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We present a new measurement of the positive muon magnetic anomaly, a_{µ}≡(g_{µ}-2)/2, from the Fermilab Muon g-2 Experiment using data collected in 2019 and 2020. We have analyzed more than 4 times the number of positrons from muon decay than in our previous result from 2018 data. The systematic error is reduced by more than a factor of 2 due to better running conditions, a more stable beam, and improved knowledge of the magnetic field weighted by the muon distribution, ω[over Ë]_{p}^{'}, and of the anomalous precession frequency corrected for beam dynamics effects, ω_{a}. From the ratio ω_{a}/ω[over Ë]_{p}^{'}, together with precisely determined external parameters, we determine a_{µ}=116 592 057(25)×10^{-11} (0.21 ppm). Combining this result with our previous result from the 2018 data, we obtain a_{µ}(FNAL)=116 592 055(24)×10^{-11} (0.20 ppm). The new experimental world average is a_{µ}(exp)=116 592 059(22)×10^{-11} (0.19 ppm), which represents a factor of 2 improvement in precision.
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BACKGROUND: Machine learning is increasingly advocated to develop prediction models for postoperative complications. It is, however, unclear if machine learning is superior to logistic regression when using structured clinical data. Postoperative pancreatic fistula and delayed gastric emptying are the two most common complications with the biggest impact on patient condition and length of hospital stay after pancreatoduodenectomy. This study aimed to compare the performance of machine learning and logistic regression in predicting pancreatic fistula and delayed gastric emptying after pancreatoduodenectomy. METHODS: This retrospective observational study used nationwide data from 16 centers in the Dutch Pancreatic Cancer Audit between January 2014 and January 2021. The area under the curve of a machine learning and logistic regression model for clinically relevant postoperative pancreatic fistula and delayed gastric emptying were compared. RESULTS: Overall, 799 (16.3%) patients developed a postoperative pancreatic fistula, and 943 developed (19.2%) delayed gastric emptying. For postoperative pancreatic fistula, the area under the curve of the machine learning model was 0.74, and the area under the curve of the logistic regression model was 0.73. For delayed gastric emptying, the area under the curve of the machine learning model and logistic regression was 0.59. CONCLUSION: Machine learning did not outperform logistic regression modeling in predicting postoperative complications after pancreatoduodenectomy.
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Gastroparesia , Pancreaticoduodenectomia , Humanos , Pancreaticoduodenectomia/efeitos adversos , Fístula Pancreática/diagnóstico , Fístula Pancreática/epidemiologia , Fístula Pancreática/etiologia , Modelos Logísticos , Gastroparesia/etiologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Aprendizado de MáquinaRESUMO
In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.
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Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Relação Dose-Resposta a Droga , Oncologia , Neoplasias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Terapias em Estudo/métodosRESUMO
INTRODUCTION: Novel therapies such as small protein molecule inhibitors and immunotherapies are tested in early phase trials before moving to later phase trials and ultimately standard practice. A key aim of these clinical trials is to define a toxicity profile, however, the emphasis is often on safety with measurements of organ toxicity. Other subjective side effects can be under-reported because they are not measured formally within the trial protocols. The concern from clinical practice is that cognitive toxicity is poorly studied and may be under-reported in this context. This could lead to toxicity profiles of new treatments not being fully described and patients with unmet need in terms of acknowledgement and support of symptoms. This protocol outlines a framework of an exploratory study with feasibility aspects to investigate the impact and experience of cognitive changes for patients on phase I trials. METHODS AND ANALYSIS: This is a mixed-methods study, combining quantitative and qualitative approaches. The sample is 30 patients with advanced cancer who are participating in phase I trials of novel therapies in the early clinical trials unit of a specialist cancer centre. A test battery of validated cognitive assessments will be taken alongside patient reported outcome measures at three time points from baseline, day eight and day 28 post start of treatment. At day 28, a semi-structured interview will be conducted and the narrative thematically analysed. Results will be integrated to offer a comprehensive description of cognitive function in this patient group. ETHICS AND DISSEMINATION: The study has received full HRA and ethical approval. It is the first study to introduce formal cognitive assessments in a cancer phase I trial context. The study has the potential to highlight previously unreported side effects and more importantly unmet need in terms of care for patients who are participating in the trials.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Humanos , Cognição , Neoplasias/tratamento farmacológico , Imunoterapia , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent. METHODS: RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq). RESULTS: miR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival. INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes. NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy. CONCLUSIONS: A balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.
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MicroRNAs , Neoplasias da Próstata , RNA Longo não Codificante , Ciclo Celular , Dano ao DNA , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.
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Neoplasias de Próstata Resistentes à Castração , Androstenos , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Humanos , Linfócitos , Masculino , Neutrófilos , Nitrilas , Feniltioidantoína , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , TaxoidesRESUMO
We present the first results of the Fermilab National Accelerator Laboratory (FNAL) Muon g-2 Experiment for the positive muon magnetic anomaly a_{µ}≡(g_{µ}-2)/2. The anomaly is determined from the precision measurements of two angular frequencies. Intensity variation of high-energy positrons from muon decays directly encodes the difference frequency ω_{a} between the spin-precession and cyclotron frequencies for polarized muons in a magnetic storage ring. The storage ring magnetic field is measured using nuclear magnetic resonance probes calibrated in terms of the equivalent proton spin precession frequency ω[over Ë]_{p}^{'} in a spherical water sample at 34.7 °C. The ratio ω_{a}/ω[over Ë]_{p}^{'}, together with known fundamental constants, determines a_{µ}(FNAL)=116 592 040(54)×10^{-11} (0.46 ppm). The result is 3.3 standard deviations greater than the standard model prediction and is in excellent agreement with the previous Brookhaven National Laboratory (BNL) E821 measurement. After combination with previous measurements of both µ^{+} and µ^{-}, the new experimental average of a_{µ}(Exp)=116 592 061(41)×10^{-11} (0.35 ppm) increases the tension between experiment and theory to 4.2 standard deviations.
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BACKGROUND: Men with metastatic castration-resistant prostate cancer (mCRPC) are living longer, therefore optimizing health-related quality of life (HRQL), as well as survival outcomes, is important for optimal patient care. The aim of this study was to assess the HRQL in patients with mCRPC receiving docetaxel or cabazitaxel. PATIENTS AND METHODS: PROSELICA (NCT01308580) assessed the non-inferiority of cabazitaxel 20 mg/m2 (C20) versus 25 mg/m2 (C25) in patients with mCRPC after docetaxel. FIRSTANA (NCT01308567) assessed the superiority of C25 or C20 versus docetaxel 75 mg/m2 (D75) in patients with chemotherapy-naive mCRPC. HRQL and pain were analyzed using protocol-defined, prospectively collected, Functional Assessment of Cancer Therapy-Prostate (FACT-P) and McGill-Melzack questionnaires. Analyses included definitive improvements in HRQL, maintained or improved HRQL, and HRQL over time. RESULTS: In total, 2131 patients were evaluable for HRQL across the two studies. In PROSELICA, 38.8% and 40.5% of patients receiving C20 and C25, respectively, had definitive FACT-P total score (TS) improvements. In FIRSTANA, 43.4%, 49.7%, and 44.9% of patients receiving D75, C20, and C25, respectively, had definitive FACT-P TS improvements. In both trials, definitive improvements started after cycle 1 and were maintained for the majority of subsequent treatment cycles. More than two-thirds of patients maintained or improved their FACT-P TS. CONCLUSIONS: In PROSELICA and FIRSTANA, >40% of the 2131 evaluable patients with mCRPC had definitive FACT-P TS improvements; improvements occurred early and were maintained. More than 75% of patients maintained or improved their FACT-P TS.
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Neoplasias de Próstata Resistentes à Castração , Docetaxel/uso terapêutico , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Qualidade de Vida , Taxoides/efeitos adversosRESUMO
BACKGROUND: In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.1245A>C variant and outcomes from metastatic castration-resistant prostate cancer (mCRPC) after first-line treatment with abiraterone (Abi) or enzalutamide (Enza). PATIENTS AND METHODS: Patients with mCRPC (n = 266) were enrolled from two centers at the time of starting first-line Abi/Enza. Outcomes after Abi/Enza included best prostate-specific antigen (PSA) response, treatment duration, and overall survival (OS). Outcomes after first-line ADT were determined retrospectively, and included treatment duration and OS. As was prespecified, we compared patients with the homozygous variant HSD3B1 genotype (CC genotype) versus the combined group with the heterozygous (AC) and homozygous wild-type (AA) genotypes. RESULTS: Among the 266 patients, 22 (8.3%) were homozygous for the HSD3B1 variant (CC). The CC genotype had no association with PSA response rate; the median Abi/Enza treatment duration was 7.1 months for the CC group and 10.3 months for the AA/AC group (log rank P = 0.34). Patients with the CC genotype had significantly worse OS, with median survival at 23.6 months for the CC group and 30.7 months for the AA/AC group (log rank P = 0.02). In multivariable analysis adjusting for age, Gleason score, PSA, prior chemotherapy, and M1 disease, the association between the CC genotype and OS remained significant (hazard ratio 1.78, 95% confidence interval 1.03-3.07, P = 0.04). Poor outcome after first-line ADT in the CC group was also observed when evaluating retrospective ADT duration data for the same combined cohort. CONCLUSIONS: In this large two-center study evaluating the HSD3B1 c.1245 genotype and outcomes after first-line Abi/Enza, homozygous variant (CC) HSD3B1 genotype was associated with worse outcomes. Novel therapeutic strategies are needed to enable treatment selection based on this genetic marker.
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Neoplasias de Próstata Resistentes à Castração , Esteroide Isomerases , Acetato de Abiraterona , Antagonistas de Androgênios , Androstenos , Benzamidas , Genótipo , Células Germinativas , Humanos , Masculino , Complexos Multienzimáticos/genética , Nitrilas , Feniltioidantoína/análogos & derivados , Progesterona Redutase/genética , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Estudos Retrospectivos , Esteroide Isomerases/genética , Resultado do TratamentoRESUMO
AIMS: The objective of the study was to determine levels of Escherichia coli O157:H7 colonization in the gastrointestinal tract (GIT) of naturally shedding cattle shedding the pathogen at low- or super-shedder levels. METHODS AND RESULTS: Over 2 years, feedlot cattle were sampled multiple times for faecal shedding of E. coli O157:H7. Just prior to harvest (1-2 days), animals that were super-shedders (≥104 CFU per gram of faeces) were specifically identified, and based on the longer term screening data, pen cohorts that were low-shedders (years 1 and 2) or chronic-shedders (year 1) were also identified. At harvest, samples were collected from throughout the GIT, including the rectoanal junction (RAJ) for enumeration and enrichment of E. coli O157:H7. The mouth samples exhibited the greatest prevalence for the pathogen, and the abomasum and rumen exhibited the lowest prevalence (P < 0·05). Super-shedders had significantly greater prevalence for all GIT locations except the mouth and abomasum compared to low-shedders, but the super-shedders were the only animals with positive abomasum samples. Samples from the super-shedders were enumerable for most GIT locations, and the rectum and RAJ locations were the only locations that were significantly greater than other locations (P < 0·05). CONCLUSIONS: Across all animals naturally exposed to E. coli O157:H7, the risk of ingestion is high, but rumen and abomasum are potential barriers to passage. In super-shedders, the passage through the GIT was greater, allowing colonization in the rectum and at the RAJ. SIGNIFICANCE AND IMPACT OF THE STUDY: Escherichia coli O157:H7 low-shedding cattle had lower pathogen levels throughout the GIT, indicating intrinsic GIT factors to these cattle may reduce pathogen passage through the GIT, including the abomasum, and minimize risk of RAJ colonization.
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Derrame de Bactérias , Escherichia coli O157/isolamento & purificação , Trato Gastrointestinal/microbiologia , Gado/microbiologia , Animais , Bovinos , Contagem de Colônia Microbiana , Exposição Dietética , Fezes/microbiologia , Trato Gastrointestinal/anatomia & histologiaRESUMO
BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.
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Neoplasias de Próstata Resistentes à Castração , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Docetaxel/uso terapêutico , Etnicidade , Humanos , Masculino , Prednisona/uso terapêutico , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.
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Neoplasias de Próstata Resistentes à Castração , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Humanos , Masculino , Nitrilas , Feniltioidantoína/análogos & derivados , Fosfatidilinositol 3-Quinases , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt , Pirimidinas , Pirróis , Resultado do TratamentoRESUMO
Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.
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Neoplasias da Mama/tratamento farmacológico , Instabilidade Genômica/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Indazóis/uso terapêutico , Indóis/uso terapêutico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/genéticaRESUMO
Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/patologia , Morfolinas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Critérios de Avaliação de Resposta em Tumores Sólidos , Proteínas Quinases S6 Ribossômicas/metabolismoRESUMO
Background: The development of treatment response and surrogate biomarkers for advanced prostate cancer care is an unmet clinical need. Patients with baseline circulating tumour cell (BLCTCs) counts <5/7.5 mL represent a good prognosis subgroup but are non-evaluable for response assessment (decrease in CTCs). The aim of the study is to determine the value of any increase in CTCs (CTC progression) as an indicator of progression in prostate cancer patients with low pre-treatment CTCs (<5). Patients and methods: We carried out a post hoc analysis of patients with BLCTCs < 5 treated in the COU-AA-301 (abiraterone or placebo + prednisone) and IMMC-38 (chemotherapy) trials. The association of CTC progression (increase in CTCs at 4, 8 or 12 weeks) with overall survival (OS) was evaluated in multi-variable Cox regression models. Performance of survival models with and without CTC progression was evaluated by calculating ROC curve area under the curves (AUCs) and weighted c-indices. Results: Overall, 511 patients with CTCs < 5 (421 in COU-AA-301 and 90 in IMMC-38) were selected; 212 (41.7%) had CTC progression at 4, 8 or 12 weeks after treatment initiation. CTC progression was associated with significantly worse OS [27.1 versus 15.1 m; hazard ratio (HR) 3.4 (95% confidence interval [CI] 2.5-4.5; P < 0.001)], independent of baseline CTCs and established clinical variables. Adding CTC progression to the OS model significantly improved ROC AUC (0.77 versus 0.66; P < 0.001). Models including CTC progression had superior ROC AUC (0.77 versus 0.69; P < 0.001) and weighted c-index [0.750 versus 0.705; delta c-index: 0.045 (95% CI 0.019-0.071)] values than those including CTC conversion (increase to CTCs ≥ 5). In COU-AA-301, the impact of CTC progression was independent of treatment arm. Conclusions: Increasing CTCs during the first 12 weeks of treatment are independently associated with worse OS from advanced prostate cancer in patients with baseline CTCs < 5 treated with abiraterone or chemotherapy and improve models with established prognostic variables. These findings must be prospectively validated.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Células Neoplásicas Circulantes/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Androstenos/administração & dosagem , Progressão da Doença , Seguimentos , Humanos , Masculino , Metástase Neoplásica , Prednisona/administração & dosagem , Prognóstico , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxa de SobrevidaRESUMO
Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.
Assuntos
Acetato de Abiraterona/administração & dosagem , Antagonistas de Androgênios/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Acetato de Abiraterona/efeitos adversos , Idoso , Antagonistas de Androgênios/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Intervalo Livre de Doença , Docetaxel/efeitos adversos , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Metanálise em Rede , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Padrão de CuidadoRESUMO
AIMS: Advanced biliary tract carcinomas (ABC) are malignancies with limited effective therapies for advanced disease. There is little published evidence of outcomes of ABC patients participating in phase I clinical trials. MATERIALS AND METHODS: Patient characteristics, treatment details and outcomes of ABC patients treated at a dedicated phase I unit were captured and analysed from case and trial records. RESULTS: In total, 123 ABC patients were included in the study, of which 48 patients participated in 41 different phase I trials; 75 (61%) did not participate due to rapid disease progression or patient choice. Molecular characterisation of tumours using a targeted panel was conducted in 15 (31%), yielding several potentially actionable mutations, including BRCA, PIK3CA, FGFR, AKT and PTEN loss. Of the 39 evaluable patients there was one exceptional responder. Eighteen (46%) other patients achieved stable disease as their best response, with a clinical benefit rate at 4 months of 10%. Treatment was generally well tolerated with grade 3 or 4 adverse events only observed in eight patients (17 %), of which six were drug related and led to trial discontinuation in one (3%), with no toxicity-related deaths. CONCLUSION: Carefully selected ABC patients have been found to tolerate experimental phase I clinical trials without excess toxicity. The aggressive nature of this disease warrants consideration of early referral to a phase I unit. Future work will require comprehensive molecular profiling in an attempt to understand the biology underlying the exceptional responders and to match patients in real-time to targeted therapies.