Homburg An D. Saar, Germany

Adjusted High-dose Chemotherapy with Autologous Stem Cell Transplant Vs. Conventional Immunochemotherapy in Elderly PCNSL Patients

Primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is a rare lymphoma affecting only the central nervous system compartment. PCNSL patients are typically 60 years or older and have poor prognoses. However, there are alternative treatment approaches to consider with the potential to improve medical outcomes for this patient population. The current standard of care in Germany and many international centres for patients 65 and older is treatment with R-MP, comprising rituximab, high-dose methotrexate (HD-MTX) and procarbazine followed by maintenance therapy with procarbazine. An alternative approach comprised of a shorter induction treatment with rituximab, HD-MTX and cytarabine (MARTA) followed by age-adjusted high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) was recently shown to be feasible and effective in elderly PCNSL patients considered eligible for high-dose chemotherapy requiring autologous stem cell transplantation. Nevertheless, data evaluating this short duration treatment approach remains scarce, and randomized trials have not yet been published. The objective of the PRIMA-CNS trial is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with R-MP followed by maintenance with procarbazine in elderly patients with newly diagnosed PCNSL; not only regarding survival and remission after treatment but also regarding standards like quality of life (QOL) and treatment related morbidities. Results of this randomized trial will either change the standard of care to an intense and shorter treatment approach or re-define R-MP as a proven treatment standard. In addition, a geriatric assessement is implemented in this trial with the goal to better define transplant eligibility. If this trial shows the superiority of HCT-ASCT, the investigators will establish an improved treatment standard with increased chances for long-term remission and cure and reduced frequency and length of chemotherapy treatment. Considering the poor prognosis of this patient population, this randomized phase III trial is of great clinical importance to provide patients, the patients' families and care takers with optimal treatment.

Capivasertib Plus Fulvestrant vs. Fulvestrant in Primary High-risk Lobular Breast Cancer

The evaluation of CCCA in the HR+/HER2- invasive lobular breast cancer patient population allows assessment of treatment efficacy with an achievable sample size of HR+/HER2- breast cancer patients within an acceptable and scientifically meaningful duration of recruitment. CCCA can be assessed immediately after last patients end of treatment. Central blinded pathological assessment of CCCA is planned in this study as a standardized preparation of the sampled tissue by the central pathologist. This pathologist is blinded regarding the study therapy administered, i. e. with or without capivasertib. The addition of capivasertib to fulvestrant in many clinical trials correlates with an improvement in PFS compared to fulvestrant alone in patients with HR+/HER2- locally advanced or metastatic breast cancer. This effect was observed regardless of a PI3K/AKT/mTOR pathway activation. None of the ongoing studies investigate the effects of the combined treatment in invasive lobular breast cancer. Given that these tumors are less likely to respond to chemotherapy, identification of patients that can be spared from chemotherapy is desirable. On the other hand, it is important to identify patients with invasive lobular breast cancer not responding to neoadjuvant ET who might be at increased risk for recurrence, who would therefore potentially benefit from further adjuvant therapies including chemotherapy. Given the high rates of PI3K pathway alterations in such tumors, it is expected that the CCCA rate could be increased by adding capivasertib to fulvestrant. GBG expect that the potential benefit of improved CCCA rate with a combination treatment compared to fulvestrant monotherapy would outweigh the potential risks due to added toxicity, which has already been shown in clinical trials to be well tolerated by patients.

Homburg Renal Evaluation Study on the Clinical Utility of Early AKI Diagnosis

Urinary dickkopf-3 (uDKK3), a stress-induced renal tubular epithelium-derived glycoprotein, has been identified as a biomarker predicting persistent kidney dysfunction. In this prospective observational trial in patients at high risk of developing acute kidney injury we will assess whether urinary dickkopf-3 serves as a predictor of acute kidney injury. Patients of the intensive care units of Saarland University Hospital will be surveyed for up to two years after their admission to the intensive care unit. The progression of the estimated Glomerular Filtration Rate and uDKK3 will be monitored.

Study of ALXN2220 Versus Placebo in Adults With ATTR-CM

Pharmacokinetics of Bisoprolol and SGLT2i in Acutely Decompensated Heart Failure

Adherence to Medication in Patients With Acute Decompensated Heart Failure

Several drugs has been shown to improve survival and to reduce the risk for hospitalization for acute heart failure (AHF) in patients with chronic heart failure. Despite optimal drug treatment, patients with heart failure suffer one hospitalization for AHF every year on average with the requirement of intravenous diuretics. Hence, AHF is one of the leading causes for emergency department visits in elderly patients. A possible cause for AHF in patients with known heart failure is nonadherence to drug treatment. Long-term-adherence to drugs of chronic diseases is low. Direct methods to assess adherence like the measurement drug levels or metabolites in body fluids are considered as the gold standard. This study aimed to i) provide (direct measured) adherence rates of patients presented with AHF to the emergency department and ii) to identify patient-related factors with impact on adherence.

Iberdomide Vs. Iberdomide Plus Isatuximab Maintenance Therapy Post ASCT in Newly Diagnosed Multiple Myeloma

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 in the GMMG-HD8/DSMM XIX trial. 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.

Durvalumab With Consolidative Radiochemotherapy and Ablative Stereotactic Radiotherapy in Oligometastatic ES-SCLC

This is an open-label, prospective, multi-center single-arm phase II trial. Patients with oligometastatic extensive stage SCLC will be enrolled in the trial. In this trial oligometastatic disease is defined as up to five tumor lesions, whereas the primary tumor including mediastinal lymph node metastases counts as one tumor lesion. The primary tumor including lymph node metastases must be suitable for radiochemotherapy and all distant metastases for stereotactic radiotherapy. Patients must have completed systemic therapy with two cycles of platinum/etoposide/durvalumab and have stable disease or partial response according to RECIST 1.1 criteria. After study inclusion, patients receive radiochemotherapy with concomitant durvalumab (MEDI4736). Concomitant chemotherapy consists of further two cycles platinum/etoposide q3w (summarized cycle 3-4). Dosing of chemotherapy is etoposide 90mg/m² body surface area (BSA) day 1-3 in combination with cisplatin 75mg/m² BSA on day 1 or carboplatin area under the curve (AUC) 5 mg/ml per minute on day 1. Split dose of platinum chemotherapy to 2-3 days is an allowed treatment option. Durvalumab is administered in fixed dose 1500mg in q3w cycles concomitant to chemotherapy and q4w cycles during maintenance treatment. Radiotherapy to the primary tumor including mediastinal lymph node metastases is delivered in single fractions of 1.8Gy once daily up to a cumulative dose of 63.0Gy by intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). In the following, stereotactic radiotherapy is delivered to the up to four further tumor locations during durvalumab maintenance therapy. Sequencing of radiotherapy of the primary tumor and metastases may be changed if radiotherapy of brain, vertebral or other symptomatic metastases is urgently necessary. Stereotactic radiotherapy will be performed according to local standards with established dose and fractionation schemes in ablative doses depending on the affected organ system.

Saruparib (AZD5305) vs Placebo in Men With Metastatic Castration-Sensitive Prostate Cancer Receiving Physician's Choice New Hormonal Agents

Approximately 1800 adult participants with mCSPC will be assigned to one of two cohorts (550 HRRm and 1250 non-HRRm) and randomized in a 1:1 ratio to receive either Saruparib (AZD5305) with NHA or placebo with NHA. They will receive their assigned treatment and regular tumor evaluation scans until disease progression, or until treatment is stopped for another reason. All patients will be followed for survival until the end of the study. Independent data monitoring committee (DMC) composed of independent experts will be convened to confirm the safety and tolerability of Saruparib (AZD5305) + physicians choice NHA.

PACCELIO - FDG-PET Based Small Volume Accelerated Immuno Chemoradiotherapy in Locally Advanced NSCLC