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Pharmacokinetic parameters of guadecitabine and decitabine after guadecitabine injection

LINE1 changes in tumor CpG 1-3 on cycle 1 day 8 from baseline. LINE1 changes in tumor DNA in individual patient biopsy samples.

LINE1 changes in circulating DNA CpG 1-3 as compared to baseline.

Purpose:Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan.Patients and Methods:In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL −1: guadecitabine 30 mg/m2; DL −1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m2 with GFS].Results:Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and −1G), biliary drain infection (DL −1), colonic obstruction (DL −1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment.Conclusions:We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.

The 20 short tandem repeat (STR) markers of the combined DNA index system (CODIS) are the basis of the vast majority of forensic genetics in the United States. One argument for permissive rules about the collection of CODIS genotypes is that the CODIS markers are thought to contain information relevant to identification only (such as a human fingerprint would), with little information about ancestry or traits. However, in the past 20 years, a quickly growing field has identified hundreds of thousands of genotype-trait associations. Here we conduct a survey of the landscape of such associations surrounding the CODIS loci as compared with non-CODIS STRs. We find that the regions around the CODIS markers are enriched for both known pathogenic variants (>90th percentile) and for SNPs identified as trait-associated in genome-wide association studies (GWAS) (≥95th percentile in 10kb and 100kb flanking regions), compared with other random sets of autosomal tetranucleotide-repeat STRs. Although it is not obvious how much phenotypic information CODIS would need to convey to strain the “DNA fingerprint” analogy, the CODIS markers, considered as a set, are in regions unusually dense with variants with known phenotypic associations.

Background Vascular patients with tissue loss requiring minor amputations could be an early sign of a terminal event. The long-term outcomes and timing of revascularisation for these patients are not well-studied. The aim of this study was to determine the clinical outcomes following minor amputations. Primary outcomes were functional status, limb loss, and mortality. Secondary outcomes compared immediate and delayed revascularisation. Methods A retrospective analysis of 200 vascular patients who required minor amputations at Austin Hospital, Melbourne was performed over 5 years. Demographics, details of revascularisation, functional status, and clinical outcomes such as recurrent tissue loss, limb loss and death were recorded. Results Of the entire cohort requiring minor amputations, 118 (59%) patients underwent revascularisation. 111 (94%) revascularisation procedures were performed within 90 days of minor amputation. Over all 5-year limb preservation was 89.9%. Patients who required revascularisation were not statistically significantly more at risk for limb loss at 5 years [13.6% vs. 6.6%; P=0.08]. Limb salvage at 1 year was not different between groups revascularized before and after amputation [89.5% vs. 90.9%; P=0.70]. Over all 5-year mortality rate was 50%. In the diabetic subset, those who had revascularisation after minor amputation had a greater 5-year mortality [67.9% vs. 50%; P=0.03]. A scoring system based on risk factors was developed but was not reliable based on the study data. Conclusions The data from this study suggest that patients with diabetes who undergo revascularisation after minor amputation have worse outcomes than those revascularised prior to minor amputation. A predictive model applied at presentation could help detect high-risk patients but requires further work.

Threshold regression models are useful for identifying subgroups with heterogeneous parameters. The conventional threshold regression models split the sample based on a single and observed threshold variable, which enforces the threshold point to be equal for all subgroups of the population. In this paper, we consider a more flexible single-index threshold model in the quantile regression setup, in which the sample is split based on a linear combination of predictors. We propose a new estimator by smoothing the indicator function in thresholding, which enables Gaussian approximation for statistical inference and allows characterizing the limiting distribution when the quantile process is interested. We further construct a mixed-bootstrap inference method with faster computation and a procedure for testing the constancy of the threshold parameters across quantiles. Finally, we demonstrate the value of the proposed methods via simulation studies, as well as through the application to an executive compensation data.

Background: SHP2 is an oncogenic tyrosine phosphatase that transduces receptor tyrosine kinase signaling to the RAS/MAPK pathway via its phosphatase-mediated regulation of guanine nucleotide exchange factors. ERAS-601 is a potent, selective, and orally bioavailable allosteric inhibitor of SHP2. In combination with cetuximab, an antibody that targets epidermal growth factor receptor (EGFR), ERAS-601 has demonstrated robust nonclinical activity in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) and RAS/RAF wild-type colorectal cancer (CRC) tumors. Method: FLAGSHP-1 is the first-in-human trial of ERAS-601 administered as monotherapy and in combination with other cancer therapies in patients with advanced or metastatic solid tumors. The primary objectives are to characterize the safety profile, determine the maximum tolerated dose (MTD)/recommended dose (RD), and characterize the pharmacokinetics (PK) profile of ERAS-601 as a monotherapy and in combination with other cancer therapies. Secondary objectives include tolerability and antitumor activity in solid tumors. Presented here are results from the combination dose escalation cohorts in which patients received ERAS-601 twice a day for three weeks followed by a one-week break (BID 3/1) in combination with cetuximab (500mg/m2) administered every 2 weeks (Q2W) on a 28-day cycle. Results: As of October 31, 2022, a total of 15 patients with previously treated advanced or metastatic solid tumors received ERAS-601 BID 3/1 at the following dose levels: 20 mg BID 3/1 (n=4), 40 mg BID 3/1 (n=8), or 60 mg BID 3/1 (n=3) in combination with cetuximab. Combination therapy MTD was determined​ to be 40 mg BID 3/1. ERAS-601 Treatment Related Adverse Events (TRAEs) at or below the MTD were all Grade 1 and 2. TRAEs occurring in ≥20% of patients included diarrhea (27%), AST increase (27%), ALT increase (20%), dermatitis acneiform (20%). Grade ≥3 TRAEs included Grade 4 hypokalaemia, Grade 3 diarrhea, platelet count decreased anemia (each 7%); high grade TRAEs were only observed at 60 mg BID 3/1 (above the MTD). Dose limiting toxicities (DLTs) were only observed at the 60mg BID 3/1 dose levels and included Grade 3 platelet count decreased (n=1) and Grade 4 hypokalemia (n=1). Pharmacokinetics of ERAS-601 and cetuximab in combination were generally comparable to historical monotherapy PK values, suggesting lack of drug-drug interaction. The evaluation of clinical activity is still ongoing. Conclusions: ERAS-601 in combination with cetuximab in patients with previously treated advanced or metastatic solid tumors shows promising preliminary safety and tolerability with reversible and manageable TRAEs. Further evaluation in relevant tumor types are ongoing. Citation Format: Meredith McKean, Ezra Rosen, Minal Barve, Tarek Meniawy, Judy Wang, David S. Hong, Jennifer Yang, Zhengrong Li, Roxana Picard, Les Brail, Daniela Vecchio, Thomas John, Ezra Cohen, Gregory Obara, Aparna Parikh. Preliminary dose escalation results of ERAS-601 in combination with cetuximab in FLAGSHP-1: a phase I study of ERAS-601, a potent and selective SHP2 inhibitor, in patients with previously treated advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT184.

Extreme value theory provides essential mathematical foundations for modelling tail risks and has wide applications. The emerging of big and heterogeneous data calls for the development of new extr...

Frailty predicts adverse perioperative outcomes and increased mortality in patients having vascular surgery. Frailty assessment is a potential tool to inform resource allocation, and shared decision-making about vascular surgery in the resource constrained COVID-19 pandemic environment. This cohort study describes the prevalence of frailty in patients having vascular surgery and the association between frailty, mortality and perioperative outcomes.The COVID-19 Vascular Service in Australia (COVER-AU) prospective cohort study evaluates 30-day and six-month outcomes for consecutive patients having vascular surgery in 11 Australian vascular units, March-July 2020. The primary outcome was mortality, with secondary outcomes procedure-related outcomes and hospital utilization. Frailty was assessed using the nine-point visual Clinical Frailty Score, scores of 5 or more considered frail.Of the 917 patients enrolled, 203 were frail (22.1%). The 30 day and 6 month mortality was 2.0% (n = 20) and 5.9% (n = 35) respectively with no significant difference between frail and non-frail patients (OR 1.68, 95%CI 0.79-3.54). However, frail patients stayed longer in hospital, had more perioperative complications, and were more likely to be readmitted or have a reoperation when compared to non-frail patients. At 6 months, frail patients had twice the odds of major amputation compared to non-frail patients, after adjustment (OR 2.01; 95% CI 1.17-3.78), driven by a high rate of amputation during the period of reduced surgical activity.Our findings highlight that older, frail patients, experience potentially preventable adverse outcomes and there is a need for targeted interventions to optimize care, especially in times of healthcare stress.

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10–200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1–51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

This article considers high-dimensional image-on-scalar regression, where the spatial heterogeneity of covariate effects on imaging responses is investigated via a flexible partially linear spatial...

PAC1 receptor blockade using a monoclonal antibody inhibits nociceptive neuronal activity in the trigeminocervical complex., Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed, and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near-maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the central nervous system suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.

Median arcuate ligament syndrome is a rare and poorly understood condition that can have a significant impact on the quality of life of patients. Diagnosis is often difficult and delayed because of the need to exclude other pathologic processes. Treatment strategies traditionally involve open or laparoscopic division of the median arcuate ligament, with or without vascular reconstruction. This report portrays a case of median arcuate ligament syndrome with compression of two visceral arteries and distal embolic complications. A novel hybrid technique is described using intravascular ultrasound technology to aid in laparoscopic median arcuate ligament division. This allowed real-time intravascular visualization of the compressive segment, guided release of the ligament fibers, and demonstrated confirmation of decompression. Keywords: Vascular surgery, Intravascular ultrasound, Median arcuate ligament syndrome

In panel data analysis, it is important to identify subgroups of units with heterogeneous parameters. This can not only increase the model flexibility but also produce more efficient estimation by pooling information across units within the same group. In this paper, we propose a new quantile-regression-based clustering method for panel data. We develop an iterative algorithm using a similar idea of k-means clustering to identify subgroups with heterogeneous slopes at a single quantile level or across multiple quantiles. The asymptotic properties of the group membership estimator and corresponding group-specific slope estimator are established. The finite sample performance of the proposed method is assessed through simulation and the analysis of an economic growth data.

Background Patients with KRAS-mutant cancers have limited treatment options. Here we present a phase I study of JNJ-74699157, an oral, selective, covalent inhibitor of the KRAS G12C isoform, in patients with advanced cancer harboring the KRAS G12C mutation. Methods Eligible patients (aged ≥18 years) who had previously received or were ineligible for standard treatment received JNJ-74699157 once daily on a 21-day cycle. Dose escalation was guided by a modified continual reassessment method. Results Ten patients (100 mg: 9 and 200 mg: 1) were enrolled. Tumor types included non–small cell lung cancer (n = 5), colorectal cancer (n = 4), and carcinoma of unknown primary site (n = 1). The median age was 65 (range: 36-74) years and median treatment duration was 2.91 (range: 0.5-7.5) months. Dose-limiting toxicities of grades 3–4 increased blood creatinine phosphokinase (CPK) were observed in 100 mg and 200 mg dose levels. The most common adverse event was increased blood CPK (6 patients). No significant clinical benefit was observed; the best response was stable disease in 4 patients (40%). Conclusion Based on dose-limiting skeletal muscle toxicities and the lack of efficacy at the 100 mg dose, further enrollment was stopped. The safety profile of JNJ-74699157 was not considered favorable for further clinical development. ClinicalTrials.gov Identifier NCT04006301

BackgroundInnate immune activation is a desirable goal in anticancer therapy. Stimulator of Interferon Genes (STING) agonists represent one approach to this goal; to date most studies have utilized intra-tumoral administration. SNX281 is a novel small molecule agonist of human and mammalian STING with favorable pharmacokinetic properties thatto enable systemic intravenous administration. The molecule dimerizes in the binding site of STING to induce activation. In preclinical studies using THP-1 cells or human PBMCs, SNX281 caused both pathway activation and the induction of signature cytokines, IFN-b, TNF-a and IL-6 in a STING dependent manner. Intravenously delivered SNX281 caused complete and durable tumor regression in mice bearing CT26 colon carcinomas with induction of immune memory. Mice that were cured of their primary CT26 tumors were completely resistant to re-challenge. Increased T cell responses were observed against the endogenous CT26 rejection antigen AH1. Maximal tumor control depended on CD8+ T cells, confirming the involvement of an adaptive immune component in SNX281 mediated anti-tumor activity, although some tumor control was observed even in the absence of T cells. In addition, combining STING-dependent T cell priming induced by SNX281 with anti-PD-1 resulted in robust antitumor activity and significant survival benefit in multiple tumor models (CT26, MC38 and B16- F10) that are resistant to checkpoint therapy alone.MethodsThis is a multicenter, open-label, phase I dose-escalation followed by dose expansion study of SNX281 as monotherapy and in combination with pembrolizumab. SNX281 is administered as a 30-minute intravenous infusion QW for 3 weeks followed by Q3W for six cycles. Eligible patients for the dose escalation phase will have, among other criteria, histologically confirmed advanced solid tumors or lymphomas which have failed prior therapy and/or are not eligible for therapies, as well as adequate organ function, life expectancy of at least 12 weeks, and measurable disease. Monotherapy dose escalation accrued initially with single patient cohorts advancing to a 3+3 design. The dose expansion phases of each treatment arm will begin following the determination of an MTD or alternative dose of SNX281 in each respective treatment arm. The single-agent treatment arm of SNX281 is planned to evaluate at least 2 expansion cohorts in ovarian cancer and colorectal carcinoma while the combination treatment arm of SNX281 and pembrolizumab is planned to enroll subjects with advanced cancer who have relapsed on or have become refractory to prior immune checkpoint therapy given in an indicated setting. Clinical Trial Information: NCT04609579Trial RegistrationNCT04609579Ethics ApprovalIRB approval from IntegReview IORG0000689.

In this paper, we propose a functional partially linear regression model with latent group structures to accommodate the heterogeneous relationship between a scalar response and functional covariates. The proposed model is motivated by a salinity tolerance study of barley families, whose main objective is to detect salinity tolerant barley plants. Our model is flexible, allowing for heterogeneous functional coefficients while being efficient by pooling information within a group for estimation. We develop an algorithm in the spirit of the K-means clustering to identify latent groups of the subjects under study. We establish the consistency of the proposed estimator, derive the convergence rate and the asymptotic distribution, and develop inference procedures. We show by simulation studies that the proposed method has higher accuracy for recovering latent groups and for estimating the functional coefficients than existing methods. The analysis of the barley data shows that the proposed method can help identify groups of barley families with different salinity tolerant abilities.

This publication is based upon work supported by King Abdullah University of Science and Technology (KAUST), Officeof Sponsored Research (OSR) under Award No. OSR-2019-CRG7-3800; by the IR/D program and grant DMS-1712760from the National Science Foundation. Any opinion, findings, and conclusions or recommendations expressed in thismaterial are those of the authors and do not necessarily reflect the views of the National Science Foundation. The authorsthank Dr. Howard H. Chang for providing the satellite data.