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Purpose: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (SNAr/SN). Methods: After predicting the theoretical solubility of the fragments by LogP and LogS during the selection process, we determined their experimental solubility using a turbidimetric solubility assay. The reactivities of the different compounds were measured in a high-throughput 5,5'-dithiobis-(2-nitrobenzoic acid) DTNB assay, followed by a (glutathione) GSH stability assay. We employed the CovLib in a (differential scanning fluorimetry) DSF-based screening against different targets: c-Jun N-terminal kinase 3 (JNK3), ubiquitin-specific protease 7 (USP7), and the tumor suppressor p53. Finally, the covalent binding was confirmed by intact protein mass spectrometry (MS). Results: In general, the purchased fragments turned out to be sufficiently soluble. Additionally, they covered a broad spectrum of reactivity. All investigated α-cyanoacrylamides/acrylates and all structurally confirmed epoxides turned out to be less reactive compounds, possibly due to steric hindrance and reversibility (for α-cyanoacrylamides/acrylates). The SNAr and vinyl sulfone fragments are either highly reactive or stable. DSF measurements with the different targets JNK3, USP7, and p53 identified reactive fragment hits causing a shift in the melting temperatures of the proteins. MS confirmed the covalent binding mode of all these fragments to USP7 and p53, while additionally identifying the SNAr-type electrophile SN002 as a mildly reactive covalent hit for p53. Conclusion: The screening and target evaluation of the CovLib revealed first interesting hits. The highly cysteine-reactive fragments VS004, SN001, SN006, and SN007 covalently modify several target proteins and showed distinct shifts in the melting temperatures up to +5.1 °C and -9.1 °C.
Assuntos
Proteína Quinase 10 Ativada por Mitógeno , Proteína Supressora de Tumor p53 , Peptidase 7 Específica de Ubiquitina , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/química , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Peptidase 7 Específica de Ubiquitina/metabolismo , Peptidase 7 Específica de Ubiquitina/química , Humanos , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 10 Ativada por Mitógeno/química , Sulfonas/química , Sulfonas/farmacologia , Estrutura Molecular , Solubilidade , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Acrilamidas/química , Acrilamidas/farmacologia , Acrilatos/química , Acrilatos/farmacologia , Ligação ProteicaRESUMO
BACKGROUND: This Phase 1b/2 study assessed the efficacy in terms of objective response rate (ORR) of the FGFR1/2/3 kinase inhibitor derazantinib as monotherapy or in combination with atezolizumab in patients with metastatic urothelial cancer (mUC) and FGFR1-3 genetic aberrations (FGFR1-3GA). METHODS: This multicenter, open-label study comprised 5 substudies. In Substudies 1 and 5, patients with mUC with FGFR1-3GA received derazantinib monotherapy (300 mg QD in Substudy 1, 200 mg BID in Substudy 5). In Substudy 2, patients with any solid tumor received atezolizumab 1200 mg every 3 weeks plus derazantinib 200 or 300 mg QD. In Substudy 3, patients with mUC harboring FGFR1-3GA received derazantinib 200 mg BID plus atezolizumab 1200 mg every 3 weeks. In Substudy 4, patients with FGFR inhibitor-resistant mUC harboring FGFR1-3GA received derazantinib 300 mg QD monotherapy or derazantinib 300 mg QD plus atezolizumab 1200 mg every 3 weeks. RESULTS: The ORR for Substudies 1 and 5 combined was 4/49 (8.2%, 95% confidence interval = 2.3% to 19.6%), which was based on 4 partial responses. The ORR in Substudy 4 was 1/7 (14.3%, 95% confidence interval = 0.4% to 57.9%; 1 partial response for derazantinib 300 mg monotherapy, zero for derazantinib 300 mg plus atezolizumab 1200 mg). In Substudy 2, derazantinib 300 mg plus atezolizumab 1200 mg was identified as a recommended dose for Phase 2. Only 2 patients entered Substudy 3. CONCLUSIONS: Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC. Clinicaltrials.gov NCT04045613, EudraCT 2019-000359-15.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Idoso de 80 Anos ou mais , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Neoplasias Urológicas/genética , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/secundárioRESUMO
BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).
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Antibacterianos , Bacteriemia , Daptomicina , Infecções Estafilocócicas , Staphylococcus aureus , Adulto , Humanos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Cefalosporinas/administração & dosagem , Cefalosporinas/efeitos adversos , Cefalosporinas/uso terapêutico , Daptomicina/administração & dosagem , Daptomicina/efeitos adversos , Daptomicina/uso terapêutico , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Resultado do Tratamento , Método Duplo-Cego , Administração Intravenosa , Aztreonam/administração & dosagem , Aztreonam/efeitos adversos , Aztreonam/uso terapêuticoRESUMO
As an orthogonal principle to the established (hetero)aryl halides, we herein highlight the usefulness of CF2X (X = Cl, Br, or I) moieties. Using tool compounds bearing CF2X moieties, we study their chemical/metabolic stability and their logP/solubility, as well as the role of XB in their small molecular crystal structures. Employing QM techniques, we analyze the observed interactions, provide insights into the conformational flexibilities and preferences in the potential interaction space. For their application in molecular design, we characterize their XB donor capacities and its interaction strength dependent on geometric parameters. Implementation of CF2X acetamides into our HEFLibs and biophysical evaluation (STD-NMR/ITC), followed by X-ray analysis, reveals a highly interesting binding mode for fragment 23 in JNK3, featuring an XB of CF2Br toward the P-loop, as well as chalcogen bonds. We suggest that underexplored chemical space combined with unconventional binding modes provides excellent opportunities for patentable chemotypes for therapeutic intervention.
Assuntos
Química Farmacêutica , Halogênios , Halogênios/química , Estrutura Molecular , Descoberta de Drogas , BiologiaRESUMO
Microtubules are major components of the cellular cytoskeleton, ubiquitously founded in all eukaryotic cells. They are involved in mitosis, cell motility, intracellular protein and organelle transport, and maintenance of cytoskeletal shape. Avanbulin (BAL27862) is a microtubule-targeted agent (MTA) that promotes tumor cell death by destabilization of microtubules. Due to its unique binding to the colchicine site of tubulin, differently from other MTAs, avanbulin has previously shown activity in solid tumor cell lines. Its prodrug, lisavanbulin (BAL101553), has shown early signs of clinical activity, especially in tumors with high EB1 expression. Here, we assessed the preclinical anti-tumor activity of avanbulin in diffuse large B cell lymphoma (DLBCL) and the pattern of expression of EB1 in DLBCL cell lines and clinical specimens. Avanbulin showed a potent in vitro anti-lymphoma activity, which was mainly cytotoxic with potent and rapid apoptosis induction. Median IC50 was around 10 nM in both ABC and GCB-DLBCL. Half of the cell lines tested showed an induction of apoptosis already in the first 24 h of treatment, the other half in the first 48 h. EB1 showed expression in DLBCL clinical specimens, opening the possibility for a cohort of patients that could potentially benefit from treatment with lisavanbulin. These data show the basis for further preclinical and clinical evaluation of lisavanbulin in the lymphoma field.
RESUMO
Isavuconazole is a triazole with broad-spectrum antifungal activity. In this post-hoc analysis of two prospective clinical trials (VITAL and SECURE), the safety and efficacy of isavuconazole in patients aged ≥ 65 years with invasive fungal diseases were evaluated. Patients were divided into two subgroups (≥ 65 and < 65 years). Adverse events (AEs); all-cause mortality; and overall, clinical, mycological, and radiological response were assessed. A total of 155 patients ≥ 65 years were enrolled in both trials. Most patients reported AEs. In the isavuconazole arm of both studies, serious AEs (SAEs) were greater in patients ≥ 65 versus < 65 years: 76.7% versus 56.9% (VITAL); 61.9% versus 49.0% (SECURE). In SECURE, SAE rates were similar in the ≥ 65 years subgroup of both treatment arms (61.9% vs 58.1%), while in the < 65 years subgroup the SAE rate was lower in the isavuconazole arm (49.0% vs 57.4%). In VITAL, all-cause mortality through day 42 (30.0% vs 13.8%) was higher, and overall response at end of treatment (27.6% vs 46.8%) was lower in patients ≥ 65 years versus < 65 years. In SECURE, all-cause mortality was similar between both subgroups, and isavuconazole (20.6% vs 17.9%) and voriconazole (22.6% vs 19.4%) treatment arms. The overall response was lower in the ≥ 65 years than the < 65 years subgroup in the isavuconazole (23.7% vs 39.0%) and voriconazole (32.0% vs 37.5%) arms. The safety and efficacy of isavuconazole were better in patients < 65 versus ≥ 65 years, and the safety profile was more favorable than that of voriconazole in both subgroups.Clinicaltrials.gov identifier NCT00634049 and NCT00412893.
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Aspergilose , Infecções Fúngicas Invasivas , Idoso , Humanos , Antifúngicos/efeitos adversos , Aspergilose/tratamento farmacológico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Nitrilas/efeitos adversos , Estudos Prospectivos , Triazóis/efeitos adversos , Voriconazol/efeitos adversosRESUMO
PURPOSE: Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m2. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma. Clinicaltrials.gov registration: NCT02895360.
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Glioblastoma , Neoplasias Ovarianas , Humanos , Feminino , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologiaRESUMO
INTRODUCTION: This review evaluates the clinical role of fibroblast growth factor receptor 2 (FGFR2) inhibition with derazantinib in patients with intrahepatic cholangiocarcinoma (iCCA) harboring actionable oncogenic FGFR2 fusions/rearrangements, mutations and amplifications. FGFR inhibitors such as derazantinib are currently being evaluated to address the unmet medical need of patients with previously treated, locally advanced or metastatic iCCA harboring such genetic aberrations. AREAS COVERED: We summarize the pharmacokinetics, and the emerging safety and efficacy data of the investigational FGFR inhibitor derazantinib. We discuss the future directions of this novel therapeutic agent for iCCA. EXPERT OPINION: Derazantinib is a potent FGFR1â3 kinase inhibitor which also has activity against colony stimulating factor-1âreceptor (CSF1R) and vascular endothelial growfth factor receptorâ2 (VEGFR2), suggesting a potentially differentiated role in the treatment of patients with iCCA. Derazantinib has shown clinically meaningful efficacy with durable objective responses, supporting the therapeutic potential of derazantinib in previously treated patients with iCCA harboring FGFR2 fusions/rearrangements, mutations and amplifications. The clinical safety profile of derazantinib was well manageable and compared favorably to the FGFR inhibitor class, particularly with a low incidence of drug-related hand-foot syndrome, stomatitis, retinal and nail toxicity. These findings support the need for increased molecular profiling of cholangiocarcinoma patients.
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Compostos de Anilina/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Quinazolinas/uso terapêutico , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacologia , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Rearranjo Gênico , Humanos , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/efeitos adversos , Quinazolinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Aim: To evaluate the efficacy and safety of ceftobiprole in patients from East Asia. Materials & methods: A post hoc analysis was conducted of two randomized, double-blind, Phase III studies in patients with community- or hospital-acquired pneumonia. Results: Findings for East Asian patients were consistent with the overall study populations. A trend toward higher microbiological eradication rates and numerically lower rates of all-cause mortality were reported for ceftobiprole versus comparators (all-cause mortality [intent-to-treat]: community-acquired pneumonia, 1.5 vs 2.8%; hospital-acquired pneumonia excluding ventilator-associated pneumonia, 5.9 vs 11.4%). The incidence of adverse events was similar between treatment groups. Conclusion: This post hoc analysis supports the efficacy and tolerability of ceftobiprole in East Asian patients. ClinicalTrials.gov trial identifiers: NCT00326287, NCT00210964, NCT00229008.
Lay abstract Pneumonia is a major cause of morbidity and mortality in East Asia and treatment is complicated by increasing rates of antibiotic resistance in this region. This study analyzed results from two clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in patients from mainland China, Hong Kong, Taiwan and South Korea. In East Asian patients with either community- or hospital-acquired pneumonia, outcomes following ceftobiprole treatment were similar to those achieved with established antibiotics. There was also an indication that ceftobiprole may improve the rate at which causative bacteria were eradicated and may potentially reduce mortality rates compared with other antibiotics. Ceftobiprole was well tolerated in this population and will be a useful option for the treatment of pneumonia in East Asia.
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Cefalosporinas/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Cefalosporinas/efeitos adversos , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Ásia Oriental , HumanosRESUMO
Aim: To evaluate the efficacy and safety of ceftobiprole in patients aged ≥65 years. Materials & methods: We conducted a post hoc analysis of three randomized, double-blind, Phase III studies in patients with acute bacterial skin and skin structure infections, community-acquired pneumonia and hospital-acquired pneumonia. Results: Findings for patients aged ≥65 years (n = 633) were consistent with those for the overall study populations, although a trend toward improved outcomes was reported in some subgroups, for example, patients aged ≥75 years with community-acquired pneumonia were more likely to achieve an early clinical response with ceftobiprole than comparator (treatment difference 16.3% [95% CI:1.8-30.8]). The safety profile was similar between treatment groups in all studies. Conclusion: This analysis further supports the efficacy and safety of ceftobiprole in older patients with acute bacterial skin and skin structure infections or pneumonia. Clinicaltrials.gov trial identifiers: NCT03137173, NCT00326287, NCT00210964, NCT00229008.
Lay abstract Infections are a common cause of severe disease and death in older patients. Antibiotic treatment may also be complicated by age-related changes within the body. The present study analyzed results from three large clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in the older population. In patients aged over 65 years with skin infections or with pneumonia acquired either in the community or in a hospital setting, ceftobiprole offered similar benefits to established antibiotics. There was also some preliminary evidence that older patients may respond more quickly to ceftobiprole compared with the other antibiotics used in these studies. Overall, ceftobiprole was well tolerated and will be a useful treatment option for infections in older patients. Clinical trial registration: NCT03137173, NCT00326287, NCT00210964, NCT00229008 (Clinicaltrials.gov).
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Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase III como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pneumonia/tratamento farmacológico , Pneumonia/mortalidade , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens. METHODS: TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection. RESULTS: In total, 679 patients were randomized to ceftobiprole (nâ =â 335) or vancomycin/aztreonam (nâ =â 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles. CONCLUSIONS: TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit. CLINICAL TRIALS REGISTRATION: NCT03137173.
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Staphylococcus aureus Resistente à Meticilina , Dermatopatias Bacterianas , Antibacterianos/uso terapêutico , Aztreonam/uso terapêutico , Cefalosporinas/uso terapêutico , Método Duplo-Cego , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Humanos , Dermatopatias Bacterianas/tratamento farmacológico , Resultado do Tratamento , Vancomicina/uso terapêuticoRESUMO
BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.
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Benzimidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Oxidiazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Progressão da Doença , Feminino , Humanos , Infusões Intravenosas , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Oxidiazóis/efeitos adversos , Oxidiazóis/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Fuso Acromático/efeitos dos fármacos , Reino UnidoRESUMO
Although Staphylococcus aureus is a common cause of bacteremia, treatment options are limited. The need for new therapies is particularly urgent for methicillin-resistant S. aureus bacteremia (SAB). Ceftobiprole is an advanced-generation, broad-spectrum cephalosporin with activity against both methicillin-susceptible and -resistant S. aureus. This is a Phase III, randomized, double-blind, active-controlled, parallel-group, multicenter, two-part study to establish the efficacy and safety of ceftobiprole compared with daptomycin in the treatment of SAB, including infective endocarditis. Anticipated enrollment is 390 hospitalized adult patients, aged ≥18 years, with confirmed or suspected complicated SAB. The primary end point is overall success rate. Target completion of the study is in the second half of 2021. Clinicaltrials.gov identifier: NCT03138733.
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Bacteriemia/tratamento farmacológico , Cefalosporinas/uso terapêutico , Daptomicina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Adulto , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Ensaios Clínicos como Assunto , Método Duplo-Cego , Farmacorresistência Bacteriana Múltipla , Feminino , Hospitalização , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
Purpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15-21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m2. Three grade 3 DLTs occurred: hypotension (70 mg/m2), hyponatremia and neutropenia (both 90 mg/m2). The MTD for 48-h IV BAL101553 was 70 mg/m2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the Cmax was 144 ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.
Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Oxidiazóis/uso terapêutico , Pró-Fármacos/uso terapêutico , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Microtúbulos , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Oxidiazóis/efeitos adversos , Oxidiazóis/sangue , Oxidiazóis/farmacocinética , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Resultado do TratamentoRESUMO
Mucormycosis is a rare but important invasive fungal disease that most often affects immunocompromised hosts. The incidence of mucormycosis appears to be increasing worldwide, as risk factors such as the use of immunosuppressive therapies become more common. We report the results of a literature review of 143 mucormycosis cases reported in South America between 1960 and 2018. The number of reported cases has increased by decade, from 6 in the 1960s to 51 in the 2010s. The most common underlying conditions associated with mucormycosis in South America were diabetes mellitus (42.0%) and penetrating trauma/burns (20.0%). Underlying conditions involving immunosuppression, including treatment of haematologic malignancy, solid organ transplant, and corticosteroid use, also accounted for a large proportion of cases (45.5%). Between 1960 and 2018, cases of mucormycosis associated with conditions involving immunosuppression accounted for the highest mortality rate (58.5%), followed by diabetes mellitus (45.0%), and penetrating trauma/burns (37.9%). Overall mortality decreased from 100% to 39.4% during this period, mainly driven by the increasing availability and use of antifungal therapies and surgical intervention. However, these treatments are not yet universally utilised across the region in the treatment of mucormycosis; efforts to improve availability of effective treatments would be likely to improve outcomes.
Assuntos
Infecções Fúngicas Invasivas/epidemiologia , Mucormicose/sangue , Mucormicose/epidemiologia , Antifúngicos/uso terapêutico , Complicações do Diabetes , Neoplasias Hematológicas/complicações , Humanos , Hospedeiro Imunocomprometido , Terapia de Imunossupressão/efeitos adversos , Infecções Fúngicas Invasivas/tratamento farmacológico , Mucormicose/tratamento farmacológico , Transplante de Órgãos/efeitos adversos , América do Sul/epidemiologiaRESUMO
BACKGROUND: Patients with pneumonia who are elderly or severely ill are at a particularly high risk of mortality. This post hoc retrospective analysis of data from two Phase III studies evaluated early improvement outcomes in subgroups of high-risk patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP, excluding ventilator-associated pneumonia [VAP]). METHODS: One study included hospitalised CAP patients randomised to ceftobiprole or ceftriaxone ± linezolid treatment. The other study included HAP patients, who were randomised to ceftobiprole or ceftazidime plus linezolid treatment. The primary outcome was rate of early clinical response (Day 3 in CAP and Day 4 in HAP patients). Additional outcome measures included clinical cure at a test-of-cure visit, 30-day all-cause mortality and safety. RESULTS: The overall high-risk group comprised 398 CAP patients and 307 HAP patients with risk factors present at baseline. The rate of early response was numerically higher in ceftobiprole-treated patients vs comparator-treated patients in the following high-risk groups: CAP patients aged ≥75 years (16.3% difference, 95% confidence interval [CI]: 1.8, 30.8); CAP patients with COPD (20.1% difference, 95% CI: 8.8, 31.1); all high-risk HAP patients (12.5% difference, 95% CI: 3.5, 21.4); HAP patients with >10 baseline comorbidities (15.3% difference, 95% CI: 0.3, 30.4). CONCLUSIONS: Previous studies show that ceftobiprole is an efficacious therapy for patients with pneumonia who are at high risk of poor outcomes. This post hoc analysis provides preliminary evidence that ceftobiprole treatment may have advantages over other antibiotics in terms of achieving early improvement in high-risk patients with HAP (excluding VAP) and in some subgroups of high-risk CAP patients. TRIAL REGISTRATION: NCT00210964 : registered September 21, 2005; NCT00229008 : registered September 29, 2005; NCT00326287 : registered May 16, 2006.
Assuntos
Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Pneumonia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Ceftazidima/uso terapêutico , Ceftriaxona/uso terapêutico , Infecções Comunitárias Adquiridas/mortalidade , Infecção Hospitalar/mortalidade , Feminino , Humanos , Linezolida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pneumonia/mortalidade , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.
Assuntos
Antibacterianos/uso terapêutico , Pneumonia Bacteriana/microbiologia , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Consenso , Cuidados Críticos/métodos , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Humanos , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Resultado do TratamentoRESUMO
OBJECTIVES: This analysis evaluated the variability of isavuconazole plasma concentrations between subjects and between sampling times, and assessed their relationship to outcomes for subjects with invasive fungal disease (IFD) in the SECURE trial. METHODS: Isavuconazole-treated subjects received 372 mg of isavuconazonium sulphate (corresponding to 200 mg of isavuconazole) three times daily for 2 days, then once daily. Plasma samples were collected after day 4 and analysis sets were constructed as follows: analysis set 1 included all samples from subjects with proven/probable/possible IFD who received ≥1 dose of isavuconazole; analysis set 2 included samples from subjects in analysis set 1 who had provided >1 sample; and analysis set 3 included samples from subjects in analysis set 1 with proven/probable invasive aspergillosis. Assessments included overall distributions of plasma concentrations and variability between samples (analysis sets 1 and 2) as well as relationships to outcomes [all-cause mortality (day 42), overall response (end of treatment) and treatment-emergent adverse events; analysis sets 1 and 3]. RESULTS: Analysis sets 1, 2 and 3 included samples from 160, 97 and 98 subjects, respectively. Trough concentrations for each were distributed similarly [mean (SD): 3406.6 (1511.5), 3495.6 (1503.3) and 3368.1 (1523.2) ng/mL, respectively]. The mean coefficient of variation between samples in analysis set 2 was 23.2%; differences between concentrations in first samples and subsequent samples were <2-fold for 85/97 subjects. In quartiles of subject data, no concentration-dependent relationships were observed for efficacy or safety. CONCLUSIONS: Plasma concentrations of isavuconazole were reasonably consistent between subjects and sampling times, and were not associated with differences in outcomes.
Assuntos
Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Triazóis/farmacocinética , Triazóis/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergillus/efeitos dos fármacos , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. METHODS: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. RESULTS: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. CONCLUSIONS: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. CLINICAL TRIALS REGISTRATION: NCT00413218.