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BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
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Resistencia a Medicamentos Antineoplásicos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , MAP Quinase Quinase 1/metabolismo , Sistema de Sinalização das MAP Quinases , Melanoma/genética , Camundongos , Mutação , Transplante de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/genética , Resultado do Tratamento , Vorinostat/farmacologiaRESUMO
BACKGROUND: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).
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Imunoterapia Adotiva , Linfócitos do Interstício Tumoral , Melanoma , Humanos , Terapia Baseada em Transplante de Células e Tecidos , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológicoRESUMO
INTRODUCTION: Increasing use of expensive oral anticancer medicines comes with the downside of a financial and environmental burden, partially caused by unused medication. Returned oral anticancer medicine to the pharmacy could be considered for redispensing providing guaranteed quality. This study aimed to identify and implement quality aspects and criteria for redispensing oral anticancer medicine in daily pharmacy practice. METHODS: A systematic analysis was conducted to determine the eligibility of oral anticancer medicine for redispensing. Over a one-year period, the number of returned oral anticancer medicine accepted for redispensing was quantified, and the reduction in financial waste and environmental burden calculated based on this assessment. RESULTS: Four categories of quality aspects were identified for determining the eligibility of oral anticancer medicine for redispensing: Product presentation suitability (stability characteristics, storage requirements), physical condition (unopened or opened secondary or primary packaging, visual appearance), authentication (Falsified Medicines Directive, confirmation of initial dispense, recall), and additional aspects (remaining shelf life, period of storage in uncontrolled conditions). A standardized procedure for redispensing was implemented in daily pharmacy practice. During the study period, 10,415 oral anticancer medicine dose units out of 13,210 returns (79%) were accepted for redispensing. The total value of oral anticancer medicine accepted for redispensing was 483,301, accounting for 0.9% of the total value dispensed during this period. Furthermore, the potential reduction in environmental burden was estimated at 1132.1â g of potent active pharmaceutical ingredient. CONCLUSIONS: By implementing strict procedures considering all relevant quality aspects, redispensing of oral anticancer medicine can be successfully implemented into daily pharmacy practice, resulting in a significant reduction in financial waste and environmental burden.
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AIM/BACKGROUND: In this study, the prolonged physical and chemical stability of the anticancer agent cabazitaxel, commercially available as Jevtana®, was examined. Both concentrate-solvent mixture and infusion solution were examined with the aim to extend the use of multidose left-over cabazitaxel and infusion solutions and with that reduce financial and environmental waste. METHODS: A validated stability-indicating high-pressure liquid chromatography (HPLC) method with ultraviolet (UV) and photodiode array (PDA) detection was used to examine the purity and any degradation of cabazitaxel. The concentrate-solvent mixture and infusion solution samples that were tested had been stored out of the range of the criteria stated in the summary of product characteristics (SmPC). The concentrate-solvent mixtures were stored at 3-5°C, 18-21°C, and 40 °C, whereas the infusion solution was stored at 3-5°C. All samples were tested at t = 0, t = 1 week and t = 2 weeks. RESULTS: All samples showed that purity and concentration had remained within the criteria of <5% as stated in the European Pharmacopoeia. However, the concentrate-solvent mixtures stored at 18-21°C and 40 °C showed a degradation product forming in all the samples lowering the purity of the samples from 100% to 99.91% and 98.20% respectively, whereas all samples stored at 3-5°C remained at 100%. CONCLUSION: Concentrate-solvent mixture and infusion solution of cabazitaxel, Jevtana®, can be used up to 2 weeks after preparation if stored at 3-5°C and prepared under aseptic conditions.
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Antineoplásicos , Taxoides , Solventes/química , Antineoplásicos/química , Estabilidade de Medicamentos , Taxoides/química , Cromatografia Líquida de Alta PressãoRESUMO
Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicities (DLTs) were recorded. The aim of current analysis was to develop a pharmacokinetic (PK)-toxicodynamic (TOX) model to quantify the relationship between docetaxel plasma exposure and DLTs. Methods A total of 85 patients was included in the current analysis, 18 patients showed a DLT in the four-week observation period. A PK-TOX model was developed and simulations based on the PK-TOX model were performed. Results The final PK-TOX model was characterized by an effect compartment representing the toxic effect of docetaxel, which was linked to the probability of developing a DLT. Simulations of once-weekly, once-daily 60 mg and once-weekly, twice-daily 30 mg followed by 20 mg of oral docetaxel suggested that 14% and 34% of patients, respectively, would have a probability >25% to develop a DLT in a four-week period. Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens.
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Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Docetaxel , Modelos Biológicos , Ritonavir , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Simulação por Computador , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Docetaxel/farmacocinética , Docetaxel/toxicidade , Humanos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Ritonavir/toxicidadeRESUMO
PURPOSE: Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). METHODS: Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. RESULTS: A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. CONCLUSION: The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1-14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.
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Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Capecitabina/administração & dosagem , Capecitabina/farmacologia , Cronofarmacoterapia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Capecitabina/efeitos adversos , Capecitabina/sangue , Ritmo Circadiano , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Fluoruracila/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Timidilato Sintase/metabolismo , Uridina Trifosfato/análogos & derivados , Uridina Trifosfato/sangueRESUMO
PURPOSE: The aim of this study was to ascertain whether the absolute bioavailability of oral imatinib (Glivec®) during steady state plasma pharmacokinetics in cancer patients could be determined through a concomitant intravenous administration of a single 100 µg microdose of deuterium labeled imatinib (imatinib-d8). Secondly, the usefulness of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was investigated for simultaneous analysis of orally and intravenously administered imatinib. METHODS: Included patients were on a stable daily dose of 400 mg oral imatinib prior to study participation. On day 1, patients received a 100 µg intravenous imatinib-d8 microdose 2.5 h after intake of the oral dose. Plasma samples were collected for 48 h. Imatinib and imatinib-d8 concentrations were simultaneously quantified using a validated LC-MS/MS assay. The absolute bioavailability was calculated by comparing the dose-normalized exposure with unlabeled and stable isotopically labeled imatinib in plasma. RESULTS: A total of six patients were enrolled. All patients had a history of gastrointestinal stromal tumors (GIST). The median absolute bioavailability of oral imatinib at steady state was 76% (range 44-106%). Imatinib and imatinib-d8 plasma concentrations were quantified in all collected plasma samples, with no samples below the limit of quantification for imatinib-d8. CONCLUSION: The absolute bioavailability of imatinib was successfully estimated at steady state plasma pharmacokinetics using the stable isotopically labeled microdose trial design. This study exhibits the use of a stable isotopically labeled intravenous microdose to determine the absolute bioavailability of an oral anticancer agent in patients with LC-MS/MS as the analytical tool.
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Antineoplásicos/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Administração Intravenosa , Administração Oral , Idoso , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Cromatografia Líquida , Deutério , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Mesilato de Imatinib/sangue , Mesilato de Imatinib/farmacocinética , Marcação por Isótopo , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas em TandemRESUMO
The clinical benefit of treatment with BRAF- and MEK-inhibitors in melanoma is limited due to resistance associated with emerging secondary mutations. Preclinical and clinical studies have shown that short-term treatment with the HDAC inhibitor vorinostat can eliminate cells harboring these secondary mutations causing resistance. This proof of concept study is to determine the efficacy of sequential treatment with vorinostat and BRAFi/MEKi in resistant BRAFV600E mutant melanoma. The primary aim is demonstrating anti-tumor response of progressive lesions according to RECIST 1.1. Secondary end points are to determine that emerging resistant clones with a secondary mutation in the MAPK pathway can be detected in circulating tumor DNA and purged by short-term vorinostat treatment. Exploratory end points include pharmacokinetic, pharmacodynamic and pharmacogenetic analyses (NCT02836548).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Vorinostat/uso terapêutico , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/genética , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Estudo de Prova de Conceito , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidoresRESUMO
BACKGROUND/PURPOSE: In the absence of thorough microbiological, chemical and physical stability data, high amounts of pharmaceutical products, from which the seal has been broken, are to be discarded after preparation. We performed a generic microbiological validation study for several marketed monoclonal antibody products, in order to define conditions under which leftovers from partially extracted product can be used in order to minimize loss. METHODS: From the daily practice of the Central Preparation Unit of the Netherlands Cancer Institute, used monoclonal antibody product vials were collected. To examine the integrity of the primary packaging, a VDT/S Vacuum Leak tester from Erweka was used. Vials were punctured with different types of spikes or a needle prior to experiments and examined for leakage afterward. In addition, microbiological monitoring was performed by broth simulation of the preparation method. RESULTS: All vials (631 vials, 18 different monoclonal antibody products) showed no leakage after puncturing with a 18 G needle. However, the use of a spike system resulted in leakage in 108 of the 435 tested vials. Results from the broth simulations confirmed a higher risk of contamination after puncturing with a spike as compared to needle-punctured vials (0.5% vs. 0.05%). CONCLUSION: When working under aseptic preparation conditions and making use of appropriate needle, the risk of contamination is acceptably low to justify storage and reuse of leftover monoclonal antibody product from a microbiological perspective. The spikes tested lead to an unacceptably high level of loss of integrity and subsequent risk of microbiological contamination if stored in a non-classified environment. We concluded that these results could be applied generically to all monoclonal antibody products with a primary packaging composed of a glass vial and rubber stopper.
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Anticorpos Monoclonais , Contaminação de Medicamentos , Embalagem de Medicamentos/métodos , Vidro , Humanos , BorrachaRESUMO
INTRODUCTION: Research has shown that sustained-release (SR) dexamphetamine is a promising agonist treatment for cocaine dependence. However, little is known about the pharmacokinetics (PKs) of SR oral dexamphetamine. This study examined the PKs of a new SR dexamphetamine formulation in cocaine plus heroin-dependent patients currently in heroin-assisted treatment. METHODS: The study was designed as an open-label PK study in 2 cohorts: n = 5 with once daily 60 mg and n = 7 with once daily 30 mg SR oral dexamphetamine. Five days of blood plasma dexamphetamine concentrations measured with liquid chromatography-mass spectrometry with PK parameter estimates using noncompartmental analysis. RESULTS: Twelve cocaine-dependent plus heroin-dependent patients in heroin-assisted treatment were included. The initial cohort 1 dose of 60 mg once daily was adjusted to 30 mg after mild to moderate adverse events. After oral administration, tmax values (coefficient of variation %) were 6.0 (17.0%) and 6.3 (16.3%) hours and t1/2 were 11 (24.6%) and 12 (25.4%) hours for 60 mg and 30 mg SR dexamphetamine, respectively. At steady state, CSSmax values were reached at 100 (27.5%) ng/mL and 58.4 (14.4%) ng/mL, whereas CSSmin values were 39.5 (38.9%) ng/mL and 21.8 (19.8%) ng/mL for 60 mg and 30 mg, respectively. CONCLUSIONS: The investigated SR formulation of dexamphetamine showed favorable slow-release characteristics in cocaine and heroin-dependent patients. A dose-proportional steady-state concentration was achieved within 3 days. These findings support the suitability of the SR formulation in the treatment of cocaine dependence.
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Estimulantes do Sistema Nervoso Central/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/reabilitação , Dextroanfetamina/administração & dosagem , Dependência de Heroína/reabilitação , Administração Oral , Adulto , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estimulantes do Sistema Nervoso Central/farmacocinética , Cromatografia Líquida , Estudos de Coortes , Preparações de Ação Retardada , Dextroanfetamina/efeitos adversos , Dextroanfetamina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Heroin-assisted treatment is effective for methadone treatment-refractory heroin-dependent patients, but continued comorbid cocaine dependence remains problematic. Sustained-release dexamfetamine is a promising agonist pharmacotherapy for cocaine dependence and we aimed to assess its acceptance, efficacy, and safety. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, patients who were treatment-refractory, as indicated by at least two earlier failed treatments aimed at reducing or abstaining from cocaine use, and who regularly (≥8 days/month) used crack-cocaine were enrolled from four heroin-assisted treatment centres in the Netherlands. Eligible patients were randomly assigned (1:1) to receive either 12 weeks of daily, supervised prescription of 60 mg/day oral sustained-release dexamfetamine or placebo in addition to co-prescribed methadone and diacetylmorphine. Randomisation was done by the collaborating pharmacist, using a computer-generated random number sequence with stratification by treatment centre in blocks of four per stratum. Randomisation was masked to patients, staff, and researchers throughout the study. The primary outcome was the number of self-reported days of cocaine use during study treatment, assessed every 4 weeks. Primary and safety analyses were done in the intention-to-treat population. The study was registered with the European Union Drug Regulating Authorities Clinical Trials (EUdraCT 2013-004024-11) and with The Netherlands Trial Register (NTR2576). FINDINGS: Between Aug 8, 2014, and Feb 27, 2015, 111 patients were assessed for eligibility, of whom 73 were enrolled and randomised; 38 patients were assigned to the sustained-release dexamfetamine group and 35 to the placebo group. Sustained-release dexamfetamine treatment resulted in significantly fewer days of cocaine use than placebo treatment (mean 44·9 days [SD 29·4] vs 60·6 days [24·3], respectively [95% CI of difference 3·1-28·4]; p=0·031; Cohen's standardised effect size d=0·58). One or more adverse events were reported by 28 (74%) patients in the dexamfetamine group and by 16 (46%) patients in the placebo group. Most adverse events were transient and well-tolerated. INTERPRETATION: Sustained-release dexamfetamine is a well accepted, effective, and safe agonist pharmacotherapy for comorbid treatment-refractory cocaine dependence in heroin-dependent patients in heroin-assisted treatment. Future research should aim to replicate these findings in chronic cocaine-dependent and other stimulant-dependent patients in more routine treatment settings, including strategies to optimise treatment adherence like medication management interventions and contingency management. FUNDING: Netherlands Organisation for Health Research and Development.
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Estimulantes do Sistema Nervoso Central/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/reabilitação , Cocaína Crack , Dextroanfetamina/administração & dosagem , Administração Oral , Estimulantes do Sistema Nervoso Central/efeitos adversos , Doença Crônica , Preparações de Ação Retardada , Dextroanfetamina/efeitos adversos , Método Duplo-Cego , Feminino , Dependência de Heroína/reabilitação , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Resultado do TratamentoRESUMO
BACKGROUND: Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH). METHODS: The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16+ uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry. RESULTS: Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4+ and/or CD8+ T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1ß (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients. CONCLUSION: DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.
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DNA/genética , Papillomavirus Humano 16/genética , Proteínas Oncogênicas Virais/imunologia , Vacinas de DNA/imunologia , Neoplasias Vulvares/genética , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Vulvares/terapiaRESUMO
Recent literature reviews and registration documents covering novel Signal Transduction Inhibitors in the treatment of cancer paint a picture of inefficiency and variability, where formulation improvements could be valuable. In this article, we discuss apparent drug design flaws as we impose the current standard formulation practice.
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Antineoplásicos/química , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biofarmácia/métodos , Composição de Medicamentos/métodos , Humanos , Terapia de Alvo Molecular , Neoplasias/metabolismo , SolubilidadeRESUMO
BACKGROUND: Z-endoxifen (further referred to as endoxifen, unless stated otherwise) is proposed as the most important metabolite of tamoxifen. Patients receiving adjuvant tamoxifen treatment with endoxifen levels below the threshold of 5.9 ng/mL may have an increased risk of breast cancer recurrence. Several factors, such as genetic polymorphisms, drug interactions, and (non)adherence, lead to large interpatient variability in endoxifen exposure, resulting in a substantial number of patients showing subtherapeutic levels. As genotyping and phenotyping are not able to adequately predict endoxifen exposure, therapeutic drug monitoring (TDM) seems to be the best approach for tailored tamoxifen therapy. METHODS: To support TDM services, a rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry assay for the quantification of endoxifen in human serum was developed and validated. Validation was performed according to the latest US FDA and EMA guidelines on bioanalytical method validation. RESULTS: The successfully validated serum assay quantifies endoxifen with a linear regression calibration model (weighted 1/x) in the concentration range from 1.00 to 25.0 ng/mL. The assay was validated with an inaccuracy of ±7.7% and an imprecision of ≤3.9%, obtained with an IS normalized matrix factor of 0.925 and a signal-to-noise ratio of >66. CONCLUSIONS: All validation parameters fulfilled their acceptance criteria, and the developed assay is now successfully being used to support TDM services. Thus far, 32.7% of the more than 500 determined endoxifen serum levels were below the threshold of 5.9 ng/mL.
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Antineoplásicos Hormonais/sangue , Tamoxifeno/análogos & derivados , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Feminino , Genótipo , Humanos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Tamoxifeno/sangue , Tamoxifeno/uso terapêutico , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND: A liquid chromatography/tandem mass spectrometry assay was developed to facilitate therapeutic drug monitoring (TDM) for 10 anticancer compounds (dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and vemurafenib) and the active metabolite, N-desethyl-sunitinib. METHODS: The TDM assay is based on reversed-phase chromatography coupled with tandem mass spectrometry in the positive ion mode using multiple reaction monitoring for analyte quantification. Stable isotopically labeled compounds were used as internal standards. The sample pretreatment consisted of protein precipitation with acetonitrile using a small plasma volume of 50 µL. The validation procedures were based on the guidelines on bioanalytical methods issued by the US Food and Drug Administration and were modified to fit the requirements of the clinical TDM environment. RESULTS: The method was validated over a linear range of 5.00-100 ng/mL for dasatinib, sunitinib, and N-desethyl-sunitinib; 50.0-1000 ng/mL for gefitinib and lapatinib; 125-2500 ng/mL for erlotinib, imatinib, and nilotinib; and 500-10,000 ng/mL for pazopanib, sorafenib, and vemurafenib. The results of the validation study demonstrated good intra-assay and interassay accuracy (bias <6.0%) and precision (12.2%) for all analytes. CONCLUSIONS: This newly validated method met the criteria for TDM and has successfully been applied to routine TDM service for tyrosine kinase inhibitors.
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Antineoplásicos/sangue , Plasma/química , Inibidores de Proteínas Quinases/sangue , Cromatografia Líquida/métodos , Cromatografia de Fase Reversa/métodos , Monitoramento de Medicamentos/métodos , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
PURPOSE: The number of patients with bariatric surgery who receive oral anticancer drugs is rising. Bariatric surgery may affect the absorption of oral anticancer drugs. Strikingly, no specific drug dosing recommendations are available. We aim to provide practical recommendations on the application of oral anticancer drugs in patients who underwent bariatric surgery. METHODS: Patients with any kind of bariatric surgery were extracted retrospectively in a comprehensive cancer center. In addition, a flowchart was proposed to assess the risk of inadequate exposure to oral anticancer drugs in patients who underwent bariatric surgery. Subsequently, the flowchart was evaluated retrospectively using routine Therapeutic drug monitoring (TDM) samples. RESULTS: In our analysis, 571 cancer patients (0.4% of 140.000 treated or referred patients) had previous bariatric surgery. Of these patients, 78 unique patients received 152 oral anticancer drugs equaling an overall number of 30 unique drugs. The 30 different prescribed oral anticancer drugs were categorized as low risk (13%), medium risk (67%), and high risk (20%) of underdosing. TDM plasma samples of 25 patients (82 samples) were available, of which 21 samples post-bariatric surgery (25%) were below the target value. CONCLUSIONS: The proposed flowchart can support optimizing the treatment with orally administered anticancer drugs in patients who underwent bariatric surgery. We recommend performing TDM in drugs that belong to BCS classes II, III, or IV. If more risk factors are present in BCS classes II or IV, a priori switches to other drugs may be advised. In specific cases, higher dosages can be provided from the start (e.g., tamoxifen).
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Antineoplásicos , Cirurgia Bariátrica , Monitoramento de Medicamentos , Humanos , Estudos Retrospectivos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Feminino , Pessoa de Meia-Idade , Masculino , Administração Oral , Monitoramento de Medicamentos/métodos , Adulto , Neoplasias/cirurgia , Neoplasias/tratamento farmacológico , IdosoRESUMO
INTRODUCTION: Naked DNA vaccination could be a powerful and safe strategy to mount antigen-specific cellular immunity. We designed a phase I clinical trial to investigate the toxicity of naked DNA vaccines encoding CD8+ T-cell epitope from tumor-associated antigen MART-1 in patients with advanced melanoma. METHODS: This dose escalating phase Ia clinical trial investigates the toxicity and immunological response upon naked DNA vaccines encoding a CD8+ T-cell epitope from the tumor-associated antigen MART-1, genetically linked to the gene encoding domain 1 of subunit-tetanus toxin fragment C in patients with advanced melanoma (inoperable stage IIIC-IV, AJCC 7th edition). The vaccine was administrated via intradermal application using a permanent make-up or tattoo device. Safety was monitored according to CTCAE v.3.0 and skin biopsies and blood samples were obtained for immunologic monitoring. RESULTS: Nine pretreated, HLA-A*0201-positive patients with advanced melanoma expressing MART-1 and MHC class I, with a good performance status, and adequate organ function, were included. With a median follow-up of 5.9 months, DNA vaccination was safe, without treatment-related deaths. Common treatment-emergent adverse events of any grade were dermatologic reactions at the vaccination site (100%) and pain (56%). One patient experienced grade 4 toxicity, most likely related to tumor progression. One patient (11%) achieved stable disease, lasting 353 days. Immune analysis showed no increase in vaccine-induced T cell response in peripheral blood of 5 patients, but did show a MART-1 specific CD8+ T cell response at the tattoo administration site. The maximum dose administered was 2 mg due to lack of clinical activity. CONCLUSION: We showed that the developed DNA vaccine, applied using a novel intradermal application strategy, can be administered safely. Further research with improved vaccine formats is required to show possible clinical benefit of DNA vaccination.
Assuntos
Vacinas Anticâncer , Melanoma , Estadiamento de Neoplasias , Tatuagem , Vacinas de DNA , Humanos , Melanoma/imunologia , Melanoma/terapia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Pessoa de Meia-Idade , Feminino , Masculino , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Injeções Intradérmicas , Idoso , Adulto , Neoplasias Cutâneas/imunologia , Antígeno MART-1/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinação/métodos , Resultado do Tratamento , Antígeno HLA-A2/imunologia , Epitopos de Linfócito T/imunologiaRESUMO
INTRODUCTION: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis. METHODS: A Markov decision model was constructed to estimate expected costs (expressed in 2021) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed. RESULTS: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were 347,168 for TIL-NKI/CCIT (including 67,547 for production costs) compared with 433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were 337,309 and 436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most. CONCLUSION: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Ipilimumab/uso terapêutico , Análise Custo-Benefício , Linfócitos do Interstício Tumoral/patologia , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
PURPOSE: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS AND METHODS: Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies. RESULTS: Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at the time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients. CONCLUSIONS: Intermittent treatment with vorinostat in patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores de Histona Desacetilases , Melanoma , Mutação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Vorinostat , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Melanoma/mortalidade , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vorinostat/administração & dosagem , Vorinostat/farmacologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudo de Prova de Conceito , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Idoso de 80 Anos ou maisRESUMO
OBJECTIVES: The closure integrity and process validation of closed system transfer devices (CSTDs) should be confirmed before implementation in clinical settings. We aimed to investigate the closure integrity and validate the aseptic procedure of two types of CSTDs by using a combination of the dye ingress test and a media fill test. METHODS: The dye ingress test with methylene blue was used for both CSTDs with 10 samples of drug vials of three brands. A media fill test was performed with both CSTDs (300 samples per CSTD, 150 carried out in a safety cabinet and 150 under non-classified environmental conditions). RESULTS: In all samples of both CSTDs, methylene blue was absent after visual inspection and spectrophotometric analysis. The nutrient media of one sample with CSTD A and none of the CSTD B samples were contaminated when reconstituted in a GMP grade A environment. Under non-classified environmental conditions, one sample of CSTD A and two samples of CSTD B were contaminated. CONCLUSIONS: Both CSTDs connected to the drug vials met the terms of closure integrity by using the dye ingress test. The aseptic procedure of CSTD B was validated with the media fill test when reconstituted in a GMP grade A environment, but failed for CSTD A. Both CSTDs failed the media fill test when reconstituted under non-classified environmental conditions.