An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela™)

Introduction: A study was undertaken to determine the acute effects of a beverage made with Avela™ (R)-1,3-butanediol, on blood beta-hydroxybutyrate (BHB) levels (using the Keto-Mojo monitor), gastrointestinal (GI) tolerability (using the modified visual analogue scale GI Symptoms Tool), and sleepiness (using the Stanford Sleepiness Scale).Methods: Following a 12-h overnight fast, 26 healthy adults consumed one beverage containing 11.5 g of (R)-1,3-butanediol at each of 0, 30, and 60 min, culminating in a total intake of 34.5 g of (R)-1,3-butanediol. Blood BHB levels, GI tolerability, and sleepiness were assessed at baseline (0 min), and at 30, 60, 90, 120, 180, 240, and 300 min. At 240 min, a protein bar was consumed.Results: The mean (±SD) BHB fasting baseline level, maximal concentration, time at maximal concentration, and incremental area under the curve over 300 min were 0.23 ± 0.21 mmol/L, 2.10 ± 0.97 mmol/L, 133.85 ± 57.07 min, and 376.73 ± 156.76 mmol/L*min, respectively. BHB levels at each time point were significantly increased relative to baseline. In females, BHB Tmax was significantly greater (p = 0.046), and BHB iAUC0–300 min nearly significantly greater (p = 0.06) than in males.Discussion: The beverage formulated with Avela™ had no impact on sleepiness and was generally well-tolerated, with no or mild GI symptoms reported in most participants. Mild headaches were reported as an adverse event by five participants and judged possibly related to the study product in two of the participants

Exoskeletal predator defenses of juvenile California spiny lobsters (Panulirus interruptus) are affected by fluctuating ocean acidification-like conditions

Spiny lobsters rely on multiple biomineralized exoskeletal predator defenses that may be sensitive to ocean acidification (OA). Compromised mechanical integrity of these defensive structures may tilt predator-prey outcomes, leading to increased mortality in the lobsters’ environment. Here, we tested the effects of OA-like conditions on the mechanical integrity of selected exoskeletal defenses of juvenile California spiny lobster, Panulirus interruptus. Young spiny lobsters reside in kelp forests with dynamic carbonate chemistry due to local metabolism and photosynthesis as well as seasonal upwelling, yielding daily and seasonal fluctuations in pH. Lobsters were exposed to a series of stable and diurnally fluctuating reduced pH conditions for three months (ambient pH/stable, 7.97; reduced pH/stable 7.67; reduced pH with low fluctuations, 7.67 ± 0.05; reduced pH with high fluctuations, 7.67 ± 0.10), after which we examined the intermolt composition (Ca and Mg content), ultrastructure (cuticle and layer thickness), and mechanical properties (hardness and stiffness) of selected exoskeletal predator defenses. Cuticle ultrastructure was consistently robust to pH conditions, while mineralization and mechanical properties were variable. Notably, the carapace was less mineralized under both reduced pH treatments with fluctuations, but with no effect on material properties, and the rostral horn had lower hardness in reduced/high fluctuating conditions without a corresponding difference in mineralization. Antennal flexural stiffness was lower in reduced, stable pH conditions compared to the reduced pH treatment with high fluctuations and not correlated with changes in cuticle structure or mineralization. These results demonstrate a complex relationship between mineralization and mechanical properties of the exoskeleton under changing ocean chemistry, and that fluctuating reduced pH conditions can induce responses not observed under the stable reduced pH conditions often used in OA research. Furthermore, this study shows that some juvenile California spiny lobster exoskeletal defenses are responsive to changes in ocean carbonate chemistry, even during the intermolt period, in ways that can potentially increase susceptibility to predation among this critical life stage

Algorithm development for Prognostics and Health Management (PHM).

This report summarizes the results of a three-year LDRD project on prognostics and health management. System failure over some future time interval (an alternative definition is the capability to predict the remaining useful life of a system). Prognostics are integrated with health monitoring (through inspections, sensors, etc.) to provide an overall PHM capability that optimizes maintenance actions and results in higher availability at a lower cost. Our goal in this research was to develop PHM tools that could be applied to a wide variety of equipment (repairable, non-repairable, manufacturing, weapons, battlefield equipment, etc.) and require minimal customization to move from one system to the next. Thus, our approach was to develop a toolkit of reusable software objects/components and architecture for their use. We have developed two software tools: an Evidence Engine and a Consequence Engine. The Evidence Engine integrates information from a variety of sources in order to take into account all the evidence that impacts a prognosis for system health. The Evidence Engine has the capability for feature extraction, trend detection, information fusion through Bayesian Belief Networks (BBN), and estimation of remaining useful life. The Consequence Engine involves algorithms to analyze the consequences of various maintenance actions. The Consequence Engine takes as input a maintenance and use schedule, spares information, and time-to-failure data on components, then generates maintenance and failure events, and evaluates performance measures such as equipment availability, mission capable rate, time to failure, and cost. This report summarizes the capabilities we have developed, describes the approach and architecture of the two engines, and provides examples of their use. 'Prognostics' refers to the capability to predict the probability o

Open-label, randomized, multi-center study comparing the sequence of high dose Aldesleukin (Proleukin® (HD IL-2) and Ipilimumab Yervoy® ) in patients with metastatic melanoma (proclivity 02)

Purpose: To investigate whether the sequence of HD IL-2 and a checkpoint inhibitor, Ipilimumab, will have additive or synergistic efficacy or toxicity when used in rapid sequence. Schema: Adult patients with Stage IV or unresectable Stage III metastatic melanoma who are eligible to receive HD IL-2, treatment naïve or have received prior adjuvant therapy are randomized to a sequential administration of 4 doses of Ipilimumab or 4 cycles of HD IL-2 dosed according to their package inserts. Fifty of the patients will start with one drug and 50 the other. The second drug will begin as soon as practically possible, without waiting for relapse. Entry criteria have recently been amended to include prior treatment with anti-PD-1 or anti-PDL-1. Twelve US sites are currently enrolling patients. An independent Data and Safety Monitoring Committee oversees the study. The primary endpoint is the proportional one year survival in the ITT population and a protocol defined population of patients who have received at least half of the planned doses of both study drugs. Clinical response and progression free survival will also be assessed. The primary endpoint is the proportional one year survival in the ITT population and a protocol defined population of patients who have received at least half of the planned doses of both study drugs. Clinical response and progression free survival will also be assessed. Current status: Twelve US sites are currently enrolling patients. To date 16 patients have been enrolled, 9 on the Ipilimumab first and 7 on the HD IL-2 first arms. No synergistic toxicity has been observed, but one death occurred in the HD IL-2 arm and one colectomy on the Ipilimumab arm, both prior to administration of the other drug

A Phase I Study of Visilizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Severe Steroid-Refractory Ulcerative Colitis

BACKGROUND & AIMS: To evaluate the safety and biological activity of visilizumab (a humanized anti-CD3 monoclonal antibody) and to determine a maximum tolerated dose in patients with severe ulcerative colitis that had not responded to 5 days of treatment with intravenous corticosteroids. METHODS: In this open-label phase 1 study, 32 subjects received visilizumab at a dose of 10 or 15 microg/kg, administered intravenously on 2 consecutive days. Clinical response was defined as a Modified Truelove and Witts Severity Index <10 with a minimum decrease of 3 points; remission was <4 points. Endoscopic remission was a Mayo endoscopic subscore of 0 or 1. RESULTS: Eight patients received 15 microg/kg visilizumab. Because of dose-limiting toxicities (T-cell recovery >30 days in 2 of 8 patients), the dose was reduced to 10 microg/kg in 24 patients. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission. Forty-five percent of patients did not require salvage therapies or colectomy during the first year postdose. Mild to moderate symptoms of cytokine release occurred in 100% and 83% of patients in the 15- and 10-microg/kg dose groups, respectively. All patients exhibited a rapid decrease in circulating CD4(+) T-cell counts, which returned to baseline values by day 30 in 26 of 30 evaluable patients (86%). There were no serious infections. CONCLUSIONS: Visilizumab had an acceptable safety profile at the 10-microg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid-refractory ulcerative colitis

SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial

Background Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer, Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. Methods The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1–5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. Discussion SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC

A multi-center study of high dose Aldesleukin (Proleukin® (HD IL-2) + Vemurafenib Zelboraf® ) therapy in patients with BRAFV600 mutation positive metastatic melanoma (proclivity 01)

Purpose: To investigate whether the Vemurafenib-induced increased tumor antigen expression, T lymphocyte infiltration and tumor debulking improve the complete response rate induced by HD IL-2 in metastatic melanoma and if there is synergistic toxicity using the drugs in close approximation. Schema: Adult patients with measurable metastatic or unresectable Stage III melanoma with no prior therapy and a BRAFV600 mutation who are candidates for HD IL-2 are eligible for entry into the first cohort of 135 patients (figure 1). Six weeks of Vemurafenib therapy per package insert precedes up to 2 courses of HD IL-2. Vemurafenib is administered during the outpatient intervals between cycles of HD IL-2 and following completion. A second cohort of up to 50 similar patients already responding or stable with < 18 weeks of Vemurafenib therapy will also be accrued. The study was amended to permit prior anti-PD-1 therapy. The primary endpoint is Complete Response (CR) and near CR at 6 months of therapy. Current status: Sixteen sites have enrolled patients. 41 patients have been enrolled to date, 27 in Cohort 1 and 14 in cohort 2. The Data Safety and Monitoring Board performed an initial safety analysis after the initial 8 patients which demonstrated no unexpected safety signal. An analysis of the effect of the combination on Progression Free Survival in both cohorts will be performed after the first 20% of patients in Cohort 1 have received at least one course of HD IL-2. The results of this analysis should be available at the time of the SITC meeting. Figure 1 Treatment of metastatic melanoma with HD IL-2 immunotherapy and targeted agent vemurafenib Treatment of metastatic melanoma with HD IL-2 immunotherapy and targeted agent vemurafenib

A step towards personalizing next line therapy for resected pancreatic and related cancer patients: A single institution\u27s experience

Background: There is a lack of precision medicine in pancreatic ductal adenocarcinoma (PDA) and related cancers, and outcomes for patients with this diagnosis remain poor despite decades of research investigating this disease. Therefore, it is necessary to explore novel therapeutic options for these patients who may benefit from personalized therapies. Objective: Molecular profiling of hepatopancreaticobiliary malignancies at our institution, including but not limited to PDA, was initiated to assess the feasibility of incorporating molecular profiling results into patient oncological therapy planning. Methods: All eligible patients from Thomas Jefferson University (TJU) with hepatopancreaticobiliary tumors including PDA, who agreed to molecular testing profiling, were prospectively enrolled in a registry study from December 2014 to September 2017 and their tumor samples were tested to identify molecular markers that can be used to guide therapy options in the future. Next generation sequencing (NGS) and protein expression in tumor samples were tested at CLIA-certified laboratories. Prospective clinicopathologic data were extracted from medical records and compiled in a de-identified fashion. Results: Seventy eight (78) patients were enrolled in the study, which included 65/78 patients with PDA (local and metastatic) and out of that subset, 52/65 patients had surgically resected PDA. Therapy recommendations were generated based on molecular and clinicopathologic data for all enrolled patients. NGS uncovered actionable alterations in 25/52 surgically resected PDAs (48%) which could be used to guide therapy options in the future. High expression of three proteins, TS (p = 0.005), ERCC1 (p = 0.001), and PD-1 (p = 0.04), was associated with reduced recurrence-free survival (RFS), while TP53 mutations were correlated with longer RFS (p = 0.01). Conclusions: The goal of this study was to implement a stepwise strategy to identify and profile resected PDAs at our institution. Consistent with previous studies, approximately half of patients with resected PDA harbor actionable mutations with possible targeted therapeutic implications. Ongoing studies will determine the clinical value of identifying these mutations in patients with resected PDA

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)