Optimal Dose Research Articles

Update of phase 1b/2 study of muzastotug (ADG126, an anti-CTLA-4 SAFEbody) in combination with pembrolizumab in advanced/metastatic MSS CRC.

193 Background: ADG126 is an anti-CTLA-4 IgG1 masked antibody with cleavable masking peptides that is preferentially activated in the tumor microenvironment, which in turn binds to a unique epitope to block CTLA-4 function, prime T cells and deplete Tregs. We previously reported that repeated dosing of the IO doublet therapy ADG126 plus pembrolizumab (Pembro) was well-tolerated with promising clinical efficacy in 3L MSS CRC patients (pts) free of liver metastasis (NCT05405595) 1,2 . Here we update clinical safety and efficacy of the study as result of continued dose optimization for the IO doublet therapy. Methods: This is a Phase 1b/2, open-label, multicenter dose escalation (DE) and expansion (EXP) study. Primary endpoints were safety and tolerability. Secondary endpoints were PK, ADA, ORR, DCR, DOR, PFS and OS. Results: A total of 72 pts were dosed with ADG126/Pembro (Table). 27.8% pts had ≥ 3 prior therapies and 6.9% pts had prior IO therapies. There was no Grade 4/5 TRAE, and MTD was not reached. Grade 3 TRAEs were 5.9% (1/17), 16.2% (6/37), 33% (4/12) for 10 mg/kg Q6W, 10 mg/kg Q3W and 20 mg/kg loading dose (LD) & cohorts, respectively. Repeated dosing of ADG126 at 20 mg/kg (Q3W)/Pembro was not well-tolerated. In MSS CRC EXP cohorts, ADG126 of 10 mg/kg Q3W/Pembro treatment resulted in 4 confirmed PRs (n=24 EE), 17% ORR (95% CI: 5-37%), 75% DCR, 4.7-mon mPFS and OS rate of 88% (6 mons) and 75% (9 mons). Subgroup analysis revealed that in pts without liver and peritoneal metastasis (NLPM), ADG126 of 10 mg/kg Q6W/Pembro (10 EE) showed 70% SD and ~ 100% OS (6 and 9 mons); ADG126 of 10 mg/kg Q3W/Pembro (17 EE) showed 24% ORR (4 PR (95% CI: 7-50%)), 88% DCR, 47% CBR, 8.5-mon mPFS and OS rate of 89% (6 mons) and 83% (9 mons). Detailed safety and efficacy results, including those from ADG126 20 mg/kg LD cohort, will be reported. Conclusions: Extensive effort on ADG126 dose optimization, aided by PK-informed dosing strategy, suggested that ADG126 10 mg/kg Q6W and Q3W are appropriate dose/regimen for the IO doublet; this is supported by the well-balanced safety and efficacy (ORR, PFS and OS) profile observed in MSS CRC. ADG126 20 mg/kg Q3W appears to have reached safety ceiling for the IO doublet. The totality of the data further verifies that ADG126 possesses potential best-in-class therapeutic index, and provides basis for continued development of the IO doublet in MSS CRC and for additional exploration of the IO doublet in combination with SOCs/other anti-cancer agents in broader patient populations. Clinical trial information: NCT05405595 . Patient number for safety and efficacy evaluation. Evaluated for ADG126 Dose/Pembro* 10 mg/kg Q6W 10 mg/kg Q3W 20 mg/kg Q3W 20 mg/kg LD & Overall Safety (all pts of DE & EXP) 17 37 6 12 72 Efficacy (MSS CRC NLM, EXP) 10 24 / 5 39 *200mg, Q3W, IV; & 20 mg/kg LD: 20 mg/kg x1 cycle followed by 10 mg/kg Q3W. NLM: liver metastasis-free; DE: Dose Escalation; EXP: Dose Expansion; EE: efficacy evaluable. Data cut date: Aug 30, 2024.

MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D -mutant solid tumors.

TPS845 Background: KRAS G12D mutations occur in ~35%, 13%, and 4% of pancreatic, colorectal, and non-small cell lung cancers, respectively and less commonly in other cancers. Currently, there are no approved therapies for patients with KRAS G12D -mutant solid tumors. LY3962673 is a potent and orally bioavailable inhibitor of GDP-bound KRAS G12D that is highly selective for KRAS G12D against wild-type KRAS and other RAS mutations or amplifications. Preclinically, LY3962673 demonstrated robust anti-tumor activity in vivo as a single-agent and in combination with other agents in multiple KRAS G12D PDX models (Gong X, et al. Poster presented at AACR 2024). Methods: MOONRAY-01 is a global, open-label, multicenter, first-in-human phase 1 study of oral LY3962673 in participants (pts) with KRAS G12D -mutant solid tumors conducted in 2 phases: phase 1a dose escalation (Part A) to evaluate LY3962673 monotherapy and phase 1b dose expansion/randomized dose optimization (Parts B-E) to evaluate LY3962673 monotherapy and in combination with other anticancer therapies (Table). In phase 1a, additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. In phase 1b, each combination cohort will include a safety lead-in of 3-6 pts. Phase 1a/b escalation will utilize the mTPI-2 method. The DLT evaluation period will be 28 days. Eligible pts (≥18 years) must have locally advanced, unresectable, and/or metastatic cancer, measurable disease per RECIST v1.1, evidence of KRAS G12D mutation in tumors or ctDNA, and an ECOG PS of 0-1; asymptomatic CNS disease is allowed. In phase 1a, pts must have received ≥1 prior line of systemic chemotherapy for advanced or metastatic disease. In phase 1b, prior KRAS therapy is not allowed; other eligibility requirements are outlined in the Table. Key exclusion criteria include known active CNS metastases and/or carcinomatous meningitis, or significant cardiovascular disease. Key objectives are to determine the RP2D/optimal dose and assess the safety, tolerability, PK properties, and antitumor activity of LY3962673 per RECIST v1.1. The study is currently enrolling pts. Clinical trial information: NCT06586515 . Phase 1b Parts Key Eligibility Cohorts B: PDAC · B1: ≥1 prior systemic therapy· B2, B3, B4: treatment naïve allowed· B5: treatment naïve only · *B1: LY3962673· B2: LY3962673 + gemcitabine (G) + nab-paclitaxel (P)· *B3: LY3962673 + G + P· B4: LY3962673 + mFOLFIRINOX· *B5: LY3962673 + mFOLFIRINOX C: CRC · C1, C2: ≥1 prior systemic therapy· C3, C4, C5: treatment naïve allowed · C1: LY3962673 + cetuximab (C)· *C2: LY3962673 + C· C3: LY3962673 + C + FOLFOX· C4: LY3962673 + C + FOLFIRI· *C5: LY3962673 + C + FOLFIRI / FOLFOX D: NSCLC · ≥1 prior systemic therapy · *D1: LY3962673 E: Other solid tumors · ≥1 prior systemic therapy · E1: LY3962673 * Cohorts randomized to various LY3962673 doses.

Optimal multi-walled carbon nanotube dosage for improving the mechanical and thermoelectric characteristics of ultra-high-performance fiber-reinforced concrete

Optimal multi-walled carbon nanotube dosage for improving the mechanical and thermoelectric characteristics of ultra-high-performance fiber-reinforced concrete

Remediation of Various Phenanthrene-contaminated Soils using Persulfate-Pseudomonas aeruginosa GZ7: Soil Properties, Radical Formation, and Microbial Community

In this study, the complex interaction of oxidizing conditions, soil composition, microbial activity, and phenanthrene (PHE) degradation was explored in persulfate (PS)-Pseudomonas aeruginosa GZ7 remediation of four PHE-contaminated soils: Paddy soil (PAS), Saline soil (SS), Red soil (RS), and Cinnamon soil (CS). Batch experiments displayed the optimal PS dosage was 0.750% (w/w), except for CS (0.125%), achieving PHE degradation rates of 54.79% ~ 81.92% on the 27-day. The zeta potential of soil clay component after 0.750% PS oxidation was lower than 0.125% and 2.000% PS, resulting in a higher PHE bioavailability and biodegradation. The electron paramagnetic resonance (EPR) spectroscopy analysis showed that the abundance of dominant hydroxyl radicals (·OH) in CS was 3 times higher than in PAS at 0.750% PS and PS to Fe2+ molar ratio of 2:1, indicating that a higher soil organic matter would decrease the content of ·OH thus diminishing PHE removal. Stepwise linear regression and sensitivity analysis indicated that the key influential factors in the PHE degradation rate were the residual PHE content after oxidation (60.12%) and hydrolase nitrogen content (30.97%). High-throughput sequencing results showed the bacterial diversity and richness in four soils decreased after combined remediation compared to pristine soil. Redundancy analyses revealed that the fluorescein diacetate (FDA) hydrolase enzyme was the key factor effect of soil bacterial community development in SS; and electrical conductivity and FDA hydrolase enzyme were the key factors in RS, CS, and PAS. This study may provide technical support for optimizing chemical conditions for PS-microbial remediation.

Effects of tannic acid on growth performance, intestinal health, and tolerance in broiler chickens.

This study investigated the optimal tannic acid dosage and assessed tolerance levels in broiler chickens. In experiment 1, 525 broilers were randomly divided into 5 treatment groups, the control group (CON group) and groups TA1 to TA4, corresponding to treatments of 0.025, 0.05, 0.075, and 0.1 % tannic acid, respectively, to determine the effect of tannic acid on broiler growth performance and gut health. Experiment 2 was performed to evaluate the tolerance of tannic acid; 416 broilers were randomly divided into control (CTR), 0.075 % tannic acid (TA), 0.375 % tannic acid (5TA), and 0.75 % tannic acid (10TA) groups. In the first experiment, compared with that in the CON group, the growth performance and the ileal intestinal villi height to crypt depth ratio showed a quadratic curve increase with tannic acid supplementation (P < 0.05). Adding 0.05 % to 0.075 % tannic acid significantly improved the growth performance, intestinal morphology, and intestinal barrier function (P < 0.05). Tannic acid concentrations of 0.075 % significantly increased the abundance of Firmicutes and Lactobacillaceae in the ileum and decreased the abundance of Vibrionaceae and Yersiniaceae (P < 0.05). In experiment 2, the growth performance of the TA group significantly improved compared with that of the CTR group (P < 0.05). The F/G was significantly higher in the 5TA and 10TA groups than in the CTR group (P < 0.05), and the 10TA group had significantly reduced body weight on d 21 (P < 0.05). The addition of tannic acid resulted in significant glomerular and glandular hyperplasia, as well as muscularis thickening of the gizzard mucosa. However, broilers could not tolerate tannic acid doses of 0.375 % and above. Tannic acid supplementation may protect the proventriculus mucosal layer, reduce villi atrophy, and enhance growth performance by positively influencing the intestinal microbiota, villus morphology, and intestinal barrier function.

Unraveling the multiple role of UV in PAA/Fe(III) advanced oxidation: Mechanism, efficiency, and toxicity analysis

In recent years, the advanced Fenton-like oxidation technology based on peracetic acid (PAA) has attracted increasing attention, while accelerating the cycle of Fe(III)/Fe(II) remains a limitation for widespread PAA/Fe(III) system application. Herein, in this study, the dual mechanism of UV synchronous acceleration of Fe(III)/Fe(II) cycling and activation of PAA was systematic investigated with the introduction of UV in PAA/Fe(III) systems. Results suggested that the target pollutant Rhodamine B (RhB) could achieve over 95% degradation within 12minutes in the Fe (III)/PAA/UV system. The crucial roles of UV radiation has been determined to activate PAA independently, and synchronously accelerates the transfer of Fe (III) to Fe (II) to generate hydroxyl radicals (·OH), while also enhancing the generation of Fe (IV), ultimately achieving a redox cycle in Fe (III)/PAA/UV system. The ·OH, Fe(IV) and organic free radicals (R-O·) were identified as the mainly active substances via the various analysis methods including characteristic product detection, quenching experiments, electron paramagnetic resonance (EPR), and fluorescence analysis, and the contribution to the RhB degradation followed as ·OH(68.61%) > Fe(IV) (17.52%) > R-O·(11.69%). 12 intermediates and two potential degradation pathways of RhB were identified by combining density functional theory (DFT) calculations and Ultra-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UPLC-QTOF-MS) analyses, and the ecotoxicity was evaluated through Ecological Structure Activity Relationships (ECOSAR) program. Response surface methodology was employed to analyze optimal degradation conditions, considering Fe(III) and PAA dosage, pH, and inhibitory effects of anions. This study systematically revealed the internal mechanism of Fe(III)/PAA/UV system for organic pollutant degradation and verified its efficiency and eco-friendliness.

Cone beam computed tomography - Frequency and exposure settings at University (Dental) hospitals in Central and Northern Europe.

To investigate the frequency of CBCT scans, the exposure settings, volume sizes and the patient demographics (age and sex) of patients undergoing CBCT scans in university-based dental hospitals in different European countries over a one-year period. Eight University Dental Hospitals from eight countries in central and northern Europe agreed to collect data from their CBCT-databases. Exposure data including field of view (FOV), dose area product (DAP) and optimization settings plus (anonymous) age and sex of the patients were collected for the entire year 2023. In addition, centre- and healthcare-system- related characteristics were assembled. Data were statistically evaluated using R Statistical Software. A total of 7320 CBCT-scans from eight centres and eight different CBCT-machines were evaluated. DAPs ranged between 34 and 4390mGycm2 (mean: 700.8mGycm2), kV between 60kV and 120kV. Patient age (range 4yrs to 97yrs) differed significantly between the centres, yet with a cumulative peak between 10 and 20yrs. Optimization protocols were observed for all centres, depending on their centre- and also healthcare-characteristics. 21% of the scans applied some sort of special dose reduction means. The overall age-peak between 10 and 20yrs highlights the need to optimized maxillofacial CBCT-protocols. The differences between the centres seem to be mainly related to healthcare-system and centre-related characteristics, which differ largely between the eight centres.

Microcoleus vaginatus: a Novel Amendment for Constructing Artificial Soil from Tailings

Due to lack of soil structure, the fine-grained tailings were difficult with nutrient retention and eco-restoration. Establishing suitable arable soil structures is crucial for the effective restoration of the ecological environment in tailings stockpiles. In this study, the novel amendment, living Microcoleus vaginatus, was employed to help shaping the soil structure of tailings for promoting vegetation growth on tailings soil. Different dosage of M. vaginatus was added into the tailings in pot experiments, and it was found that microalgae could increase the organic matter content, geometric mean diameter, and improve plant growth under the optimal dosage of 1:15000 (w/w). With the optimized microalgae inoculation dosage in the field trials, the plant height and weight increased by 4.48% and 14.93%, respectively. Moreover, the bulk density decreased by 9.23%, significantly, with the content of macro-aggregates, mean weight diameter and geometric mean diameter in soil increased by 33.81%, 110% and 101%, respectively. The water content increased by 1.57 times, and porosity by 2 times. Furthermore, the organic matter content increased by 20.49%, with the surge of the ecologically beneficial species Thiobacillus. This study confirms the positive effect of M. vaginatus on the formation of soil structure in fine tailings, effectively improving the nutrients possessing and microbial metabolic functions of tailings, which provides a new technical approach for ecological restoration in mine.

Safety study of fluralaner solution on poultry red mite: A clinical study screening of the optimal dose and focusing on hepatic and renal parameters.

The poultry red mite (PRM), Dermanyssus gallinae, a significant ectoparasite causing diseases in poultry, is globally prevalent and necessitates effective control strategies. There are restrictions on the use of acaricides in poultry across several nations due to worries about medication residues. Consequently, finding safe and efficient treatments for PRM is imperative. Fluralaner solution has emerged as a potential therapeutic agent, distinguished by its rapid onset, enduring efficacy, and lack of a withdrawal period for egg production. To ascertain the optimal dosage and therapeutic efficacy of fluralaner solution in PRM treatment, this study evaluated blood biochemical parameters and mite populations across various treatment groups. A cohort of 500 laying hens was randomly assigned to one of five treatment groups, each comprising 100 individuals:high-dose group (0.1 ml/kg-bw, group 4 ×, coop 1), medium-dose group (0.05 ml/kg-bw, group 2 ×, coop 5), low-dose group (0.025 ml/kg-bw, group 1 ×, coop 2), drug-control group (Intervet Productions, 0.05 ml/kg-bw recommended dose, coop 3) and blank control group (coop 4). Hens received their respective dosages of the fluralaner solution via oral administration on Days 0 (D0) and 7 (D7) of the experimental period. Over the study's ninety days, blood biochemical markers and mite counts in each coop were measured to evaluate the drug's safety, effectiveness, and ideal dosage. Data analysis was performed utilizing SPSS software. The study findings indicated that, for effective PRM infestation treatment, a dosage of 0.5 mg fluralaner per kilogram of body weight (equivalent to 0.05 ml) administered daily, followed by a subsequent dose post a 7-day interval, is recommended. Additionally, clinical observations coupled with blood biochemical assessments confirmed the safety of fluralaner across the three tested dosage levels in hens.

Finger roots (Uvaria chemea) and African greenheart (Cylicodiscus gabunensis): Alternative Potent Therapy to Sildenafil in Erectile Dysfunction

Background and aimErectile dysfunction (ED) is a prevalent condition affecting men worldwide, characterized by the inability to achieve or maintain an erection sufficient for sexual intercourse. Traditional herbal remedies, rooted in cultural practices, have been explored as alternative therapies for ED, and this study focuses on Uvara chemea and Cylicodiscus gabunensis, two plants with reported medicinal properties, as potential alternatives to sildenafil, a standard pharmaceutical for ED. Experimental procedureForty male Wistar rats were randomly divided into five groups: control (treated with distilled water), low, medium, and high doses (treated with 61.23, 122.47, and 183.71 mg/kg each of Uvara chemea and Cylicodiscus gabunensis respectively), and a positive control group (treated with sildenafil citrate). The rats were treated for 21 days, and their erectile responses were estimated ResultsSignificant improvements in erectile responses were observed in rats treated with Uvara chemea and Cylicodiscus gabunensis extracts compared to the control group. When compared to sildenafil citrate, the extracts showed comparable effects in most parameters, with a significant disparity noted in intromission frequency at low and high dosages. Strikingly, there was no significant difference between the extracts treated animals and their counterparts treated with sildenafil citrate. ConclusionUvara chemea and Cylicodiscus gabunensis extracts demonstrated potential in ameliorating erectile dysfunction in rats, suggesting their viability as alternative or complementary therapeutic options to sildenafil citrate. Further investigations are necessary to elucidate the underlying mechanisms of action, determine optimal dosages, and evaluate the long-term safety profiles of these herbal extracts for potential human applications.

Polystyrene nanoplastics sequester the toxicity mitigating potential of probiotics by altering gut microbiota in grass carp (Ctenopharyngodon idella)

This study evaluated the role of probiotics in enhancing intestinal immunity and mitigating polystyrene nanoplastics (PS-NPs)-induced toxicity in grass carp (Ctenopharyngodon idella). Grass carp were fed probiotics (Bacillus subtilis, Bacillus velezensis, Lactobacillus reuteri, and Lactococcus lactis) for two weeks before being exposed to PS-NPs for five days. Probiotic pretreatment alleviated PS-NPs-induced intestinal damage, with Bacillus velezensis and Lactococcus lactis groups showing milder vacuolation and villus breakage than other groups. Probiotic-treated fish exhibited transient increases in antioxidant enzyme activities (CAT, SOD, MPO) and immune gene expression (IL-6, IL-8, IL-10, IL-1β, TNF-α, and IFN-γ2) shortly after exposure, followed by significant downregulation over time. Higher abundance of the gut dominant phylum Proteobacteria was observed in four probiotic groups exposed to PS-NPs than that in the blank control group. The Clostridium phylum showed a significant decrease in the abundance both in the LRS-PS100 and LLS-PS100 groups, while the abundance of the Thick-walled phylum increased. The Spearman correlation matrix revealed that specific gut microbiota, such as Serratia, Neisseria, and Lactococcus, were significantly associated with enzymatic activities and immune system related genes’ expressions. Probiotic pretreatment enhanced the intestinal immune response of grass carp. However, this enhanced immune response was insufficient to counteract the toxic effects of PS-NPs exposure, particularly in terms of oxidative stress levels and gut microbial diversity. This study offers new insights into the potential of probiotics to combat NPs pollution in aquaculture. It emphasizes the need for further research to explore various probiotic combinations. Future studies should also investigate optimal dosages and durations to effectively mitigate the biological toxicity of NPs pollution.

Beneficial Effects of Spirulina on Brain Health: A Systematic Review

&lt;p&gt;Background: This review provides a concise overview of existing scientific research concerning the potential advantages of incorporating spirulina, a blue-green algae, into one's diet to promote brain health. The substantial nutritional composition and associated health benefits of algae have drawn significant interest. &lt;/p&gt; &lt;p&gt; Methods: Numerous studies have illuminated the neuroprotective characteristics of spirulina, contributing to its positive influence on brain functionality. Primarily, spirulina boasts antioxidants, like phycocyanin and beta-carotene, that effectively counter oxidative stress and curb inflammation within the brain. This is particularly significant as these factors play roles in the advancement of neurodegenerative conditions like Parkinson's and Alzheimer's disease. Additionally, spirulina has demonstrated the capacity to enhance cognitive capabilities and enrich memory and learning aptitudes. &lt;/p&gt; &lt;p&gt; Results: Animal-based investigations have revealed that introducing spirulina can bolster spatial learning and memory, as well as guard against cognitive decline linked to aging. Research has indicated its potential in shielding against neurotoxins, encompassing heavy metals and specific environmental pollutants. Its potential to neutralize heavy metals and counteract free radicals contributes to these protective effects, potentially thwarting neuronal harm. &lt;/p&gt; &lt;p&gt; Conclusion: In conclusion, the extant scientific literature proposes that spirulina integration can elicit advantageous outcomes for brain health. Its antioxidative, neuroprotective, cognitiveenhancing, and mood-regulating properties present a promising avenue for bolstering brain health and potentially diminishing the susceptibility to neurodegenerative ailments. Nonetheless, further research, notably well-designed human clinical trials, is imperative to ascertain the optimal dosing, duration, and enduring consequences of spirulina supplementation concerning brain health.&lt;/p&gt;

Potential for reduction of radiation dose in the assessment of the lead orientation in directional deep brain stimulation electrodes.

Directional deep brain stimulation (dDBS) relies on electrodes steering the stimulation field in a specific direction. Post implantation, however, the intended and real orientation of the lead frequently deviates e.g. due to torque of the electrode. The orientation is assessed by postoperative imaging such as C-arm cone-beam CT (CBCT) using 3D rotational fluoroscopy and multi-slice CT (MSCT). The objective is to determine the effect of different X-ray systems such as CBCT and MSCT, and scan acquisition parameters on effective radiation doses. We retrospectively investigated the dose area product (DAP) and dose length product (DLP) of patients who underwent both CBCT and MSCT after dDBS surgery. These metrics were then converted into the effective dose by established conversion coefficients. For CBCT, the feasible dose optimization by collimation was virtually assessed. Univariate analysis was performed to determine differences. Among 88 patients median effective dose was 0.20±0.07mSv in CBCT and 2.11±0.33mSv in MSCT (p<0.001). The field of view (FOV) in CBCT can be collimated in craniocaudal orientation by 33.6% and mediolaterally by 60.8%. This optimized collimation implies an effective dose reduction of 76% (p<0.001). Comparison of the effective dose of MSCT vs. CBCT revealed a significant dose reduction by 90.3% (p<0.001), whereas optimal collimation by 97.7% (p<0.001). For assessment of dDBS orientation, CBCT had significantly lower radiation doses compared to MSCT. Optimized collimation in CBCT allows for a further substantial dose reduction. Moreover, the proposed approach is applicable on other neuroimaging procedures such as 3D visualization of treated intracranial aneurysm.

Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC).

722 Background: PDAC is the third leading cause of cancer mortality, with limited treatment options. Even with multi-agent chemotherapy, patients with second-line (2L) PDAC have a median progression-free survival (PFS) of ≈2–3.5 months and median overall survival (OS) of ≈6–7 months. RAS mutations occur in &gt;90% of patients with PDAC, mainly KRAS G12X (G12X = non-synonymous mutations in KRAS codon 12 [G12]). RMC-6236 is an oral, RAS(ON), multi-selective, tri-complex inhibitor of the active GTP-bound state of both mutant and wild-type RAS. In a Phase 1 study, RMC-6236 demonstrated efficacy and manageable safety in patients with PDAC harboring KRAS G12X or other RAS mutations (NCT05379985). Data on ctDNA reduction with targeted therapy in PDAC are sparse. We report safety, updated efficacy, and exploratory analyses of early ctDNA reduction with clinically active doses of RMC-6236 in patients with RAS mutant PDAC. Methods: Escalating doses of RMC-6236 were administered orally to patients with previously treated RAS mutant PDAC. Additional patients were enrolled for dose optimization and expansion. Patients receiving clinically active doses (160–300 mg QD) of RMC-6236 ≥14 weeks before the July 23, 2024 data cutoff were included. Plasma samples were collected for ctDNA analysis of change in RAS mutant variant allele fraction at baseline (BL; cycle 1, day 1 [C1D1]), and on treatment (C2D1 or C3D1). Results: As of July 23, 2024, 127 patients with RAS mutant PDAC had received RMC-6236 160–300 mg QD. The most common (≥10% of patients) any-grade treatment-related adverse events were rash (91%), diarrhea (48%), nausea (43%), vomiting (31%), stomatitis (31%), fatigue (20%), paronychia (13%), mucosal inflammation (13%), decreased appetite (11%), and peripheral edema (10%). The Table shows objective response rate (ORR), PFS, and OS with 2L RMC-6236. Paired plasma samples were tested in 106/127 patients. Of these, 68 patients with RAS mutant allele ctDNA at BL were evaluable for ctDNA response (Table). Conclusions: RMC-6236 showed a manageable safety profile and encouraging efficacy in patients with previously treated RAS mutant PDAC, and early and deep reductions in RAS mutant ctDNA. RASolute 302, a global, randomized, Phase 3 trial evaluating RMC-6236 as 2L treatment vs chemotherapy in patients with metastatic PDAC, is ongoing. Clinical trial information: NCT05379985 . KRAS G12X RAS mutant Efficacy with 2L RMC-6236 (n=42) (n=57) ORR, % (95% CI)[confirmed + pending confirmation] 29 (16–45) 25 (14–38) Median PFS, months (95% CI) 8.5 (5.3–11.7) 7.6 (5.9–11.1) Median OS, months (95% CI) 14.5 (8.8–not evaluable) 14.5 (8.8–not evaluable) ctDNA Response with 2L+ RMC-6236 (n=56) (n=68) &gt;50% decrease from BL, n (%) 53 (95) 63 (93) 100% decrease from BL, n (%) 28 (50) 32 (47)

Adaptive Immunity Determines the Cancer Treatment Outcome of Oncolytic Virus and Anti-PD-1.

The immune checkpoint inhibitor, anti-programmed death protein-1 (anti-PD-1), enhances adaptive immunity to kill tumor cells, and the oncolytic virus (OV) triggers innate immunity to clear the infected tumor cells. We create a mathematical model to investigate how the interaction between adaptive and innate immunities under OV and anti-PD-1 affects tumor reduction. For different immunity strength, we create the corresponding virtual baseline patients and cohort patients to decipher the major factors determining the treatment outcome. Global sensitivity analysis indicates that adaptive immunity has more control on the treatment outcome than innate immunity, and whether anti-PD-1 cancels out the OV treatment efficacy depends on the OV dosage and the balance between clearance of infected tumor cells and OV by T cells. The optimal OV infection rate and dosage suggest that OV treatment is more sensitive to adaptive immunity than innate immunity. Our model prediction also indicates that tumor reduction is more sensitive to anti-PD-1 efficacy as adaptive immunity becomes stronger, and anti-PD-1 trends to cancel out the OV treatment efficacy as innate immunity becomes stronger. Based on these results, the recommended treatment protocol for patients with different immunity strength can be determined.

Model-Informed Recommendation of Mavacamten Posology for Chinese Adults With Obstructive Hypertrophic Cardiomyopathy.

Mavacamten is a cardiac myosin inhibitor for adults with obstructive hypertrophic cardiomyopathy (HCM). Dose optimization is performed 4 weeks after starting mavacamten, guided by periodic echo measurements of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Previously, a population pharmacokinetic (PPK) model was developed and exposure-response (E-R) of VLVOTg (efficacy) and LVEF (safety) was used to identify the mavacamten titration regimen with the optimal benefit/risk ratio, now included in the US prescribing information. Mavacamten is metabolized primarily by cytochrome P450 2C19 (CYP2C19) (74%), a highly polymorphic enzyme. China has a higher prevalence of poor CYP2C19 metabolizer phenotype compared with the global population; therefore, a previous model was adapted to include Chinese patients with obstructive HCM to identify the optimal dosing regimen for this population. Data from a phase I (healthy Chinese volunteers) and a phase III (EXPLORER-CN, NCT05174416; Chinese patients with obstructive HCM) trial of mavacamten were added to the previous PPK and E-R models, and the observed VLVOTg and LVEF from EXPLORER-CN were successfully simulated. Next, five echocardiography-guided titration regimens (plus the EXPLORER-CN regimen) using representative or equal CYP2C19 phenotypes were simulated. The final simulated regimen recommended with an optimal benefit/risk profile across CYP2C19 phenotypes included: down-titration at Week 4 (if VLVOTg < 20 mmHg), restart at Week 12, and up-titration at Week 12 (for VLVOTg ≥ 30 mmHg and LVEF ≥ 55%), and every 12 weeks thereafter. This supports the previously recommended regimen for Chinese patients with obstructive HCM, now approved by the National Medicinal Products Administration.

Nano-Interaction Mechanism Between Crumb Rubber and Asphalt Components: A Molecular Dynamic Study

Asphalt modified with treated waste tires has good environmental protection and application value. However, the nano-interaction mechanism of crumb rubber (CR) and asphalt (especially its components) is unclear. In this study, molecular models of asphalt, asphalt components, CR, and CR-modified asphalt (CRMA) were constructed by molecular dynamics (MD) simulation. The validity of the model construction and parameter setting was verified by multiple indexes. The influence mechanism of CRMA density, asphalt-CR compatibility, mechanical indexes, and binding energy under the influence of temperature, CR dosage, and other factors was systematically analyzed. Results showed that the optimum temperature for preparing and storing to prevent segregation did not coincide. The solubility parameters (SP) prediction model of the asphalt’s four components was obtained based on the multiple linear regression method. CR could enhance the mechanical properties of asphalt, but the improvement was limited to small dosages. Increasing the dosage can enhance the mechanical properties of asphalt; the mechanical properties can be significantly improved in medium- and high-temperature conditions. Bulk modulus and shear modulus were recommended for preferential analysis of the mechanical properties of CRMA. It is recommended that the optimal dosage be 20%.

Low dose ATG-Fresenius for GVHD prophylaxis: a comparative study with ATG-Thymoglobulin

BackgroundAnti-Thymocyte Globulin (ATG) is commonly used to prevent graft-versus-host disease (GVHD), but the optimal dosage and type of ATG remains to be determined.ObjectiveWe compared retrospectively the safety and efficacy outcomes of allogeneic transplantation using low-dose ATG-Fresenius (15mg/kg) and ATG-Thymoglobulin (10mg/kg) for GVHD prevention.Study designNinety-eight patients were included, with 46 in the ATG-T group and 52 in the ATG-F group. The median age was 48 years in the ATG-T group (range 20-71) and 50 years in the ATG-F group (range 18-73). Baseline characteristics were similar, with slightly more HLA mismatched donors and single-agent cyclosporine GVHD prophylaxis use in the ATG-T group. Additionally, the ATG-F group had more myeloid leukemia and myelodysplastic syndrome patients, while the ATG-T group had more lymphoma patients.ResultsThe cumulative incidence of acute GVHD (aGVHD) grade II-IV and chronic GVHD (cGVHD) showed no significant differences. Multivariate analysis indicated that donor HLA mismatch influenced aGVHD risk significantly (p=0.005), and myeloablative conditioning increased cGVHD risk. Bacteremia and CMV reactivation rates were similar, but EBV DNA viremia was higher in the ATG-T group (22% vs. 8%, p=0.047), with one case of Post-Transplant Lymphoproliferative Disorder (PTLD) in the ATG-T group. Cumulative incidence of overall survival (OS), relapse incidence, non-relapse mortality (NRM) and GVHD free, Relapse free Survival (GRFS) did not significantly differ.ConclusionsThis study highlights the safety and efficacy of low-dose ATG-F compared to a relatively high dose ATG-T. Prospective studies are necessary to validate the safety and efficacy of low dose ATG-F for GVHD prevention.

Translating PK-PD principles into improved methodology for clinical trials which compare intermittent with prolonged infusion of beta-lactam antibiotics.

Based on the fact that beta-lactam antibiotics demonstrate time-dependent killing, different dosing strategies have been implemented to increase the time that free (f) (unbound) antibiotic concentrations remain above the Minimal Inhibitory Concentration (MIC), including prolonged and continuous infusion. Multiple studies have been performed that compared continuous with traditional intermittent infusion to improve outcomes in patients with severe sepsis and/or septic shock. These studies have yielded inconsistent results for patients as measured by clinical response to treatment and mortality due to heterogeneity of included patients, pathogens, dosing strategies and the absence of Therapeutic Drug Monitoring (TDM). The MERCY and BLING III studies failed to show a difference in mortality between patients randomized to receive continuous and intermittent infusion of beta-lactam antibiotics. A deeper understanding of pharmacokinetic (PK) and pharmacodynamic (PD) mechanisms that occur in critically ill patients should guide us in dose optimization and improvement in methodology for future clinical trials.

Dose Evaluation and Optimization of Amoxicillin in Children Treated for Lyme Disease.

Amoxicillin is commonly used to treat erythema migrans in the first stage of Lyme disease in children, with a recommended dose of 50 mg/kg/day, administered three times a day (q8h). This model-based simulation study aimed to determine whether splitting the same daily dose into two administrations (q12h) would provide comparable drug exposure. A pharmacokinetic model suitable for a pediatric population (age: 1 month to 18 years, weight: 4-80 kg) was selected through a literature review. Simulations were performed with 15,000 virtual patients receiving 16.67 mg/kg/dose q8h, 25 mg/kg/dose q12h, or other q12h dosing variations. The target therapeutic level was defined by the percentage of time that the unbound drug concentration remained above the minimum inhibitory concentration (% fT > MIC) specific to Borrelia burgdorferi, with MICs of 0.06, 0.25, 1, 2, and 4 mg/L, requiring at least 40% and 50% of time for effective treatment. Probability of target attainment (PTA) was considered acceptable if it exceeded 50%, allowing for comparison of dosing schedules. Results indicated that the 50 mg/kg/day divided q12h regimen provided similar drug exposure to the q8h regimen for MICs below 2 mg/L (PTAs >50%). For a MIC of 2 mg/L, PTA was achieved with a higher dose of 30 mg/kg/dose q12h. However, for a MIC of 4 mg/L, the PTA criterion was not met. These findings suggest that a twice-daily dosing of 25 mg/kg/dose provides comparable bactericidal activity to the thrice-daily regimen for MICs between 0.06 and 1 mg/L. This simplified regimen may improve adherence and treatment implementation in children.