Dose Of Drug Research Articles

Phase 1b study evaluating the efficacy and safety of ABBV-400, a c-Met–targeting antibody-drug conjugate, in select advanced solid tumor indications.

TPS3162 Background: c-Met (MET protein) is commonly overexpressed in a number of tumors, including hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), biliary tract cancers (BTC), esophageal squamous cell carcinoma (ESCC), breast cancer (BC), and head and neck squamous cell carcinoma (HNSCC). Patients with c-Met–overexpressing tumors represent an underserved population, with the need for more effective c-Met–targeting therapies to become available. ABBV-400 is an antibody-drug conjugate, consisting of the c-Met–targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload. Initial results from the ongoing first-in-human study (NCT05029882) of ABBV-400 in patients with advanced solid tumors indicate a tolerable safety profile, with a maximum tolerated dose of 3 mg/kg once every 3 weeks (Q3W), and promising antitumor activity, with an overall response rate of 24.4% (1). Herein, we describe a signal-seeking study evaluating ABBV-400 treatment in patients with select solid tumors. Methods: Multicenter, open-label, phase 1 signal-seeking study(NCT06084481). Eligible patients (≥18 years) have confirmed locally advanced/metastatic disease measurable per RECIST v1.1 and Eastern Cooperative Oncology Group performance status ≤1. Approximately 220 patients are planned for enrollment across 7 cohorts (HCC, n=40; PDAC, n=40; BTC, n=20; ESCC, n=40; triple-negative BC, n=20; hormone receptor-positive/HER2-negative BC, n=20; HNSCC, n=40). The primary objectives are to assess efficacy and safety/tolerability of ABBV-400 in each tumor indication. Secondary objectives include the evaluation of pharmacokinetics (PK) and immunogenicity of ABBV-400. Pharmacodynamic (PD) and biomarker analyses are exploratory endpoints. Patients receive intravenous ABBV-400 at 3 mg/kg Q3W until disease progression, intolerable toxicity, or any other per-protocol discontinuation criteria. c-Met expression will be assessed retrospectively by immunohistochemistry. The maximum treatment duration is 2 years. Tumor assessments are performed at screening and every 6 weeks from the first dose of study drug, with objective response rate as primary efficacy endpoint and duration of response, clinical benefit rate, progression-free survival, and overall survival as secondary efficacy endpoints. Safety evaluations include adverse events monitoring (graded according to the NCI CTCAE, v5.0), physical examinations, vital sign measurements, ECG variables, and clinical laboratory testing. Blood samples for PK, PD, and biomarker analysis are collected at designated time points throughout the study. Enrollment started in November 2023. As of 19 January 2024, 24 patients have been enrolled. 1. Sharma et al. JCO 2023;41[16 suppl]:3015. Clinical trial information: NCT06084481 .

A novel doxorubicin/CTLA-4 blocker co-loaded drug delivery system improves efficacy and safety in antitumor therapy

Doxorubicin’s antitumor effectiveness may be constrained with ineffective tumor penetration, systemic adverse effects, as well as drug resistance. The co-loading of immune checkpoint inhibitors and doxorubicin into liposomes can produce synergistic benefits and address problems, including quick drug clearance, toxicity, and low drug penetration efficiency. In our previous study, we modified a nanobody targeting CTLA-4 onto liposomes (LPS-Nb36) to be an extremely potent CTLA-4 signal blocker which improve the CD8+ T-cell activity against tumors under physiological conditions. In this study, we designed a drug delivery system (LPS-RGD-Nb36-DOX) based on LPS-Nb36 that realized the doxorubicin and anti-CTLA-4 Nb co-loaded and RGD modification, and was applied to antitumor therapy. We tested whether LPS-RGD-Nb36-DOX could targets the tumor by in vivo animal photography, and more importantly, promote cytotoxic T cells proliferation, pro-inflammatory cytokine production, and cytotoxicity. Our findings demonstrated that the combination of activated CD8+ T cells with doxorubicin/anti-CTLA-4 Nb co-loaded liposomes can effectively eradicate tumor cells both in vivo and in vitro. This combination therapy is anticipated to have synergistic antitumor effects. More importantly, it has the potential to reduce the dose of chemotherapeutic drugs and improve safety.

DEFENDOR: Real-world evidence of primary prolonged G-CSF prophylaxis by empegfilgrastim for relative dose intensity compliance in patients with solid tumors—The final analysis.

e24109 Background: Myelosuppression management under chemotherapy (CT) is crucial for maintaining the relative dose intensity (RDI) of therapy and ensuring effective treatment of patients with solid tumors (ST). RDI > 85% is associated with better overall survival for the most ST. Granulocyte colony stimulating factors (G-CSF) have been the standard of care for the prevention of chemotherapy-induced neutropenia (CIN). Here we present the final results of a multicenter prospective observational post-marketing study of safety and efficacy of pegylated G-CSF Extimia (INN: empegfilgrastim, JSC BIOCAD) in pts with ST who receive cytotoxic therapy. Methods: The primary endpoint was the RDI of CT courses (4-8 cycles per course are allowed) with empegfilgrastim support. RDI was calculated for each single agent in the chemotherapy-based (CTb) regimen and for the CTb regimen in total. Extimia (7,5 mg) was administered subcutaneously once per chemotherapy cycle. Results: The study included 3218 pts with various tumor types across 41 centers in Russia. 3217 (99.97%) pts received at least one dose of the study drug. 2663 (82.8%) pts were included in the RDI assessment population per protocol. The average age of pts was 56.9 (18–84) y.o. Individuals aged ≥65 y.o accounted for almost one third of all pts. RDI ≥ 85% was achieved in 2415 (90.7%) pts (Table 1). 1447 (54.3%) pts have at least one FN risk factor whereas age ≥ 65 years is the most common (763/2663 (28.6%) pts). 91.5% RDI was registered in pts < 65 y.o and 88.7% RDI - in pts ≥ 65 y.o. Neutropenia was reported in 19 (0.7%) cases as a reason of RDI decrease. Grade 3-4 AEs were recorded in 74 (1.8%) cases in 59 pts whereas neutropenia (n = 22), anemia (n = 8) and diarrhea (n = 6) were the most common (CTCAE (v. 5.0)). Conclusions: Primary prolonged G-CSF prophylaxis by empegfilgrastim allows effectively maintaining RDI across various tumor types (TT) and treatment groups in pts with ST in routine clinical practice. Clinical trial information: NCT0481144 . [Table: see text]

Complementary use of conduction system pacing techniques for the “pace and ablate” strategy in permanent atrial fibrillation - a case report

Abstract Introduction The feasibility of the conduction system pacing combined with atrioventricular node ablation was demonstrated in patients with atrial fibrillation in whom rate control can’t be achieved with medication and heart failure. Clinical case We present a case of an 82-year-old man with a personal history of permanent atrial fibrillation, admitted with symptoms of heart failure. The resting electrocardiogram showed a very fast ventricular response, and the echocardiography showed a depressed left ventricular function, raising the suspicion of a tachycardia-mediated cardiomyopathy. Since the patient was on maximum doses of atrioventricular nodal-blocking drugs, we opted for a physiological pacing and atrioventricular node ablation strategy. First, the His bundle capture was achieved at low pacing thresholds, and ablation of the atrioventricular node was attempted. Unfortunately, after several failed attempts, an acute increase in the His bundle capture threshold was noted, suggesting inadvertent tissue ablation beneath the pacing lead. In this scenario, we removed the lead from the His bundle area and achieved optimal left bundle branch area pacing. With the lead in this position, atrioventricular node ablation was performed during the first attempt. At the six-month follow-up, there was no recovery of atrioventricular node conduction. Device interrogation revealed stable pacing and sensing parameters, and there was a significant improvement in clinical status and left ventricular function. Conclusions Mastering both His bundle pacing and left bundle branch area pacing offers the potential to overcome intraprocedural challenges, giving alternative strategies to achieve physiological pacing. These approaches can be used interchangeably based on the evolving dynamics of the procedure and the patient’s specific needs.

Comparing Bispectral Index Monitoring vs Clinical Assessment for Deep Sedation in the ICU: Effects on Delirium Reduction and Sedative Drug Doses—A Randomized Trial

BackgroundSedative overdoses pose a delirium risk among Intensive Care Unit (ICU) patients, with potential mitigation through the use of a processed EEG monitor (BIS) to guide depth of sedation. Research QuestionCan BIS-guided deep sedation (RASS -4, -5) reduce sedative dosage and increase delirium-free and coma-free (DFCF) days? Study Design and MethodsA randomized controlled trial was conducted in a tertiary mixed ICU, enrolling patients requiring deep sedation for >8 hours. Patients were randomly assigned to either the Clinical Assessment (CA) or BIS groups (BIS range of 40-60). Both groups utilized a BIS sensor, while the CA group's screen remained covered. After deep sedation, BIS sensors were removed, and delirium was assessed twice daily by researchers blinded to the randomization. The primary outcome was the number of DFCF days within 14 days after deep sedation. Additionally, we compared doses of sedative drugs and BIS values during deep sedation. ResultsNinety-nine patients were included in the study. We found no significant difference in DFCF (p=0.1) between CA and BIS arms, but propofol doses were significantly lower in the BIS group (CA group 1.77 mg/kg/hr [95% CI 1.60, 1.93] vs. BIS group 1.44 mg/kg/hr [95% CI 1.04, 1.83]; p=0.03). During deep sedation, the CA group spent 46% of the total hours (95% CI 35, 57%) with BIS values below 40, whereas the BIS group spent 32% (95% CI 25, 40%), (p=0.03). Subgroup analysis focusing on patients sedated for more than 24 hours revealed an increase in DFCF in the BIS group (CA group median of 1 day [IQR 0, 9] vs. BIS group 8 days [IQR 0, 13]; p=0.04). InterpretationBIS-guided deep sedation did not improve DFCF days but reduced sedative drug use. In patients requiring sedation for more than 24 hours, it showed an improvement in DFCF days.

Antibiotic exposure and colon carcinogenesis: In-depth profiling of a 492-patient cohort, with a focus on antibiotic classifications and subtypes.

e15643 Background: To investigate whether the use of specific antibiotics is associated with an increased risk of colon cancer incidence. Methods: We conducted a retrospective cohort study comprising 492 patients diagnosed with colon cancer between 2012 and 2022, with no prior malignancies and a minimum 5-year follow-up period. We collected demographic data, medical histories, and records of antibiotic exposure, categorizing antibiotics systematically based on the Anatomical Therapeutic Chemical (ATC) classification system. Patient antibiotic histories, including drug names, dosages, durations, and therapeutic indications, were included. Antibiotics were classified as broad-spectrum, narrow-spectrum, or extended-course. We performed univariate and multivariate logistic regression models and used propensity score matching to control for potential confounding variables, such as age, gender, co-morbidities, and concurrent medications. Subgroup analyses were conducted to identify specific antibiotic classes associated with an increased risk of colon cancer. Results: The mean age of the cohort was 65.7 years (SD ± 8.3), with an equal gender distribution. Adenocarcinoma was the predominant histological subtype (429 cases, 87%), with rare subtypes accounting for the remaining cases. Common co-morbidities included hypertension (226 cases, 46%), diabetes mellitus (108 cases, 22%), and hyperlipidemia (88 cases, 18%). The most frequently prescribed antibiotics were fluoroquinolones (158 cases, 32%), followed by cephalosporins (108 cases, 22%), and macrolides (88 cases, 18%). Extended-course antibiotics were administered in 138 cases (28%). Preliminary analysis revealed a statistically significant correlation between the use of extended-course antibiotics and the risk of colon cancer (Odds Ratio = 1.89, 95% Confidence Interval: 1.32-2.71, p < 0.05). No substantial association was observed with broad-spectrum or narrow-spectrum antibiotics. Subgroup analysis identified specific agents within the extended-course antibiotics, such as fluoroquinolones and clindamycin, with an elevated risk profile. Conclusions: This study suggests a potential association between the use of extended-course antibiotics and the development of colon cancer. Further validation through larger-scale, prospective studies is strongly recommended to confirm these findings. Further in-depth mechanistic inquiries, particularly in cellular signaling pathways and microbial interactions within the gut microbiome, are warranted to elucidate the underlying biological mechanisms driving this association.

Oxytetracycline dose reduction in salmon farming: Assessing a micro encapsulated novel formulation in an in vivo model

Oxytetracycline (OTC) is used in Chilean salmonid farming for bacterial pathogens treatment, mainly orally administered. Oral bioavailability of OTC in salmonids is low, so a high percentage of the dose is excreted by fishes. To increase OTC oral absorption, Zn-alginate microparticles were developed by spray drying, with a yield of 59.09%. An in vivo study was performed using Oncorhynchus mykiss (Rainbow trout) to compare OTC Zn-alginate micro-particles oral absorption in plasma and muscle matrices. Seven sampling points for plasma and four for muscle were considered. OTC was quantified in both matrices by UPLC-MS/MS. Results indicated a statistically significant difference between plasma concentrations of the OTC microparticles with respect to the commercial OTC formulation, reflecting a higher absorption of the microencapsulated drug, reaching maximum concentration 4 h earlier than the commercial formulation. In addition, the microparticles showed a release of OTC that remained constant for 12 h. In muscle, OTC microparticles reached twice the maximum concentration than the commercial formulation at 8 h. In conclusion, OTC microparticles improve the oral absorption of the molecule, which could allow drug delivery optimization and dose reduction in bacterial pathogens treatment in salmon production, consequently, decrease contamination of the environment with OTC residues.

H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive (ER+), HER2 negative (–) breast cancer (BC).

1015 Background: H3B-6545 is a novel selective ER covalent antagonist (SERCA) that inactivates wild-type and mutant ERα. This phase 1/2 study aimed to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and characterize safety and efficacy of H3B-6545 in women with advanced/metastatic ER+, HER2– BC. Methods: This multicenter, open-label study included dose-escalation [ph1] and -expansion [ph2] phases. Females (postmenopausal or concurrently receiving a luteinizing hormone-releasing hormone agonist) with ER+, HER2–BC who had disease progression on standard therapy were eligible. Prior therapy must have included a minimum of 2 hormonal therapies (HTs), or 1 HT + 1 chemotherapy, or 1 HT + a CDK4/6 inhibitor. H3B-6545 was administered orally QD at doses of 100-600 mg. The MTD was the highest dose at which ≤1 of 6 patients (pts) had a dose-limiting toxicity (DLT). In ph2, efficacy of the RP2D was examined. The primary endpoints were determination of RP2D (ph1) and efficacy (ph2; including objective response rate [ORR], duration of response [DOR], and progression-free survival [PFS] per RECIST v1.1 by investigator, and overall survival [OS]). Safety and PK were secondary endpoints. Results: At data cutoff (30 Nov 22), 151 pts received ≥1 dose of H3B-6545 during ph1 or ph2. Pts had a median (m [range]) of 2 (1-7) prior endocrine- and 1 (1-6) non-endocrine–containing therapies; 90.1% of pts received prior CDK4/6 inhibitors. During ph1, DLTs of grade (G) 3 rash (n=1) and G 3 fatigue (n=1) were observed at 600 mg; thus, 450 mg was determined to be the MTD/RP2D. In the full analysis set (N=151), 100% and 50.3% of pts had any grade and G ≥3 treatment-emergent adverse events (TEAEs), respectively. TEAEs leading to drug interruption, dose reduction, and withdrawal occurred in 38.4%, 20.5%, and 8.6% of pts, respectively. Nausea (45.7% [2.0% G ≥3]), sinus bradycardia (44.4% [0% G ≥3]), and diarrhea (41.1% [1.3% G ≥3]) were the most common TEAEs. QT prolongation occurred in 9.9% [3.3% G ≥3] of pts. Among 94 response-evaluable pts treated at 450 mg, ORR was 20.2% (95% CI 12.6–29.8) and clinical benefit rate (CBR) was 41.5% (95% CI 31.4–52.1); mPFS (95% CI) was 5.06 (3.15–7.26) months. Among all pts treated at 450 mg (n=115), mOS (95% CI) was 21.52 (16.56–25.46) months. Plasma concentration of H3B-6545 increased as dose increased. Additional results are shown (Table). Conclusions: H3B-6545 had a low rate of G ≥3 TEAEs and showed clinically meaningful antitumor activity in heavily pretreated female patients with ER+, HER2– BC. Clinical trial information: NCT03250676 . [Table: see text]

Pooled analysis on characteristics of nausea and vomiting in patients receiving trastuzumab deruxtecan (T-DXd) in clinical studies.

12118 Background: The efficacy and safety profile of T-DXd has been established in patients (pts) with various tumor types, and nausea and vomiting are the most common treatment-emergent adverse events (TEAEs). T-DXd study protocols were refined over time to recommend prophylaxis (eg, neurokinin or serotonin receptor antagonists and/or steroids) before T-DXd treatment, in line with antiemetic and institutional guidelines. We conducted a pooled, post hoc analysis capturing safety information across tumor types; we report results on nausea and vomiting. While this analysis was not designed to assess antiemetic effectiveness, it reveals the incidence of nausea and vomiting in clinical trials of T-DXd 5.4 mg/kg in more detail across a large dataset. Methods: 1449 pts treated with ≥1 dose of 5.4 mg/kg T-DXd (every 3 wks) were included from 7 phase 1-3 clinical trials in metastatic HER2+ and HER2-low breast cancer, HER2+ gastric cancer, and HER2-mutant non–small cell lung cancer (DESTINY-Breast01, -Breast02, -Breast03, -Breast04, -Lung01, -Lung02, and the first-in-human phase 1 study J101 in multiple tumor types; study enrollment starting 2015-2021). Regardless of antiemetic use (including prophylaxis), the incidence, severity, time to onset, and duration of nausea and vomiting TEAEs were assessed along with event outcomes. Results: Of 1449 pts receiving T-DXd 5.4 mg/kg (median [range] number of 3-wk treatment cycles: 13 [1-60]), 74.6% (n=1081) experienced nausea, and 41.6% (n=603) reported vomiting. Most pts had grade 1/2 nausea (41.2%/27.6%) and/or vomiting (26.2%/12.8%). Grade 3 TEAEs of nausea were reported in 5.8% of pts, with grade ≥3 TEAEs of vomiting observed in 2.6% of pts. By the data cutoff for each trial, 66.9% of pts with nausea and 87.6% with vomiting had their symptoms resolve. Most pts who experienced nausea and vomiting did so during the initial 21 days (cycle 1; n=879 [81.3%] and 336 [55.7%], respectively; 35.8% of all pts received antiemetic prophylaxis at cycle 1); both TEAEs declined notably in subsequent cycles. Rates of drug discontinuation, dose reduction, and drug interruption due to nausea and vomiting were generally low (Table). Conclusions: Most nausea and vomiting events were reported during the first 3 wks of treatment and resolved. Appropriate prophylaxis of nausea and vomiting is a key management strategy and allows pts to benefit from longer treatment durations with T-DXd. Ongoing studies are exploring the implementation and impact of prophylaxis for T-DXd–related emesis. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 , NCT03734029 , NCT03505710 , NCT04644237 , NCT02564900 . [Table: see text]

Body composition measures as a determinant of alpelisib-related toxicity.

e13093 Background: Body composition has emerged as an important prognostic factor in patients treated with cancer. Severe depletion of skeletal muscle, sarcopenia, has been associated with poor performance status and worse oncological outcomes. We studied patients with metastatic breast cancer receiving alpelisib, to determine if sarcopenia and additional body composition measures accounting for muscle and adiposity are associated with toxicity. Methods: A retrospective observational analysis was conducted, including 38 women with metastatic breast cancer and a PIK3CA mutation, treated with alpelisib as advanced line of therapy. Sarcopenia was determined by measuring skeletal muscle cross-sectional area at the third lumbar vertebra using computerized tomography. Various body composition metrics were assessed along with drug toxicity, dose reductions, treatment discontinuation, and hospitalizations. Results: Sarcopenia was observed in half of the patients (n=19, 50%), spanning normal weight, overweight, and obese individuals. Among the body composition measures, lower skeletal muscle density (SMD) was associated with an increased risk of treatment-related hyperglycaemia (P=0.03). Additionally, lower visceral adipose tissue (VAT) was associated with alpelisib-induced rash (P=0.04) and hospitalizations (P=0.04). Notably, alpelisib treatment discontinuation was not impacted by alpelisib toxicity. Conclusions: Body composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to predict toxicity, allowing for personalized therapeutic observation and intervention.

Combined drug anti-deep vein thrombosis therapy based on platelet membrane biomimetic targeting nanotechnology

After orthopedic surgeries, such as hip replacement, many patients are prone to developing deep vein thrombosis (DVT), which in severe cases can lead to fatal pulmonary embolism or major bleeding. Clinical intervention with high-dose anticoagulant therapy inevitably carries the risk of bleeding. Therefore, a targeted drug delivery system that adjusts local DVT lesions and potentially reduces drug dosage and toxic side effects important. In this study, we developed a targeted drug delivery platelet-derived nanoplatform (AMSNP@PM-rH/A) for DVT treatment that can simultaneously deliver a direct thrombin inhibitor (DTI) Recombinant Hirudin (rH), and the Factor Xa inhibitor Apixaban (A) by utilizing Aminated mesoporous silica nanoparticles (AMSNP). This formulation exhibits improved biocompatibility and blood half-life and can effectively eliminate deep vein thrombosis lesions and achieve therapeutic effects at half the dosage. Furthermore, we employed various visualization techniques to capture the targeted accumulation and release of a platelet membrane (PM) coating in deep vein thrombosis and explored its potential targeting mechanism.

Recent Advances in Targeted Therapies for Infantile Hemangiomas.

Targeted therapy for infantile hemangiomas (IHs) has been extensively studied as they can concentrate drugs, increase therapeutic efficacy and reduce drug dosage. Meanwhile, they can extend drug release times, enhance drug stability, decrease dosing frequency, and improve patient compliance. Moreover, carriers made from biocompatible materials reduced drug immunogenicity, minimizing adverse reactions. However, current targeted formulations still face numerous challenges such as the non-absolute safety of carrier materials; the need to further increase drug loading capacity; the limitation of animal hemangioma models in fully replicating the biological properties of human infantile hemangiomas; the establishment of models for deep-seated hemangiomas with high incidence rates; and the development of more specific targets or markers. In this review, we provided a brief overview of the characteristics of IHs and summarized the past decade's advances, advantages, and targeting strategies of targeted drug delivery systems for IHs and discussed their applications in the treatment of IHs. Furthermore, the goal is to provide a reference for further research and application in this field.

Niosomes as a Promising Therapeutic Approach against Colorectal Cancer: A Focus on the Delivery of Chemotherapeutics and Natural Products.

Nanotechnology has emerged as an effective approach to cancer treatment, including Colorectal Cancer (CRC). While conventional treatments, such as chemotherapeutic agents, are used to manage CRC, their efficacy can be improved using drug delivery systems that enhance their bioavailability and reduce side effects. Niosomes, polymeric nanoparticles, have shown promise as biocompatible vehicles that can transport hydrophilic and lipophilic molecules. This can result in reduced drug dosage and increased efficacy. This review examines the use of niosomal formulations as a delivery platform for treating CRC and provides practical insights into their clinical applications.

A first-in-human, phase I, dose-escalation study to evaluate pharmacokinetics, safety, and tolerability of KD6001, a novel anti-CTLA-4 monoclonal antibody (mAb) in patients with advanced solid tumors.

e14501 Background: KD6001, a novel fully human anti-CTLA4 IgG1 monoclonal antibody, exhibits immunomodulatory effects, enhances T-cell-mediated antitumor immune response and shows promising activity in preclinical models of solid tumors. Here we present the pharmacokinetics, safety and tolerability data from the phase 1 study of KD6001 (NCT05230290) in patients with advanced solid tumors. Methods: patients were enrolled in a 3+3 dose escalation phase 1 study with the following pre-defined KD6001 cohorts: 0.2mg/kg, 1mg/kg, 3mg/kg or 6mg/kg, every 2 weeks via intravenous infusion for 4 cycles. The primary objective was to evaluate the safety and tolerability of KD6001 and determine the MTD/RP2D. The secondary objectives were to measure antitumor activity, immunogenicity and pharmacokinetics (PK). All AEs are graded using NCI CTCAE v5.0. Efficacy assessments are per RECIST 1.1. Blood samples are obtained for pharmacokinetics (PK) and for immunogenicity assessments, measured by the development of anti-drug antibodies. Results: The study had been completed. Thirteen pts with melanoma had been enrolled and treated at 0.2 mg/kg (n = 1), 1mg/kg (n = 3), 3 mg/kg (n = 6) and 6mg/kg (n = 3) at Beijing Cancer Hospital. The average age was 57.2 years (range 34-68). Baseline ECOG scores were 0 (n = 5), 1(n = 8) with all pts. Seven pts (53.85%) received ≥ 2 lines of previous systemic therapies and 12 pts (92.31%) received previous PD-1/PD-L1 treatment. KD6001 was well-tolerated with no dose-limiting toxicities (DLTs) observed, nor was the MTD reached at the highest doses administered. All the thirteen pts had at least one adverse event during treatment, and eleven of them (84.62%) had Treatment Related Adverse Events (TRAEs), most of which were Grades 1-2. There were no permanent drug discontinuation or deaths due to adverse events. Pharmacokinetic analysis indicated a linear correlate between the drug exposure (Cmax, AUC0-t and AUC0-inf) and study drug dosages evaluated. The geometric mean T1/2 was 10 days (CV%: 31%). The peak concentration and exposure level increased proportionally to dose from 0.2mg/kg to 6 mg/kg. No anti-drug antibodies were detected in any of the patient’s serum samples. Clinical efficacy was observed in 12 evaluable pts: 3 patients at 3mg/kg had a stable disease (SD) and 1 patient at 3mg/kg had a confirmed partial response (PR). The ORR of the 3mg/kg dose group was 16.7% (1/6), the DCR was 66.67% (4/6). The median PFS was 109 days and the median OS was not reached. Conclusions: KD6001 showed promising antitumor activity and a tolerable safety profile in patients with advanced solid tumors. Hence, 3mg/kg was selected as the RP2D. Clinical trial information: NCT05230290 .

Updated results from ALTER-S002: A single-arm multicenter trial of the combination of anlotinib with chemotherapy in patients with stage IIB classic osteosarcoma of the extremity.

11529 Background: The overexpression of multiple tyrosine kinase receptors in osteosarcoma indicated a promising therapy targeting these receptors. Anlotinib is a multi-targeted tyrosine kinase inhibitor that potentially inhibits tumor angiogenesis. The combination of anti-angiogenic drugs with chemotherapeutic agents is proposed to act synergistically to achieve favorable tumor control, especially as the neoadjuvant therapy. We had reported the neoadjuvant therapy data of anlotinib in combination with chemotherapy for treatment-naive stage IIB classical osteosarcoma of the extremity in the 2023 ESMO congress. Here we report an update on the effectiveness and safety of the follow-up. Methods: In this open-label, single-arm, multicenter phase II clinical trial. Eligible patients(pts) were aged 12-40 years with histologically confirmed primary localized extremity classic osteosarcoma, stage IIB, operable. Pts received anlotinib (10mg, po, d1-14, q3w), doxorubicin (A) (20-25mg/m2 iv, d1-3, q3w) and cisplatin (P) (70-90mg/m2, iv, d1, q3w) for the first nine weeks. Pts underwent radical surgery after the exclusion of contraindications at week 10. After surgery, pts received A+P at weeks 12-14, and anlotinib plus A+P at weeks 15-20 with the drug dose unchanged. Since week 21, anlotinib (12mg, po, d1-14, q3w) monotherapy was maintained until week 104 or the occurrence of an EFS event. The primary endpoint was 24-month EFS rate, secondary endpoints were 36-month EFS rate, local recurrence rate, lung metastasis rate, 3-year OS rate and safety. Results: From May 2020 to Apr 2022, 52 eligible pts were enrolled, while 51 pts underwent surgery after 3 cycles of neoadjuvant therapy. At the data cut-off date (Oct. 2023), the median EFS was not reached, 12 and 24-month EFS rates were 84.18% (95% CI :70.82, 91.77) and 73.43% (95% CI :57.40, 84.21), respectively. The stratified analysis of EFS showed that the length and diameter of the target lesion are independent prognostic factors. The median OS was not reached, the 24-month OS rate was 95.92% (95% CI :84.65, 98.96). Among the 51 pts who underwent surgical treatment, 12(23.53%, 95% CI: 12.79, 37.49) pts experienced recurrence or metastasis. Most treatment-related adverse events (TRAEs) were grade 1-2. Grade 3/4 TRAEs (≥20%) included neutropenia (51.92%), leukopenia (38.46%), thrombocytopenia (36.54%) and anemia (32.69%). Conclusions: The updated results suggested that anlotinib combined with doxorubicin and cisplatin in the perioperative period showed favorable efficiency and manageable adverse events in Stage IIB classic osteosarcoma of the extremity. Clinical trial information: ChiCTR 2000033298.

Ambulatory Blood Pressure Parameters Among Men With Hypogonadism Treated With Testosterone Transdermal Therapy

ObjectiveStudies are needed to examine the effects of testosterone replacement therapy on ambulatory blood pressure (BP) parameters. This study assessed a testosterone transdermal system (TTS) using 24-hour ambulatory BP monitoring. MethodsIn a single-arm, noninferiority trial conducted at 41 US sites, 168 men (mean age: 56.2 years) with hypogonadism not receiving testosterone replacement therapy in the past 6 months were enrolled and received ≥1 study drug dose. Nightly TTS treatment was administered for 16 weeks (starting dose: 4 mg/d; min, max dose: 2, 6 mg/d) to achieve testosterone concentration of 400−930 ng/dL. The primary endpoint was mean change from baseline to week 16 in 24-hour systolic BP (SBP). Noninferiority was determined based on the upper bound of the 2-sided 95% CI <3.0 mmHg. ResultsSixty-two men had ≥85% study drug compliance and a valid week 16 ambulatory BP monitoring session. Mean change from baseline to week 16 in 24-hour average SBP was 3.5 mmHg (95% CI, 1.2−5.8 mmHg; n = 62). Since the upper limit of the CI was >3 mmHg, an effect of TTS could not be ruled out. Mean changes were larger at daytime vs nighttime and in subgroups of men with vs without hypertension. Cardiovascular adverse events were rare (<2%) and nonserious; no major cardiovascular adverse events were reported. ConclusionA meaningful effect of 16-week TTS treatment on 24-hour average SBP among men with hypogonadism could not be ruled out based on the study’s noninferiority criterion. The magnitude of mean changes observed may not be clinically meaningful regarding cardiovascular events.

Impact on chemotherapy induced peripheral neuropathy of nadunolimab, a first-in-class monoclonal antibody against IL1RAP, in patients with pancreatic cancer, with supportive mouse model data.

4148 Background: Chemotherapy induced peripheral neuropathy (CIPN) is one of the major nonhematological adverse events arising from chemotherapies. CIPN is a neuroinflammatory condition that can be driven by immune cell activation and interleukin-1 (IL-1) release. Nadunolimab is a fully humanized monoclonal IgG1 antibody targeting IL1 receptor accessory protein (IL1RAP). Through binding IL1RAP, nadunolimab can induce ADCC of IL1RAP-expressing tumor cells and inhibits tumor-promoting signals mediated by both IL-1α and IL-1β in the tumor microenvironment. The phase I/IIa CANFOUR trial of nadunolimab in combination with nab-paclitaxel and gemcitabine (GN) in previously untreated, unresectable, locally advanced or metastatic PDAC, showed promising efficacy with median OS: 13.2 months; median iPFS: 7.2 months; 1-year survival: 58% and iORR: 33%, with a good safety profile. Notably, only 1 of 73 patients reported a grade ≥ 3 peripheral neuropathy suggesting that targeting IL1RAP may also alleviate the neuroinflammation leading to CIPN. Methods: To assess the potential neuroprotective activity of nadunolimab, we investigated the impact of nadunolimab on CIPN in the CANFOUR trial where 73 PDAC patients received nadunolimab at 1 mg/kg (n=20), 2.5 mg/kg (n=20), 5 mg/kg (n=25) or 7.5 mg/kg (n=8) in combination with GN. Adverse events were monitored at weekly to biweekly intervals. Relations between study drugs dosing and occurrence, severity and timing of adverse events indicative of CIPN were investigated using exploratory statistical analyses. In mice, CIPN was induced by i.p. administration of vincristine at 0.5 mg/kg, or nab-paclitaxel at 4 mg/kg. The effects of an anti-mouse IL1RAP surrogate antibody (i.p. at 10 mg/kg) on CIPN were evaluated using electronic von Frey apparatus, Parallel Rod Floor apparatus and grip strength meter. Results: Among the 73 PDAC patients in CANFOUR, patients in the individual 2.5 mg/kg, 5 mg/kg and 7.5 mg/kg dose groups all had trends towards lower incidence of onset and longer time to onset of CIPN compared to the 1 mg/kg group. When pooled, patients in the 2.5-7.5 mg/kg dose groups compared to the 1 mg/kg dose group had a lower incidence of any-grade CIPN; 36% vs 60% (Chi-square test p=0.06) and a significantly longer time to onset; median not estimable vs 112 days (hazard ratio=0.48, log-rank p=0.04). In mice, vincristine and nab-paclitaxel caused long-lasting (2 weeks) CIPN. This was abrogated by co-administration of the anti-mouse IL1RAP surrogate antibody, without a negative impact on motor performance, blood values or animal body weight. Conclusions: Data from PDAC patients receiving nadunolimab + GN and experiments in preclinical models suggest that targeting IL1RAP by nadunolimab may combine antitumor activity with potent reduction of CIPN. Clinical trial information: NCT03267316 .

Overview of self-medication pharmaceutical preparations by the public

Introduction: self-medication is an effort made by an individual to obtain medication and use it without diagnosis, prescription, supervision, or consultation with a doctor to treat certain minor illnesses. Self-medication is self-medication without a doctor's prescription. In disease treatment, risks such as misdiagnosis, use of excessive drug doses, and long-term use can cause adverse effects on patients. Objective: to determine the description of the public's use of self-medicated pharmaceutical preparations. Methods: This type of research uses a descriptive method, namely research that includes surveys with data collection in the form of questionnaires with a total of 81 respondents. The sampling method uses Non-Probability Sampling with Purposive Sampling techniques using an open-ended questionnaire format in collecting data and recording reports. Result: results of research data collection that the description of the use of pharmaceutical preparations by self-medication in the Bung Permai Housing Community is that 81 respondents (100.00%) carry out self-medication, the source of drug information is from print and electronic media, namely 36 respondents (44.45%), the place of purchase of medicine was at the pharmacy/clinic, namely 43 respondents (53.02%), the disease suffered was fever, 23 respondents (28.40%), and the pharmaceutical preparation used was paracetamol, 27 respondents (33.33%). Conclusion: the description of self-help's use of pharmaceutical preparations in the Permai Community Housing is mostly self-medication. Therefore, there is a need for better education and supervision of using pharmaceutical preparations independently to increase understanding and safety in self-medication. It is hoped that in the future, there will be research on public knowledge and behavior regarding self-medication of pharmaceutical preparations so that changes in respondents' knowledge and behavior can be seen after being given good and correct information.

Comparison of the Safety and Efficacy of Remimazolam Besylate versus Dexmedetomidine for Patients Undergoing Fiberoptic Bronchoscopy: A Prospective, Randomized Controlled Trial.

Remimazolam besylate is a novel ultra-short-acting benzodiazepine that is rapidly hydrolyzed to zolpidem propionic acid by tissue lipases. We designed this study to compare the safety and efficacy of remimazolam besylate alfentanil versus dexmedetomidine-alfentanil for fiberoptic bronchoscopy (FB). One hundred and twenty patients undergoing FB into this prospective randomized controlled trial were divided into two groups. The anesthesia induction consisted of 6 mg/kg/h of remimazolam besylate in the RA group and 0.5 μg/kg of dexmedetomidine in the DA group. 1-2 mg/kg/h of remimazolam besylate or 0.2-0.7 µg/kg/h of dexmedetomidine were administered to maintain during FB. The lowest oxygen saturation, success rate of FB, hemodynamics, time metrics, bronchoscopy feasibility, drug dose requirements, patient and bronchoscopist satisfaction scores, occurrence of intraoperative awareness, number of patients willing to repeat FB with the same sedation regimen, and occurrence and severity of adverse events. The lowest oxygen saturation during the FB was significantly higher in the RA group (P = 0.001). Compared with the variables in the DA group, peripheral oxygen saturation, systolic blood pressure, and diastolic blood pressure were significantly lower at T2 and T3 in the RA group (P < 0.05). Heart rates were significantly higher from T2 to T4 in the DA group (P < 0.05). More patients experienced bradycardia in the DA group (P = 0.041). Compared with time metrics in the DA group, the induction time, fully-alert time, and recovery room-leaving time were all significantly shorter in the RA group (P < 0.05). The bronchoscopy feasibility scores in the RA group were significantly lower at T2, whereas they were lower at T3 in the DA group (P < 0.05). Remimazolam besylate is superior to dexmedetomidine when combined with alfentanil during FB, promoting faster patients' recovery, better operative conditions and respiratory stability with similar rates of occurrence and severity of adverse events.

Clinical impact and financial feasibility of remote oncology pharmacists' roles in community oncology practices.

1545 Background: The clinical and financial impact of oncology-trained pharmacists in the community oncology setting has not been well documented. The US Oncology Network has introduced a novel remote oncology pharmacist model which provides clinical services to oncology community practices to alleviate the burden on oncologists, enhance patient care, and improve workflows. Methods: Oncology-trained pharmacists remotely reviewed chemotherapy regimens across 12 community oncology practices. Pharmacists identified opportunities to modify therapy based on clinical criteria, waste reduction, and/or financial stewardship. These modifications were discussed with the treatment team or implemented in accordance with practice-approved policies. Clinical and financial metrics were tracked to assess the overall impact of the pharmacist interventions and provider time saved. Results: From January 1, 2023, through December 31, 2023, 27,938 reviews were documented for 19,962 patients. Among these reviews, the majority (14,572, 73%) required modification by the pharmacist, and many (3,005, 21%) were deemed clinically significant by the intervening pharmacist. The most common clinically significant interventions included changes to anticancer drug doses (1155, 38%), modifications to supportive care (742, 25%) and recommendations for additional monitoring (426, 14%). Across 12 practices, 63 drug-related workflow policies were implemented allowing pharmacists to autonomously auto-substitute products, order laboratory tests and adjust chemotherapy doses. These policies saved over 600 hours of physician time. Pharmacist involvement resulted in medication-related margin improvements totaling $9.3M. Practices also experienced a $4.3M reduction in the total cost of care in medication expenses. The cost of the pharmacists during this period was $1.4M, equating to a 560% return on investment compared to margin improvement. Conclusions: Community oncology practices operate within a resource-constrained model with limited access to oncology pharmacists. As invaluable members of the care team, pharmacists identified opportunities to significantly enhance clinical care by focusing on medication safety, dosing, and regimen optimization, while demonstrating a tremendous financial impact on small-scale budgets. Oncology-trained pharmacists play a vital role in alleviating care burden of the clinical team by collaboratively developing practice-approved policies and reviewing clinical orders in a high-risk patient population.