- MeSH
- centrální žilní katétry MeSH
- cévní přístupy MeSH
- denosumab aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- metastázy nádorů terapie MeSH
- nádory kostí farmakoterapie sekundární MeSH
- nádory plic * komplikace ošetřování terapie MeSH
- neutropenie chemicky indukované terapie MeSH
- odvykání kouření MeSH
- paliativní péče MeSH
- randomizované kontrolované studie jako téma MeSH
- trombóza prevence a kontrola terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM.
- MeSH
- bortezomib terapeutické užití MeSH
- dexamethason terapeutické užití MeSH
- fenylalanin * analogy a deriváty MeSH
- lidé MeSH
- melfalan * analogy a deriváty MeSH
- mnohočetný myelom * diagnóza farmakoterapie MeSH
- monoklonální protilátky * MeSH
- nádory plazmocelulární * MeSH
- neutropenie * chemicky indukované MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- senioři MeSH
- trombocytopenie * MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- MeSH
- analýza přežití MeSH
- bevacizumab škodlivé účinky terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- klinické zkoušky, fáze III jako téma * MeSH
- kolorektální nádory * farmakoterapie MeSH
- kombinovaná farmakoterapie metody MeSH
- lidé MeSH
- neutropenie chemicky indukované MeSH
- trifluridin škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- tipiracil,
- MeSH
- bevacizumab aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- klinická studie jako téma MeSH
- kolorektální nádory * farmakoterapie MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- neutropenie chemicky indukované MeSH
- pyrrolidiny aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- thymin aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- trifluridin aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit with monotherapy in a phase 2 study in relapsed or refractory (R/R) follicular lymphoma (FL). CITADEL-102 (NCT03039114), a phase 1, multicenter study, assessed the efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with R/R FL. Patients were ≥18 years of age with histologically confirmed and documented CD20-positive FL, and R/R to previous rituximab-containing treatment regimens. Part one (safety run-in) determined the maximum tolerated dose of parsaclisib in combination with standard dosage regimens of obinutuzumab and bendamustine. Part two (dose expansion) was an open-label, single-group design evaluating safety, tolerability (primary endpoint), and efficacy (secondary endpoint) of parsaclisib combination therapy. Twenty-six patients were enrolled in CITADEL-102 and all patients received parsaclisib 20 mg once daily for 8 weeks, followed by 20 mg once weekly thereafter, in combination with obinutuzumab and bendamustine. One patient in safety run-in experienced a dose-limiting toxicity of grade 4 QT interval prolongation that was considered related to parsaclisib. Eight patients (30.8%) discontinued treatment due to treatment-emergent adverse events (TEAEs) of colitis (2 [7.7%]), alanine aminotransferase and aspartate aminotransferase increase (both in one patient [3.8%]), neutropenia, thrombocytopenia, QT prolongation, tonsil cancer, and maculopapular rash (each 1 [3.8%]). The most common reported TEAEs were pyrexia (53.8%), neutropenia (50.0%), and diarrhea (46.2%). Twenty-three patients (88.5%) experienced grade 3 or 4 TEAEs; the most common were neutropenia (34.6%), febrile neutropenia (23.1%), and thrombocytopenia (19.2%). Seventeen patients (65.4%) had a complete response and 3 patients (11.5%) had a partial response, for an objective response rate of 76.9%. Overall, results from CITADEL-102 suggest that the combination of parsaclisib with obinutuzumab and bendamustine did not result in unexpected safety events, with little evidence of synergistic toxicity, and demonstrated preliminary efficacy in patients with R/R FL who progressed following prior rituximab-containing regimens.
- MeSH
- bendamustin hydrochlorid MeSH
- folikulární lymfom * patologie MeSH
- lidé MeSH
- neutropenie * chemicky indukované MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- rituximab MeSH
- trombocytopenie * etiologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- multicentrická studie MeSH
SIGNIFICANCE STATEMENT: Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV prevention strategy to avoid indirect effects of the virus. In this randomized trial involving 140 kidney transplant recipients, incidence of acute rejection at 12 months was not lower with valganciclovir prophylaxis (for at least 3 months) compared with preemptive therapy initiated after detection of CMV DNA in whole blood. However, prophylaxis was associated with a lower risk of subclinical rejection at 3 months. Although both regimens were effective in preventing CMV disease, the incidence of CMV DNAemia (including episodes with higher viral loads) was significantly higher with preemptive therapy. Further research with long-term follow-up is warranted to better compare the two approaches. BACKGROUND: The optimal regimen for preventing cytomegalovirus (CMV) infection in kidney transplant recipients, primarily in reducing indirect CMV effects, has not been defined. METHODS: This open-label, single-center, randomized clinical trial of valganciclovir prophylaxis versus preemptive therapy included kidney transplant recipients recruited between June 2013 and May 2018. After excluding CMV-seronegative recipients with transplants from seronegative donors, we randomized 140 participants 1:1 to receive valganciclovir prophylaxis (900 mg, daily for 3 or 6 months for CMV-seronegative recipients who received a kidney from a CMV-seropositive donor) or preemptive therapy (valganciclovir, 900 mg, twice daily) that was initiated after detection of CMV DNA in whole blood (≥1000 IU/ml) and stopped after two consecutive negative tests (preemptive therapy patients received weekly CMV PCR tests for 4 months). The primary outcome was the incidence of biopsy-confirmed acute rejection at 12 months. Key secondary outcomes included subclinical rejection, CMV disease and DNAemia, and neutropenia. RESULTS: The incidence of acute rejection was lower with valganciclovir prophylaxis than with preemptive therapy (13%, 9/70 versus 23%, 16/70), but the difference was not statistically significant. Subclinical rejection at 3 months was lower in the prophylaxis group (13% versus 29%, P = 0.027). Both regimens prevented CMV disease (in 4% of patients in both groups). Compared with prophylaxis, preemptive therapy resulted in significantly higher rates of CMV DNAemia (44% versus 75%, P < 0.001) and a higher proportion of patients experiencing episodes with higher viral load (≥2000 IU/ml), but significantly lower valganciclovir exposure and neutropenia. CONCLUSION: Among kidney transplant recipients, the use of valganciclovir prophylaxis did not result in a significantly lower incidence of acute rejection compared with the use of preemptive therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Optimizing Valganciclovir Efficacy in Renal Transplantation (OVERT Study), ACTRN12613000554763 .
- MeSH
- antivirové látky škodlivé účinky MeSH
- cytomegalovirové infekce * epidemiologie MeSH
- Cytomegalovirus genetika MeSH
- lidé MeSH
- neutropenie * chemicky indukované komplikace MeSH
- příjemce transplantátu MeSH
- transplantace ledvin * škodlivé účinky MeSH
- valganciklovir škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- ribociklib,
- MeSH
- doba přežití bez progrese choroby MeSH
- inhibiční proteiny cyklin-dependentních kinas * aplikace a dávkování škodlivé účinky MeSH
- jednostranný karcinom prsu terapie MeSH
- klinické zkoušky, fáze III jako téma MeSH
- kombinovaná farmakoterapie MeSH
- kvalita života MeSH
- letrozol terapeutické užití MeSH
- lidé MeSH
- metastázy nádorů farmakoterapie MeSH
- nádorová bolest MeSH
- nádory kostí farmakoterapie sekundární MeSH
- nádory prsu * farmakoterapie terapie MeSH
- neutropenie chemicky indukované farmakoterapie MeSH
- progrese nemoci MeSH
- protinádorové látky aplikace a dávkování škodlivé účinky MeSH
- randomizované kontrolované studie jako téma MeSH
- senioři MeSH
- stárnutí MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known. METHODS: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings. RESULTS: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed. CONCLUSIONS: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).
- MeSH
- aminopyridiny aplikace a dávkování škodlivé účinky MeSH
- analýza podle původního léčebného záměru MeSH
- analýza přežití MeSH
- letrozol aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu farmakoterapie mortalita patologie MeSH
- neutropenie chemicky indukované MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- puriny aplikace a dávkování škodlivé účinky MeSH
- receptor erbB-2 MeSH
- receptory pro estrogeny MeSH
- senioři MeSH
- stupeň nádoru MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).
- MeSH
- antiparkinsonika * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- aplikace orální MeSH
- chelátory železa * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- deferipron * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- dopaminové látky aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- levodopa terapeutické užití MeSH
- lidé MeSH
- mozek - chemie MeSH
- mozek diagnostické zobrazování MeSH
- neutropenie chemicky indukované MeSH
- Parkinsonova nemoc * farmakoterapie metabolismus patofyziologie MeSH
- progrese nemoci MeSH
- substantia nigra * chemie diagnostické zobrazování účinky léků metabolismus MeSH
- železo * analýza metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
