BACKGROUND: Patients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and individualized treatment that could impact patient outcomes. In an exploratory analysis of the phase III ENGOT-EN5/GOG-3055/SIENDO study of selinexor maintenance monotherapy 80 mg in advanced/recurrent endometrial cancer, a pre-specified subgroup of patients with TP53 wild type (wt) endometrial cancer showed preliminary activity at long-term follow-up with a generally manageable safety profile (median progression-free survival 27.4 months vs 5.2 months placebo, HR=0.41). PRIMARY OBJECTIVE: To evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. STUDY HYPOTHESIS: Selinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with TP53wt advanced/recurrent endometrial cancer after systemic therapy versus placebo. TRIAL DESIGN: This is a prospective, multicenter, double-blind, placebo-controlled, randomized phase III study designed to evaluate the efficacy and safety of selinexor as a maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have histologically confirmed endometrial cancer, TP53wt confirmed by next-generation sequencing, completed at least 12 weeks of platinum-based therapy with or without immunotherapy, with confirmed partial response or complete response, and primary Stage IV disease or at first relapse. PRIMARY ENDPOINT: The primary endpoint is investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat population. SAMPLE SIZE: A total of 220 patients will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: NCT05611931.

• Klíčová slova
• Uterine Cancer,
• MeSH
• dvojitá slepá metoda MeSH
• hydraziny * aplikace a dávkování   terapeutické užití   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• lokální recidiva nádoru * farmakoterapie   patologie   MeSH
• multicentrické studie jako téma MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory endometria * farmakoterapie   patologie   MeSH
• randomizované kontrolované studie jako téma MeSH
• triazoly * aplikace a dávkování   MeSH
• udržovací chemoterapie metody   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH
• Názvy látek
• hydraziny * MeSH
• nádorový supresorový protein p53 MeSH
• selinexor MeSH Prohlížeč
• TP53 protein, human MeSH Prohlížeč
• triazoly * MeSH

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

• Klíčová slova
• Disease modification, Essential thrombocythemia (ET), Myeloproliferative neoplasms (MPNs), Phase III, ROP-ET, Ropeginterferon alfa-2b,
• MeSH
• dospělí MeSH
• esenciální trombocytemie * farmakoterapie   MeSH
• interferon alfa-2 * terapeutické užití   škodlivé účinky   MeSH
• interferon alfa * terapeutické užití   škodlivé účinky   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• polyethylenglykoly * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• prospektivní studie MeSH
• rekombinantní proteiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH
• Názvy látek
• interferon alfa-2 * MeSH
• interferon alfa * MeSH
• peginterferon alfa-2b MeSH Prohlížeč
• polyethylenglykoly * MeSH
• rekombinantní proteiny * MeSH

BACKGROUND: Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known. METHODS: EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0-2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union's Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. DISCUSSION: EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023.

• Klíčová slova
• Glioblastoma, LEGATO, Lomustine, Progression, Randomized controlled trial, Reirradiation,
• MeSH
• antitumorózní látky alkylující * terapeutické užití   MeSH
• časové faktory MeSH
• chemoradioterapie metody   MeSH
• doba přežití bez progrese choroby * MeSH
• glioblastom * patologie   farmakoterapie   mortalita   radioterapie   terapie   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kvalita života MeSH
• lidé MeSH
• lomustin * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• multicentrické studie jako téma * MeSH
• nádory mozku * radioterapie   patologie   mortalita   terapie   MeSH
• pragmatické klinické studie jako téma MeSH
• progrese nemoci * MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH
• Názvy látek
• antitumorózní látky alkylující * MeSH
• lomustin * MeSH

BACKGROUND: Vaccine efficacy (VE) assessed in a randomized controlled clinical trial can be affected by demographic, clinical, and other subject-specific characteristics evaluated as baseline covariates. Understanding the effect of covariates on efficacy is key to decisions by vaccine developers and public health authorities. METHODS: This work evaluates the impact of including correlate of protection (CoP) data in logistic regression on its performance in identifying statistically and clinically significant covariates in settings typical for a vaccine phase 3 trial. The proposed approach uses CoP data and covariate data as predictors of clinical outcome (diseased versus non-diseased) and is compared to logistic regression (without CoP data) to relate vaccination status and covariate data to clinical outcome. RESULTS: Clinical trial simulations, in which the true relationship between CoP data and clinical outcome probability is a sigmoid function, show that use of CoP data increases the positive predictive value for detection of a covariate effect. If the true relationship is characterized by a decreasing convex function, use of CoP data does not substantially change positive or negative predictive value. In either scenario, vaccine efficacy is estimated more precisely (i.e., confidence intervals are narrower) in covariate-defined subgroups if CoP data are used, implying that using CoP data increases the ability to determine clinical significance of baseline covariate effects on efficacy. CONCLUSIONS: This study proposes and evaluates a novel approach for assessing baseline demographic covariates potentially affecting VE. Results show that the proposed approach can sensitively and specifically identify potentially important covariates and provides a method for evaluating their likely clinical significance in terms of predicted impact on vaccine efficacy. It shows further that inclusion of CoP data can enable more precise VE estimation, thus enhancing study power and/or efficiency and providing even better information to support health policy and development decisions.

• Klíčová slova
• Baseline covariates, Correlate of protection, Logistic regression, Relative risk, Vaccine efficacy,
• MeSH
• demografie statistika a číselné údaje   MeSH
• klinické zkoušky, fáze III jako téma statistika a číselné údaje   metody   MeSH
• lidé MeSH
• logistické modely MeSH
• počítačová simulace MeSH
• randomizované kontrolované studie jako téma statistika a číselné údaje   metody   MeSH
• účinost vakcíny * statistika a číselné údaje   MeSH
• vakcinace statistika a číselné údaje   metody   MeSH
• vakcíny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• vakcíny MeSH

• MeSH
• COVID-19 * MeSH
• fixní kombinace léků MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• neutralizující protilátky * MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• Názvy látek
• cilgavimab and tixagevimab drug combination MeSH Prohlížeč
• cilgavimab MeSH Prohlížeč
• fixní kombinace léků MeSH
• monoklonální protilátky MeSH
• neutralizující protilátky * MeSH
• tixagevimab MeSH Prohlížeč

INTRODUCTION: Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN. METHODS: These analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022). RESULTS: In OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports. CONCLUSION: These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).

• Klíčová slova
• Autologous stem cell transplant, Melphalan flufenamide, efficacy, multiple myeloma, pomalidomide, safety,
• MeSH
• autologní transplantace MeSH
• dexamethason terapeutické užití   MeSH
• hodnocení rizik MeSH
• klinické zkoušky, fáze II jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• melfalan terapeutické užití   MeSH
• mnohočetný myelom * farmakoterapie   MeSH
• následné studie MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dexamethason MeSH
• melfalan MeSH
• melflufen MeSH Prohlížeč
• pomalidomide MeSH Prohlížeč

The Phase 3 ICARIA-MM (NCT02990338) and IKEMA (NCT03275285) studies demonstrated that isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) or carfilzomib (K) and d (Isa-Kd) improved progression-free survival (PFS) versus Pd or Kd in patients with relapsed and/or refractory multiple myeloma. In this post hoc analysis of patients with soft-tissue plasmacytomas, we evaluated Isa-Pd/Isa-Kd efficacy using central radiology and central laboratory assessments. Given the low incidence of soft-tissue plasmacytomas (7.8 %, ICARIA-MM; 6.3 %, IKEMA), efficacy data were pooled across the two studies. PFS (HR, 0.47; 95 % CI, 0.21-1.08), overall response rate (50.0 % vs 17.7 %), and very good partial response or better rate (26.9 % vs 11.8 %) were improved with Isa-Pd/Isa-Kd versus Pd/Kd, with consistent improvements within individual studies. Patients with soft-tissue plasmacytomas who received Isa-Pd/Isa-Kd had similar median PFS compared with those without soft-tissue plasmacytomas and received Pd/Kd. Safety is reported individually per study. Longer median treatment duration and more Grade ≥ 3 treatment-emergent adverse events occurred in the Isa versus control arms in ICARIA-MM (36.9 vs 8.4 weeks; 85.7 % vs 70.0 %) and IKEMA (41.9 vs 29.9 weeks; 100.0 % vs 57.1 %); however, Isa did not increase the percentage of patients with fatal events or drug discontinuation. Isa-Pd or Isa-Kd is a potential new treatment option and partially overcomes the poor prognosis associated with soft-tissue plasmacytomas in relapsed and/or refractory multiple myeloma.

• Klíčová slova
• Anti-CD38 monoclonal antibody, Isatuximab, Multiple myeloma, Soft-tissue plasmacytoma,
• MeSH
• dexamethason terapeutické užití   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   MeSH
• nádory plazmocelulární * farmakoterapie   MeSH
• plazmocytom * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dexamethason MeSH
• isatuximab MeSH Prohlížeč

Despite improvements in staging, surgical techniques, and the introduction of adjuvant chemotherapy for stage II and III nonsmall cell lung cancer (NSCLC), a large number of operated patients have recurrences of the disease. Due to the breakthrough results of immunotherapy in advanced stages of NSCLC, studies examining its potential benefits in operated patients were logically started. The first studies looked at the use of adjuvant immunotherapy after chemotherapy, where they had already shown the benefits of atezolizumab in a phase III study. A press release on positive data for pembrolizumab in the same indication has also been published recently. This was followed by studies with neoadjuvant immunotherapy, which in the phase III trials mostly switched to the chemoimmunotherapy regimen (with possible continuation of immunotherapy in adjuvant administration). Recently, there was a press release on the positive results of nivolumab with neoadjuvant chemotherapy. It is therefore highly likely that these treatment modalities will translate into standard treatment regimens in the near future.

• Klíčová slova
• NSCLC, adjuvant therapy, immunotherapy, immunother­apy, neoadjuvant therapy, neoadjuvant treatment,
• MeSH
• imunoterapie metody   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• nádory plic * farmakoterapie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   MeSH
• nivolumab terapeutické užití   MeSH
• staging nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nivolumab MeSH

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. Trial Registration Number: NCT04102020 (ClinicalTrials.gov).

• Klíčová slova
• BCL-2 inhibitor, CC-486 (oral azacitidine), acute myeloid leukemia, first remission, maintenance therapy, minimal residual disease conversion, phase III, relapse-free survival, venetoclax,
• MeSH
• akutní myeloidní leukemie * MeSH
• azacytidin škodlivé účinky   MeSH
• bicyklické sloučeniny heterocyklické MeSH
• buněčné dělení MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• protokoly antitumorózní kombinované chemoterapie * škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• sulfonamidy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• azacytidin MeSH
• bicyklické sloučeniny heterocyklické MeSH
• sulfonamidy MeSH
• venetoclax MeSH Prohlížeč

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.

• Klíčová slova
• Multiple sclerosis, alemtuzumab, autoimmunity, post-marketing, product surveillance, risk assessment, treatment outcome,
• MeSH
• alemtuzumab škodlivé účinky   MeSH
• autoimunita MeSH
• klinické zkoušky, fáze II jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• marketing MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   MeSH
• roztroušená skleróza * chemicky indukované   farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• alemtuzumab MeSH