RESUMO
PURPOSE: This open-label, dose-finding phase Ib/II study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E-mutant solid tumors. PATIENTS AND METHODS: In phase I, the recommended phase 2 doses (RP2D) were established (primary objective). In phase II, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated BRAF-mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma. RESULTS: A total of 126 patients with BRAF-mutant solid tumors were enrolled (phase I: 47 patients; phase II: 79 patients). The RP2D was encorafenib 450 mg once daily plus binimetinib 45 mg twice daily and pharmacokinetic data suggest that drug exposures of each agent were similar in combination compared with single-agent studies. In the phase II cohorts, confirmed responses were seen in two of 11 (18%) evaluable patients with mCRC, 11 of 26 (42%) evaluable patients with BRAFi-pretreated melanoma, and 28 of 42 (67%) BRAFi-naïve patients with melanoma. The most common grade 3/4 adverse event in phase II was increased alanine aminotransferase. CONCLUSIONS: The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600-mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.
Assuntos
Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Melanoma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Adulto , Idoso , Alanina Transaminase/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Melanoma/sangue , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/efeitos adversosRESUMO
BACKGROUND: BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. METHODS: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. RESULTS: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. CONCLUSIONS: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Vemurafenib/administração & dosagem , Vemurafenib/efeitos adversos , Vômito/induzido quimicamenteRESUMO
BACKGROUND: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. PATIENTS AND METHODS: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. RESULTS: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. CONCLUSION: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Humanos , Incidência , Masculino , Melanoma/genética , Melanoma/metabolismo , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Náusea/induzido quimicamente , Náusea/epidemiologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Vemurafenib/administração & dosagem , Vemurafenib/efeitos adversos , Vômito/induzido quimicamente , Vômito/epidemiologiaRESUMO
BACKGROUND: Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival. METHODS: COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAFV600E or BRAFV600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment. INTERPRETATION: The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAFV600-mutant melanoma. FUNDING: Array BioPharma, Novartis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Biomarcadores Tumorais/genética , Carbamatos/administração & dosagem , Melanoma/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/administração & dosagem , Vemurafenib/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Fenótipo , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Sulfonamidas/efeitos adversos , Fatores de Tempo , Vemurafenib/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma. METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator. INTERPRETATION: Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma. FUNDING: Array BioPharma, Novartis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Biomarcadores Tumorais/genética , Carbamatos/administração & dosagem , Melanoma/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/administração & dosagem , Vemurafenib/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Feminino , Humanos , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Sulfonamidas/efeitos adversos , Fatores de Tempo , Vemurafenib/efeitos adversos , Adulto JovemRESUMO
Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50-278 mg/m(2) on schedule A; 11 patients received pevonedistat 157 mg/m(2) on schedule B. The schedule A MTD was 209 mg/m(2): dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10 h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ≥6.5 months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.
Assuntos
Ciclopentanos , Melanoma/tratamento farmacológico , Pirimidinas , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Adulto , Idoso , Ciclopentanos/efeitos adversos , Ciclopentanos/farmacocinética , Ciclopentanos/farmacologia , Ciclopentanos/uso terapêutico , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Resultado do Tratamento , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
PURPOSE: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. EXPERIMENTAL DESIGN: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. RESULTS: Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥ 3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. CONCLUSIONS: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors.
Assuntos
Antineoplásicos/uso terapêutico , Ciclopentanos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/toxicidade , Ciclopentanos/toxicidade , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Pirimidinas/toxicidade , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidoresRESUMO
MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standard-of-care agents and may affect the clinical development of MLN4924. As such, we studied its interaction with other DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse xenograft model. Importantly, depletion of genes within the ataxia telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924 results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may provide useful information for the clinical development of these combinations.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Ciclopentanos/administração & dosagem , Sinergismo Farmacológico , Mitomicina/administração & dosagem , Pirimidinas/administração & dosagem , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Linhagem Celular Tumoral , Cromatina/efeitos dos fármacos , Cromatina/genética , Dano ao DNA/efeitos dos fármacos , Humanos , Camundongos , Enzimas Ativadoras de Ubiquitina/genética , Raios Ultravioleta , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Variations within proteasome ß (PSMB) genes, which encode the ß subunits of the 20S proteasome, may affect proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bortezomib and/or long-term outcomes, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity.
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Ácidos Borônicos/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Complexo de Endopeptidases do Proteassoma/genética , Pirazinas/uso terapêutico , Antineoplásicos/uso terapêutico , Bortezomib , Cisteína Endopeptidases , Resistencia a Medicamentos Antineoplásicos/genética , Frequência do Gene , Genótipo , Humanos , Mieloma Múltiplo/patologia , Polimorfismo de Nucleotídeo Único , Subunidades Proteicas/genética , Recidiva , Análise de Sequência de DNA , Análise de Sobrevida , Resultado do TratamentoRESUMO
This article outlines general strategies for the management and evaluation of pharmacokinetic drug-drug interactions (DDIs) resulting from perturbation of clearance of investigational anticancer drug candidates by concomitantly administered agents in a drug development setting, with a focus on drug candidates that cannot be evaluated in first-in-human studies in healthy subjects. A risk level classification is proposed, based on quantitative integration of knowledge derived from preclinical drug-metabolism studies evaluating the projected percentage contribution [f(i)(%)] of individual molecular determinants (e.g. cytochrome P450 isoenzymes) to the overall human clearance of the investigational agent. The following classification is proposed with respect to susceptibility to DDIs with metabolic inhibitors: a projected maximum DDI expected to result in a ≤1.33-fold increase in exposure, representing a low level of risk; a projected maximum DDI expected to result in a >1.33-fold but <2-fold increase in exposure, representing a moderate level of risk; and a projected maximum DDI expected to result in a ≥2-fold increase in exposure, representing a potentially high level of risk. For DDIs with metabolic inducers, the following operational classification is proposed, based on the sum of the percentage contributions of enzymes that are inducible via a common mechanism to the overall clearance of the investigational drug: <<25%, representing a low level of risk; <50%, representing a moderate level of risk; and ≥50%, representing a potentially high level of risk. To ensure patient safety and to minimize bias in determination of the recommended phase II dose (RP2D), it is recommended that strong and moderate inhibitors and inducers of the major contributing enzyme are excluded in phase I dose-escalation studies of high-risk compounds, whereas exclusion of strong inhibitors and inducers of the contributing enzyme(s) is recommended as being sufficient for moderate-risk compounds. For drugs that will be investigated in diseases such as glioblastoma, where there may be relatively frequent use of enzyme-inducing antiepileptic agents (EIAEDs), a separate dose-escalation study in this subpopulation is recommended to define the RP2D. For compounds in the high-risk category, if genetic deficiencies in the activity of the major drug-metabolizing enzyme are known, it is recommended that poor metabolizers be studied separately to define the RP2D for this subpopulation. Whereas concomitant medication exclusion criteria that are utilized in the phase I dose-escalation studies will probably also need to be maintained for high-risk compounds in phase II studies unless the results of a clinical DDI study indicate the absence of a clinically relevant interaction, these exclusion criteria can potentially be relaxed beyond phase I for moderate-risk compounds, if supported by the nature of clinical toxicities and the understanding of the therapeutic index in phase I. Adequately designed clinical DDI studies will not only inform potential relaxation of concomitant medication exclusion criteria in later-phase studies but, importantly, will also inform the development of pharmacokinetically derived dose-modification guidelines for use in clinical practice when coupled with adequate safety monitoring, as illustrated in the prescribing guidance for many recently approved oncology therapeutics.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Inibidores das Enzimas do Citocromo P-450 , Descoberta de Drogas , Interações Medicamentosas , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/metabolismo , Drogas em Investigação/farmacologia , Humanos , Inativação Metabólica/genética , Farmacogenética , Medição de Risco , Gestão de RiscosRESUMO
Immunohistochemical analyses of archival tumor specimens were used for pre-planned exploratory analyses of protocol-specified candidate biomarkers of bortezomib activity in 73 patients with relapsed/refractory mantle cell lymphoma in the phase 2 PINNACLE study. Consistent with other studies, elevated Ki-67 was a marker of poor prognosis, demonstrating significant associations with shorter time to progression and overall survival. Elevated NF-kappaB p65 and low PSMA5 expression demonstrated a trend for better response and were significantly associated with longer time to progression; elevated NF-kappaB p65 demonstrated a trend toward longer overall survival. This is consistent with myeloma clinical genomics research, suggesting biomarker relevance across tumor types. Elevated p27 was significantly associated with longer overall survival. Overall survival analyses by International Prognostic Index and Mantle Cell Lymphoma International Prognostic Index confirmed differential prognosis by both scores. These biomarkers data begin to illuminate bortezomib's mechanism of action in lymphoma.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Ácidos Borônicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib , Inibidor de Quinase Dependente de Ciclina p27 , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Multiple pathways have been proposed to explain how proteasome inhibition induces cell death, but mechanisms remain unclear. To approach this issue, we performed a genome-wide siRNA screen to evaluate the genetic determinants that confer sensitivity to bortezomib (Velcade (R); PS-341). This screen identified 100 genes whose knockdown affected lethality to bortezomib and to a structurally diverse set of other proteasome inhibitors. A comparison of three cell lines revealed that 39 of 100 genes were commonly linked to cell death. We causally linked bortezomib-induced cell death to the accumulation of ASF1B, Myc, ODC1, Noxa, BNIP3, Gadd45alpha, p-SMC1A, SREBF1, and p53. Our results suggest that proteasome inhibition promotes cell death primarily by dysregulating Myc and polyamines, interfering with protein translation, and disrupting essential DNA damage repair pathways, leading to programmed cell death.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Morte Celular/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Inibidores de Proteassoma , Pirazinas/farmacologia , RNA Interferente Pequeno/genética , Bortezomib , Morte Celular/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dano ao DNA , Técnicas de Silenciamento de Genes , Células HCT116 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Ribossomos/efeitos dos fármacos , Serina-Treonina Quinases TOR , TransfecçãoRESUMO
T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-theta transduces the signal from the TCR through activation of transcription factors NF-kappaB, AP-1, and NFAT. We examined the effects of PKC-theta deficiency on two Th1-dependent models of Ag-induced arthritis and found that PKC-theta-deficient mice develop disease, but at a significantly diminished severity compared with wild-type mice. In the methylated BSA model, cellular infiltrates and articular cartilage damage were mild in the PKC-theta-deficient mice as compared with wild-type mice. Quantitation of histopathology reveals 63 and 77% reduction in overall joint destruction in two independent experiments. In the type II collagen-induced arthritis model, we observed a significant reduction in clinical scores (p < 0.01) in three independent experiments and diminished joint pathology (p < 0.005) in PKC-theta-deficient compared with wild-type littermates. Microcomputerized tomographic imaging revealed that PKC-theta deficiency also protects from bone destruction. PKC-theta-deficient CD4(+) T cells show an impaired proliferative response, decreased intracellular levels of the cytokines IFN-gamma, IL-2, and IL-4, and significantly diminished cell surface expression of the activation markers CD25, CD69, and CD134/OX40 on memory T cells. We demonstrate decreased T-bet expression and significantly reduced IgG1 and IgG2a anti-collagen II Ab levels in PKC-theta-deficient mice. Collectively, our results demonstrate that PKC-theta deficiency results in an attenuated response to Ag-induced arthritis, which is likely mediated by the reduced T cell proliferation, Th1/Th2 cell differentiation and T cell activation before and during disease peak.
Assuntos
Antígenos/administração & dosagem , Artrite Experimental/imunologia , Artrite Experimental/prevenção & controle , Isoenzimas/deficiência , Isoenzimas/genética , Proteína Quinase C/deficiência , Proteína Quinase C/genética , Soroalbumina Bovina/administração & dosagem , Células Th1/imunologia , Animais , Antígenos/imunologia , Artrite Experimental/enzimologia , Artrite Experimental/genética , Autoanticorpos/biossíntese , Autoanticorpos/sangue , Movimento Celular/genética , Movimento Celular/imunologia , Proliferação de Células , Colágeno/administração & dosagem , Colágeno/imunologia , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Feminino , Imunofenotipagem , Isoenzimas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Proteína Quinase C/fisiologia , Proteína Quinase C-theta , Soroalbumina Bovina/imunologia , Proteínas com Domínio T , Linfócitos T/imunologia , Linfócitos T/patologia , Células Th1/patologia , Fatores de Transcrição/biossíntese , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. METHODS AND RESULTS: We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, P=0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 microg/mL, P<0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (Ptrend<0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). Risks were independent of standard risk factors and C-reactive protein. CONCLUSIONS: The platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before STEMI, and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.
Assuntos
Plaquetas/química , Calgranulina B/genética , Doença da Artéria Coronariana/genética , Perfilação da Expressão Gênica , Infarto do Miocárdio/genética , RNA Mensageiro/análise , Doença Aguda , Adulto , Idoso , Antígenos CD/sangue , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/sangue , Antígenos de Diferenciação de Linfócitos T/genética , Biomarcadores/sangue , Calgranulina B/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C , Masculino , Megacariócitos/química , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Razão de Chances , Valor Preditivo dos Testes , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Transcrição GênicaRESUMO
BACKGROUND: Mast cells (MCs) proliferate in response to T(H)2 cytokines and express genes de novo after activation. Limited information is available concerning the interplay between these events. OBJECTIVE: We explored the potential for T(H)2 cytokines to alter activation-dependent gene expression by MCs. METHODS: Cord blood-derived human (h)MCs maintained in stem cell factor (SCF) alone were compared with replicates treated with IL-4, IL-5, or IL-9, respectively, for their patterns of FcepsilonRI-dependent gene induction using microarray technology. RESULTS: Activation of SCF-treated hMCs upregulated their expression of roughly 140 transcripts at 2 hours, including genes involved in cell cycle progression and arrest. Each cytokine substantially modified this profile; approximately 800 inducible genes apiece were controlled by IL-5 or IL-9, whereas 169 inducible genes were controlled by IL-4. IL-4 favored the induction of cytokines and of genes associated with cell growth arrest (GADD34, GAS-1, CIDE-A, INK4D, and BAX) and completely abolished the enhanced proliferation observed in the other 3 groups after activation. Conversely, IL-5 priming induced preferential upregulation of genes involved in cell proliferation and did not abolish thymidine incorporation. CONCLUSIONS: T(H)2 cytokines differentially modulate gene induction in hMCs after FcepsilonRI cross-linkage. IL-4 uniquely controls cytokine gene expression by hMCs and might also limit their activation-driven proliferation.