ± luteinizing hormone-releasing hormone (LHRH) with curative intent according to the current effective local summary of product characteristics. In order to put the results of patients treated with ribociclib into perspective, socio-economic data, data on QoL and patient compliance will also be collected from patients treated with abemaciclib + endocrine therapy (ET) ± LHRH as described in the current effective local summary of product characteristics. To understand reasons for treatment decision, and to analyze the clinical adoption of ribociclib + AI ± LHRH after EU approval over time, baseline data will be collected from cohorts of ribociclib + AI ± LHRH, abemaciclib + ET ± LHRH, and additionally from patients treated with ET monotherapy ± LHRH and analyzed cross-sectionally. The study is planned to be rolled out into a broad set of German and Austrian breast centers and gynecological practices to describe clinical routine in a representative subset of the local healthcare eco-system. It will gather insights into the potential benefits and risks associated with ribociclib + AI ± LHRH in the adjuvant treatment of HR+/HER2- eBC patients at high risk of recurrence. This knowledge will inform about clinical decision-making and contribute to improved patient outcomes in routine practice.

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).

The goal of this study is to learn if people who receive intismeran autogene and pembrolizumab after surgery are cancer-free longer than people who receive placebo and pembrolizumab. Researchers want to know if giving intismeran autogene and pembrolizumab after surgery can help prevent the cancer from coming back in people with non-small cell lung cancer (NSCLC) whose tumors did not respond completely to treatment before surgery (neoadjuvant treatment).

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.

The MINERVA Trial aims to evaluate safety, efficacy and quality of life (QoL) for the combination of Abemaciclib with an Aromatase Inhibitor or Fulvestrant in pre- and postmenopausal patients with metastatic hormone receptor positive HER2 negative breast cancer in the first line setting. Side effect monitoring and patient reported outcomes will be captured using the web- and app-based CANKADO digital health application. Via this user-friendly tool the patients can document their therapy side effects (e.g. diarrhea) and outcomes on a day-to-day basis. The capturing of side effects using the digital health application will be done additionally to the regular AE documentation. Furthermore, translational research objectives of this trial include the investigation of biomarkers (ct-DNA, germline DNA) to evaluate whether they can give insights into the reasons for response, intrinsic or acquired resistance to the combined endocrine

The GMALL registry serves the purpose of ALL research and quality assurance. The Registry collects data about diagnostics, treatment and outcome of Adult ALL Patients in the clinical routine, whether or not the patient is treated within a clinical trial.

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial for a maintenance therapy, for patients who underwent an induction therapy and autologous stem cell transplantation (ASCT) in the GMMG-HD8/DSMM XIX trial or a similar quadruplet induction/consolidation therapy regimen followed by at least one ASCT. Investigational Medicinal Product: Iberdomid (oral), isatuximab (subcutaneous administration via a wearable injector system). Randomisation will be performed centrally by GMMG/DSMM offices after verification of the eligibility of the patient. At the time of study inclusion, randomization will be performed into arm A (iberdomide) or arm B (iberdomide + isatuximab). Randomization will be stratified by centrally assessed MRD negativity status (yes vs. no vs. unknown); assessed by NGF from BMA; sensitivity of 10\^-5; independent of standard IMWG response) and number of HDM/ASCT (single vs. tandem). Patients randomized in arm A will receive 39 cycles of the drug iberdomide, a Cereblon E3 Ubiquitin Ligase Modulating Drug (CELMoD®) that shares structural similarities to the immunomodulatory compounds (IMiDs) such as thalidomide and lenalidomide. Each cycle will last for 29 days. Patients in arm B will receive the same the 39 cycles of iberdomide plus monoclonal anti-CD38 antibody isatuximab subcutaneously. In both arms, patients will receive 20 mg dexamethasone in cycle 1, on the same days as the isatuximab administration in Arm B. End of study will be after 36 months of the maintenance therapy. There is one primary objective: \- Demonstration of superiority of iberdomide plus isatuximab compared to iberdomide with respect to bone marrow minimal residual disease (MRD) negativity rates (sensitivity 2x10\^-6 via next-generation flow cytometry \[NGF\]) after two years of maintenance therapy. There is one key secondary objective: \- PFS, defined as time from randomization to disease progression or death from any cause, whichever occurs first. Further secondary objectives are: * Rates of sustained MRD negativity (at sensitivity levels of 10-5 and 2x10\^-6 via NGF from BMA) after 1, 2 and 3 years of maintenance therapy. * Conversion from MRD positive to negative (at sensitivity levels of 10\^-5 and 2x10\^-6 via NGF from BMA). * Rates of best overall response to treatment (BOR). * Rates of partial response (PR), very good partial response (VGPR), complete response (CR) and stringent complete response (sCR). * Time-to-next-treatment (TTNT). * PFS on subsequent line of therapy. * Overall survival (OS). * Improvement of IMWG response categories (PR, VGPR, CR, sCR). * Proportions of patients in both treatment arms maintaining BOR and CR from baseline. * Assessment of quality-of-life (QoL) via the EORTC-QLQC30, EORTC-QLQMY20, and EQ-5D-5L questionnaires.

About 15% of breast cancers lack both, expression of ER and PR receptors, and amplification/over-expression of HER2 receptors, and are thus described as triple negative breast cancer (TNBC). TNBC is known for poor prognosis, aggressive patterns of disease, and significant molecular heterogeneity. (Neo)adjuvant chemotherapy (NACT) is standard of care in all node-positive and in node-negative patients with a tumour size \>5 mm according to current National Comprehensive Cancer Network (NCCN) guidelines. However, TNBC patients with lower stage disease do clearly have a better prognosis compared to more advanced stages. Patients with stage I-II node-negative disease have 3-5 year iDFS rates of 80-90% (with majority of relapses within the first three years) as shown in several trials. Our own results from the PlanB- and ADAPT-trials, and pooled analysis with SUCCESS C-trials show 3-year iDFS of 86-90% in node-negative TNBC with a tumour size \< 3 cm. Although survival results appear much better in the lower vs. higher stages, there is a high clinical need in this most common group of TNBC patients in Western Europe and USA. In the neoadjuvant setting, it has been shown that the prognosis of patients with TNBC is strongly dependent on their response to NACT: Patients achieving pathological complete response (pCR), or a near pCR (an excellent response after NACT (residual cancer burden (RCB) score 0-1), in some studies do have an excellent prognosis that is not significantly different from that observed in other breast cancer subtypes. However, patients with a less responsive disease (i.e., with RCB Score 2-3) suffer from a significantly worse prognosis compared to non-TNBC. Chemotherapy in TNBC The optimal chemotherapy regimen for patients with TNBC remains to be identified. Standard anthracycline-taxane (A/T)-based NACT combinations render pCR rates between 25-50%. However, the survival impact of anthracyclines remains controversial due to conflicting results of different randomized trials. Adding carboplatin (carbo) to A/T-containing poly-NACT or use of dose-intensified poly-NACT significantly increases pCR-rates up to 49-60% in mostly stage II-III disease with conflicting survival results and higher toxicity. Hence, use of pragmatic taxane-carboplatin anthracycline-free combinations appears as an effective treatment option in TNBC instead of further treatment escalation. This probably is independent of the germline BRCA (gBRCA) status, due to its general chemo-predictive effect. Unfortunately, no prospective phase-III-data are available so far. However, indirect comparison between trials renders similar pCR rates in taxane-carboplatin based vs. A/T+/-carbo-based regimens in early TNBC. In the ADAPT-TN neoadjuvant trial, the taxane-carbo arm (12-week nab-paclitaxel (nab-pac)+carbo) was well tolerable (only 10% SAE-rate), highly effective (pCR, ypT0/is/ypN0, of 46%) and superior to the gemcitabine (gem)-arm (nab-pac+gem, pCR of 29%). In this study, omission of further chemotherapy was allowed in patients with pCR after 12 weeks of therapy and was not associated with decreased survival after 3 years \[5\] and longer follow up. Although a standard chemotherapy as well as optimal therapy duration are still to be defined, several studies are showing a comparable efficacy for longer vs. shorter adjuvant treatments in TNBC \[3\], as well as a similar efficacy regarding pCR in HR-negative (in contrast to HR-positive) early breast cancer (eBC) \[26\]. Moreover 6 vs. 4 cycles of the same chemotherapy (AC or pac weekly) yielded a similar survival outcome in eBC despite of HR-status. No such comparison regarding treatment duration is available for modern antibody-drug conjugates like sacituzumab govitecan (SG). Therefore, an examination of shorter (12 weeks vs. 18 weeks) regimen as neoadjuvant treatment appears to be a very promising strategy at least in patients with lower risk disease or in elderly patients, who do not qualify for polychemotherapy treatments. In the Keynote-522 trial combination of carboplatin/taxane-anthracycline NACT with the anti-PD1-antibody pembrolizumab (PEM) has been shown to be associated with a significantly higher pCR and clinically meaningful better EFS and a trend to better OS. Noteworthy only patients with more advanced stages IIa-III TNBC were included into the Keynote-522 trial. Although this effect was independent of clinically assessed nodal status, there is still some uncertainty on the optimal treatment in patients with clinical stage I. In the metastatic setting, SG as a Trop-2-antibody-drug-conjugate has been shown to be highly efficacious in severely pre-treated patients (all with A/T pre-treated tumours, most of them carboplatin and 1/3 also anti-PD1 pre-treated) compared to chemotherapy of investigator´s choice. Treatment with SG was associated with significant longer median PFS (5.5 vs. 1.7 months) and longer median OS (12.1 vs. 6.7 months). Objective response was dramatically higher in the SG group vs. treatment by physician´s choice group (34.9 vs. 4.7%), in particular in the 2nd-3rd-line therapy (40% vs. 4%). Moreover, Tropics-02 trial has shown higher efficacy of SG vs. chemotherapy of investigator´s choice in patients with HR-positive/HER2-negative metastatic breast cancer. In the neoadjuvant setting, recently presented results from the NeoSTAR trial show a promising pCR-rate of 30% and RCB 0-1-rate of 36% in TNBC patients with mostly stage II-III-disease (about 80%) after only 4 cycles of SG. The following clinical questions are of highest medical need 1. Can 12-18 weeks neoadjuvant treatment with SG alone or in combination with PEM be associated with comparable pCR-rates (but more favourable safety profile) as shown for polychemotherapy in TNBC patients at lower relapse risk in historical controls? 2. Can SG-based therapy, as the most promising agent in patients with chemo-resistant disease, be associated with a such better prognosis (measured by 3-year-iDFS) compared to historical controls, which would make a randomized phase III-trial obsolete?

The current Standard of Care (SoC) in younger patients with Ph+ ALL is Imatinib in combination with low-dose chemotherapy, change of TKI in case of persistent MRD above 10-3 after consolidation I and indication for stem cell transplantation. The EVOLVE trial aims to answer three questions challenging the current SoC: Use of Ponatinib compared to Imatinib both in combination with low-dose chemotherapy and consolidation I (randomization I). In MRD good responders: Omit end of therapy in primary care and indication for SCT but continue therapy with TKI, chemotherapy and Blinatumomab as additional antileukemic compound (randomization II). In MRD poor responders: Omit indication for TKI change but give instead Blinatumomab followed by end of therapy in primary care and indication for SCT (non-randomized).

Follicular lymphoma (FL) is the second most common B-cell cancer and the most common type of cancer of lymphocytes. Unfortunately, this disease is incurable with conventional treatment and the disease recurs in almost all patients. This study will assess how safe and effective epcoritamab is in combination with lenalidomide and rituximab (R2) in treating adult participants with previously untreated FL. Adverse events and change in disease condition will be assessed. Epcoritamab is an investigational drug being developed for the treatment of FL. Study doctors put the participants in 1 of 5 groups, called treatment arms. Each group receives a different treatment. Around 1095 adult participants with previously untreated FL will be enrolled in approximately 250 sites across the world. Participants will receive R2 (intravenous \[IV\] infusion of rituximab (R) and oral capsules of lenalidomide) alone or in combination with subcutaneous injections of epcoritamab. Participants may also receive investigator's choice chemoimmunotherapy (CIT): IV infusion of obinutuzumab (G) and IV injections of cyclophosphamide, IV injections of doxorubicin, IV injections of vincristine, oral tablets of prednisone (CHOP) \[G-CHOP\]/ R-CHOP or G and IV infusion of bendamustine (Benda) \[G-Benda\]/R-Benda. The total treatment duration will be 120 weeks for all arms except A2, which is 24 weeks of treatment. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.