Model-based meta-analysis of non-small cell lung cancer with standard of care PD-1 inhibitors and chemotherapy for early development decision making.

Single-arm cohorts/trials are often used in early phase oncology programs to support preliminary clinical activity assessments for investigational products, administered alone or in combination with standard of care (SOC) agents. Benchmarking clinical activity of those combinations against other treatments, including SOC, requires indirect comparisons against external trials, which presents challenges including cross-study differences in trial populations/other factors. To facilitate such nonrandomized comparisons, we developed a comprehensive model-based meta-analysis (MBMA) framework to quantitatively adjust for factors related to efficacy in metastatic non-small cell lung cancer (mNSCLC). Data were derived from 15 published studies assessing key programmed cell death protein-1 (PD-1) inhibitors pembrolizumab (n = 8) and nivolumab (n = 7), representing current SOC in mNSCLC. In the first stage, a mixed-effects logistic regression model for overall response rate (ORR) was developed accounting for effects of various population covariates on ORR. The ORR model results indicated an odds ratio (OR) of 1.02 for squamous versus non-squamous histology and OR of 1.20 for PD-ligand 1 tumor proportion score (TPS) per every 10% increase of TPS level. Next, a nonparametric mixed-effects model for overall survival (OS) was developed with ORR/other clinical covariates as input. Subsequently, MBMA simulations of relevant hypothetical scenarios involving single-arm trial design predicted OS hazard ratios as a function of ORR with matched patient characteristics. Findings from this MBMA and derived parameter estimates can be generally applied by the reader as a framework for interpreting efficacy data from early phase trials to support ORR-based go/no-go decisions and futility rules, illustrated through examples in this report.

A method to estimate probability of disease and vaccine efficacy from clinical trial immunogenicity data.

Vaccine efficacy is often assessed by counting disease cases in a clinical trial. A new quantitative framework proposed here ("PoDBAY," Probability of Disease Bayesian Analysis), estimates vaccine efficacy (and confidence interval) using immune response biomarker data collected shortly after vaccination. Given a biomarker associated with protection, PoDBAY describes the relationship between biomarker and probability of disease as a sigmoid probability of disease ("PoD") curve. The PoDBAY framework is illustrated using clinical trial simulations and with data for influenza, zoster, and dengue virus vaccines. The simulations demonstrate that PoDBAY efficacy estimation (which integrates the PoD and biomarker data), can be accurate and more precise than the standard (case-count) estimation, contributing to more sensitive and specific decisions than threshold-based correlate of protection or case-count-based methods. For all three vaccine examples, the PoD fit indicates a substantial association between the biomarkers and protection, and efficacy estimated by PoDBAY from relatively little immunogenicity data is predictive of the standard estimate of efficacy, demonstrating how PoDBAY can provide early assessments of vaccine efficacy. Methods like PoDBAY can help accelerate and economize vaccine development using an immunological predictor of protection. For example, in the current effort against the COVID-19 pandemic it might provide information to help prioritize (rank) candidates both earlier in a trial and earlier in development.

Systematic Literature Review and Meta-Analysis of Response to First-Line Therapies for Advanced/Metastatic Urothelial Cancer Patients Who Are Cisplatin Ineligible.

OBJECTIVE: The purpose of this systematic literature review (SLR) and meta-analysis was to compile the response of historic treatment options in first-line settings for patient populations who are cisplatin ineligible. MATERIALS AND METHODS: SLR was conducted to compile objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of historic therapies for this population based on stringent criteria. Clinical trials published in English from January 1991 to June 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases. RESULTS: Eighteen studies (21 arms; N=810) were identified and used for this meta-analysis. For all treatments included in these studies, the pooled ORR was 0.36 (95% confidence interval [CI], 0.30-0.42). The ORR for the carboplatin+gemcitabine arms (6 arms; N=259), which is the National Comprehensive Cancer Network's recommended first-line treatment (before approval of atezolizumab and pembrolizumab) for this population was 0.36 (95% CI, 0.30-0.42), the median DOR (4 arms) was 7.00 months (95% CI, 4.34-11.29), and the median OS was 8.39 months (95% CI, 7.05-9.98). CONCLUSIONS: The results of this SLR clearly demonstrate the paucity of clinical studies that assess therapeutic intervention in truly cisplatin-ineligible advanced/metastatic urothelial carcinoma subjects and highlight the development of novel therapies that can create real improvement in long-term outcomes. The recent approval of 2 checkpoint inhibitors, atezolizumab and pembrolizumab, were added in the National Comprehensive Cancer Network guidance as recommended first-line treatment for cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma and has provided alternatives for this patient population.

Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose.

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. dose at 48 weeks in a phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inhibitors may increase the plasma levels of q.d. RAL. To assess this potential, the drug interaction of 1200 mg raltegravir using atazanavir, a known UGT1A1 inhibitor, was studied. An open-label, randomized, 2-period, fixed-sequence phase 1 study was performed in adult healthy male and female (non-childbearing potential) subjects ≥ 19 and ≤ 55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2 . Subjects (n = 14) received a single oral dose of 1200 mg raltegravir in period 1. After a washout period of at least 7 days, the subjects received oral doses of 400 mg atazanavir q.d. for 9 consecutive days, with a single oral dose of 1200 mg raltegravir co-administered on day 7 of period 2. Serial blood samples were collected for 72 h following raltegravir dosing and analysed using a validated bioanalytical method to quantify raltegravir plasma concentrations. Co-administration with atazanavir yielded GMRs (90% CIs) for raltegravir AUC0-∞ , Cmax and C24 of 1.67 (1.34, 2.10), 1.16 (1.01, 1.33) and 1.26 (1.08, 1.46), respectively. There was no effect of raltegravir on serum total bilirubin. In contrast, atazanavir increased the mean bilirubin by up to 200%, an effect that was preserved in the atazanavir/raltegravir treatment group. Administration of single q.d. RAL alone and co-administered with multiple oral doses of atazanavir were generally well tolerated in healthy subjects. The results show that atazanavir increased the PK exposure of raltegravir; therefore, co-administration of atazanavir with raltegravir q.d. is not recommended. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir.

OBJECTIVES: Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once-daily regimen (QD) at a dose of 1200 mg is under development. The effect of calcium carbonate and magnesium/aluminium hydroxide antacids on the pharmacokinetics of a 1200 mg dose of raltegravir was assessed in this study. METHODS: An open-label, four-period, four-treatment, fixed-sequence study in 20 HIV-infected patients was performed. Patients needed to be on raltegravir as part of a stable treatment regimen for HIV, and upon entry into the trial received 5 days of 1200 mg raltegravir as pretreatment, before they entered the four-period study: 1200 mg of raltegravir alone (period 1), calcium carbonate antacid as TUMS® Ultra Strength (US) 1000 and 1200 mg raltegravir given concomitantly (Period 2), magnesium/aluminium hydroxide antacid as 20 ml MAALOX® Maximum Strength substitute MS given 12 h after administration of 1200 mg raltegravir (period 3), and calcium carbonate antacid as TUMS® US 1000 given 12 h after administration of 1200 mg raltegravir (period 4). Patients received their dose of 1200 mg QD raltegravir during the intervals between periods to re-establish steady state. AUC0-24 , C24 , Cmax and Tmax were calculated from the individual plasma concentrations of 1200 mg QD raltegravir after administration alone or with a calcium carbonate antacid or with a staggered dose of a calcium carbonate antacid or magnesium/aluminium hydroxide antacid. Adverse events, in addition to laboratory safety tests (haematology, serum chemistry and urinalysis), 12-lead electrocardiograms and vital signs were assessed. KEY FINDINGS: All treatments were well tolerated in the study. Metal-cation antacids variably affected the pharmacokinetics of 1200 mg QD raltegravir. When calcium carbonate antacid was given with 1200 mg raltegravir concomitantly, the geometric mean ratio (GMR) and its associated 90% confidence interval (90% CI) for AUC0-24 , Cmax and C24 h were 0.28 (0.24, 0.32), 0.26 (0.21, 0.32) and 0.52 (0.45, 0.61), respectively. When calcium carbonate antacid and magnesium/aluminium hydroxide were given 12 h after raltegravir 1200 mg QD dosing, the GMR (90% CI) values for AUC0-24 and Cmax were 0.90 (0.80, 1.03), 0.98 (0.81, 1.17), and 0.86 (0.73, 1.03), 0.86 (0.65, 1.15), respectively. However, significant reduction in the trough concentrations of raltegravir was observed: C24 h 0.43 (0.36, 0.51) in the presence of calcium carbonate antacids and 0.42 (0.34, 0.52) in presence of magnesium/aluminium hydroxide, respectively. CONCLUSIONS: Overall, the use of metal-cation antacids with 1200 mg QD raltegravir is not recommended.

Integrative analysis of diffusion-weighted MRI and genomic data to inform treatment of glioblastoma.

Gene expression profiling from glioblastoma (GBM) patients enables characterization of cancer into subtypes that can be predictive of response to therapy. An integrative analysis of imaging and gene expression data can potentially be used to obtain novel biomarkers that are closely associated with the genetic subtype and gene signatures and thus provide a noninvasive approach to stratify GBM patients. In this retrospective study, we analyzed the expression of 12,042 genes for 558 patients from The Cancer Genome Atlas (TCGA). Among these patients, 50 patients had magnetic resonance imaging (MRI) studies including diffusion weighted (DW) MRI in The Cancer Imaging Archive (TCIA). We identified the contrast enhancing region of the tumors using the pre- and post-contrast T1-weighted MRI images and computed the apparent diffusion coefficient (ADC) histograms from the DW-MRI images. Using the gene expression data, we classified patients into four molecular subtypes, determined the number and composition of genes modules using the gap statistic, and computed gene signature scores. We used logistic regression to find significant predictors of GBM subtypes. We compared the predictors for different subtypes using Mann-Whitney U tests. We assessed detection power using area under the receiver operating characteristic (ROC) analysis. We computed Spearman correlations to determine the associations between ADC and each of the gene signatures. We performed gene enrichment analysis using Ingenuity Pathway Analysis (IPA). We adjusted all p values using the Benjamini and Hochberg method. The mean ADC was a significant predictor for the neural subtype. Neural tumors had a significantly lower mean ADC compared to non-neural tumors ([Formula: see text]), with mean ADC of [Formula: see text] and [Formula: see text] for neural and non-neural tumors, respectively. Mean ADC showed an area under the ROC of 0.75 for detecting neural tumors. We found eight gene modules in the GBM cohort. The mean ADC was significantly correlated with the gene signature related with dendritic cell maturation ([Formula: see text], [Formula: see text]). Mean ADC could be used as a biomarker of a gene signature associated with dendritic cell maturation and to assist in identifying patients with neural GBMs, known to be resistant to aggressive standard of care.

A rapid survival assay to measure drug-induced cytotoxicity and cell cycle effects.

We describe a rapid method to accurately measure the cytotoxicity of mammalian cells upon exposure to various drugs. Using this assay, we obtain survival data in a fraction of the time required to perform the traditional clonogenic survival assay, considered the gold standard. The dynamic range of the assay allows sensitivity measurements on a multi-log scale allowing better resolution of comparative sensitivities. Moreover, the results obtained contain additional information on cell cycle effects of the drug treatment. Cell survival is obtained from a quantitative comparison of proliferation between drug-treated and untreated cells. During the assay, cells are treated with a drug and, following a recovery period, allowed to proliferate in the presence of bromodeoxyuridine (BrdU). Cells that synthesize DNA in the presence of BrdU exhibit quenched Hoechst fluorescence, easily detected by flow cytometry; quenching is used to determine relative proliferation in treated vs. untreated cells. Finally, this assay can be used in high-throughput format to simultaneously screen multiple cell lines and drugs for accurate measurements of cell survival and cell cycle effects after drug treatment.

Genomic predictors of interindividual differences in response to DNA damaging agents.

Human lymphoblastoid cells derived from different healthy individuals display considerable variation in their transcription profiles. Here we show that such variation in gene expression underlies interindividual susceptibility to DNA damaging agents. The results demonstrate the massive differences in sensitivity across a diverse cell line panel exposed to an alkylating agent. Computational models identified 48 genes with basal expression that predicts susceptibility with 94% accuracy. Modulating transcript levels for two member genes, MYH and C21ORF56, confirmed that their expression does indeed influence alkylation sensitivity. Many proteins encoded by these genes are interconnected in cellular networks related to human cancer and tumorigenesis.

Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothers.

The long-term health outcome of prenatal exposure to arsenic has been associated with increased mortality in human populations. In this study, the extent to which maternal arsenic exposure impacts gene expression in the newborn was addressed. We monitored gene expression profiles in a population of newborns whose mothers experienced varying levels of arsenic exposure during pregnancy. Through the application of machine learning-based two-class prediction algorithms, we identified expression signatures from babies born to arsenic-unexposed and -exposed mothers that were highly predictive of prenatal arsenic exposure in a subsequent test population. Furthermore, 11 transcripts were identified that captured the maximal predictive capacity to classify prenatal arsenic exposure. Network analysis of the arsenic-modulated transcripts identified the activation of extensive molecular networks that are indicative of stress, inflammation, metal exposure, and apoptosis in the newborn. Exposure to arsenic is an important health hazard both in the United States and around the world, and is associated with increased risk for several types of cancer and other chronic diseases. These studies clearly demonstrate the robust impact of a mother's arsenic consumption on fetal gene expression as evidenced by transcript levels in newborn cord blood.