All Adverse Events Research Articles

Osimertinib Efficacy and Safety in Treating Epidermal Growth Factor Receptor Mutation-Positive Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis.

This study compared the safety and efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), with those of other TKIs and its use alongside bevacizumab in patients with EGFR mutation-positive advanced non-small-cell lung cancer. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were used to conduct extensive searches for relevant randomized controlled trials until January 30, 2024. Osimertinib monotherapy favored disease control rate, whereas the comparator treatment arm favored overall survival. Using subgroup analysis, the objective response rate and progression-free survival (PFS) were significantly elevated by Osimertinib monotherapy compared with pemetrexed combined with carboplatin or cisplatin. The comparator treatment arm receiving gefitinib or erlotinib significantly favored progression-free survival and overall survival compared with osimertinib monotherapy. In patients treated with osimertinib monotherapy, the incidence of all adverse events (AEs) decreased compared with comparator treatment arm. Anemia was the only AE associated with osimertinib monotherapy. Pemetrexed combined with carboplatin or cisplatin resulted in greater loss of appetite than osimertinib monotherapy. The most associated AE of osimertinib monotherapy was diarrhea, according to network analysis. Although its efficacy is not consistent with other EGFR TKIs, osimertinib was associated with a decrease in AEs in patients with EGFR mutation-positive advanced non-small-cell lung cancer.

Efficacy and safety of maintenance intravenous immunoglobulin in generalized myasthenia gravis patients with acetylcholine receptor antibodies: A multicenter, double-blind, placebo-controlled trial.

Prospective, randomized, controlled trials of intravenous immunoglobulin (IVIG) maintenance therapy in myasthenia gravis (MG) are lacking. In this trial, we evaluated the safety and efficacy of caprylate/chromatography-purified IVIG; (IGIV-C) in patients with generalized MG undergoing standard care. Sixty-two patients enrolled in this phase 2, multicenter, international, randomized trial (1:1 IGIV-C [2 g/kg loading dose; 1 g/kg every 3 weeks through week 21] or placebo). Efficacy was assessed by changes in Quantitative MG (QMG) score at week 24 versus baseline (primary endpoint) and percentage of patients with clinical improvement in QMG, MG Composite (MGC), and MG-Activities of Daily Living (MG-ADL) scores (secondary endpoints). Safety assessments reported all adverse events (AEs). The change in QMG at 24 weeks was -5.1 for IGIV-C and -3.1 for placebo (p = .187). Seventy percent of patients in the IGIV-C group had improvement in MG-ADL (≥2-point decrease) versus 40.6% in the placebo group (p = .025). Patients showing clinical improvement in QMG and MGC (≥3-point decrease) were 70.0% for IGIV-C versus 59.4% for placebo (p = .442) and 60.0% for IGIV-C versus 53.1% for placebo (p = .610). IGIV-C was well tolerated; serious AEs were similar between arms. Three of four MG exacerbations requiring hospitalizations occurred in the IGIV-C arm with one death. Several efficacy parameters showed numerical results greater than those seen in the placebo group. This was a small study and may have been underpowered to see significant differences. Additional studies may be warranted to fully determine the efficacy of IVIG maintenance therapy in MG.

Three-dimensional conformal radiation therapy with concurrent chemotherapy for stage III non-small cell lung cancer: protocol for a systematic review and meta-analysis

IntroductionLung cancer continues to be a common form of cancer worldwide and a primary contributor to cancer-related fatalities. Non-small cell lung cancer (NSCLC) is the most prevalent form, making up...

Safety, pharmacokinetics, and pharmacodynamics of sofnobrutinib, a novel non-covalent BTK inhibitor, in healthy subjects: First-in-human phase I study.

Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in exvivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases.

Cost of Pegfilgrastim for the Prophylaxis of Chemotherapy-induced Febrile Neutropenia in Patients with Breast Cancer Receiving Perioperative Chemotherapy in Daily Practice in Japan: A Posthoc Analysis in a Single-center Retrospective Study.

This study aimed to estimate the medical costs associated with febrile neutropenia (FN) prophylaxis with pegfilgrastim and evaluate its impact on survival outcomes in daily practice in Japan. In this single-center retrospective study, we obtained data from 296 Japanese patients with breast cancer receiving fluorouracil, epirubicin, and cyclophosphamide (FEC)-100 chemotherapy; the patients were divided into the pegfilgrastim and non-pegfilgrastim groups. We analyzed the median costs of chemotherapy, drugs for all adverse events (AEs) and FN, and hospitalization due to FN. We also assessed the survival outcomes. The pegfilgrastim group showed a significantly higher median total cost (JPY 872320.0 vs. JPY 466715.0, p<0.001). This difference was associated with the prophylactic use of pegfilgrastim. The median costs of the drugs for all AE treatments were JPY 9030.4 and JPY 24690.6, with the non-pegfilgrastim group showing a significantly higher cost (p<0.001). In 11 patients hospitalized for FN management, no significant difference in hospitalization cost was observed between the pegfilgrastim and non-pegfilgrastim groups (JPY 512390.0 vs. JPY 307555.0, p=0.102). No significant difference in the 3-year overall survival was observed between the pegfilgrastim and non-pegfilgrastim groups (79.9% vs. 88.3%, p=0.672). In this study, although the total medical cost in daily practice increased because of primary prophylaxis with pegfilgrastim, the 3-year overall survival was not impacted by the use of pegfilgrastim. Our study data suggested that the primary prophylaxis pegfilgrastim should be used during FEC-100 chemotherapy based on the patient-related FN risk factors, instead of routine use.

Vectored Thermal Pulsation as a Treatment for Meibomian Gland Dysfunction: A Review Spanning 15 Years.

The LipiFlow Thermal Pulsation System received its first marketing clearance for the treatment of meibomian gland dysfunction (MGD) 13years ago. Since then, the evidence evaluating the effectiveness and safety of LipiFlow as a treatment for MGD has grown significantly. The objective of this comprehensive review was to summarize all clinical reports evaluating the effectiveness and safety of LipiFlow over the past 15years. The literature was systematically reviewed, and 55 unique articles had subjective (patient-reported outcomes) and objective (meibomian gland function, tear production, and ocular staining) outcomes for extraction. Data were collected from 2101patients and 3521 eyes treated with LipiFlow. Of these, effectiveness was evaluated in 2041patients and 3401 eyes, and safety was evaluated in 1448 patients and 2443 eyes. Taken together, the studies demonstrate that a single 12-min treatment with LipiFlow safely improves signs and symptoms of MGD and associated evaporative dry eye disease (DED), and the benefits persist up to 3years in some cases. The findings are corroborated by multiple meta-analyses and consensus guidelines. While some studies showed that daily eyelid hygiene, warm compress, and/or massage had a similar benefit to a single LipiFlow, these treatments were limited by inconvenience, discomfort, and non-compliance. The majority of studies evaluating safety reported no discomfort or pain associated with LipiFlow treatment, which supports the patient acceptability of LipiFlow therapy. All adverse events (AEs) related to LipiFlow were transient, non-vision-threatening, and did not require treatment. No studies reported serious AEs. The data obtained from 55 studies conducted globally overwhelmingly show that LipiFlow is effective and safe for the treatment of MGD and associated evaporative DED. The conclusions are supported by the diversity of the patient populations (geography, race, disease severity, and diagnosis), the large population treated with LipiFlow, the meta-analyses, and that this review analyzed all published clinical studies to date.

Efficacy and Safety of TAS-303 in Female Patients With Stress Urinary Incontinence: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.

We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).

Efficacy and safety of HAIC combined with tyrosine kinase inhibitors versus HAIC monotherapy for advanced hepatocellular carcinoma: a multicenter propensity score matching analysis.

This study aimed to assess the clinical efficacy and safety of the combined approach involving hepatic arterial infusion chemotherapy (HAIC) and tyrosine kinase inhibitors (TKIs) for the treatment of advanced hepatocellular carcinoma (HCC). In this multicenter retrospective study conducted from January 2020 to December 2023, we reviewed advanced HCC patients who were treated either with HAIC alone or with a combination of HAIC and TKIs. To address initial disparities between the two groups, we employed propensity score matching (PSM). Tumor response evaluation was performed following RECIST 1.1 criteria. We compared survival outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), between the two treatment groups. Safety assessments were conducted for all patients. Following the eligibility review, 138 patients underwent combined treatment with HAIC and TKIs (HT group), while 198 patients received HAIC monotherapy (HA group) and met the inclusion criteria for enrollment in this study. After PSM, 107 patients were assigned to each group. The HT group exhibited a longer median OS (18.0 versus 8.8 months; hazard ratio [HR], 0.52, p < 0.001) compared to the HA group. Median PFS was also longer in the HT group, although without statistical significance (6.0 versus 4.7 months; HR, 0.85, p = 0.265). The HT group demonstrated a higher ORR (41.1% versus 25.2%; p = 0.020). No significant differences were observed between the two groups in the incidence of all adverse events (AEs) or grade 3/4 AEs (any grade: 81.2% for HT versus 78.8% for HA, p = 0.68; grade 3/4: 18.1% for HT versus 13.6% for HA, p = 0.29). Importantly, all AEs were manageable and acceptable. Notably, no grade 5 AEs occurred in either group. Combination therapy involving HAIC and TKIs effectively prolonged survival in advanced HCC patients. It represented a preferable alternative to HAIC monotherapy, with manageable safety.

Effectiveness and safety of empegfilgrastim (Extimia®) in patients with solid tumors receiving cytotoxic therapy: final results of the DEFENDOR study

Aim. To evaluate the effectiveness and safety of Extimia® (empegfilgrastim, JSC "BIOCAD") in reducing the frequency, duration of neutropenia, the incidence of febrile neutropenia (FN) and infections caused by FN in patients with solid tumors receiving myelosuppressive therapy. Materials and methods. The paper presents the final results of a multicenter prospective observational post-marketing study of the safety and effectiveness of Extimia® (empegfilgrastim) in patients with solid tumors receiving cytotoxic therapy. For the primary prevention of FN, all patients received empegfilgrastim at 7.5 mg subcutaneously once per course of chemotherapy (CT) 24 hours after the end of CT administration. The primary endpoint included an assessment of the relative dose-intensity (RDI) of the CT courses administered. The endpoints of interest included the assessment of the RDI of CT courses by nosology and CT regimen, the frequency of dose-limiting neutropenia, and the incidence of all adverse events (AEs) in patients who received at least one dose of the study medication, including serious AEs. Results. From February 2021 to December 2022, 3218 patients with various malignancies were included in 41 study centers of the Russian Fede- ration. Of these, 3217 (99.97%) patients received at least one dose of the study drug, and 2663 (82.8%) patients were included in the RDI evaluation population according to the study protocol. The mean age in this group was 56.9 (18–84) years. RDI ≥85% was achieved in 2,415 (90.7%) patients. The mean RDI was 96.2%, with a median of 100%. FN risk factors were present in 1216 (45.7%) patients, with age ≥65 years being the most common risk factor at 761/2663 (28.6%). It should be noted that in patients younger than 65 years, the RDI was 91.5%, and in elderly patients (≥65 years) 88.7%. Dose-limiting neutropenia was reported in 19 (0.7%) patients. There were 74 cases of grade 3–4 AEs (according to CTCAE v.5) in 59 (1.8%) patients. The most common were neutropenia, anemia, and diarrhea in 19 (0.7%), 7 (0.2%), and 6 (0.2%) patients, respectively. Serious AEs were reported in 17 patients (0.5%). Conclusion. Primary prophylaxis of FN with long-acting granulocyte colony-stimulating factor empegfilgrastim effectively maintains RDI in various nosological and therapeutic groups of patients with different CT regimens in real-world clinical practice.

Pharmacokinetic Bioequivalence and Safety Assessment of Two Venlafaxine Hydrochloride Extended-Release Capsules in Healthy Chinese Subjects Under Fed Conditions: A Randomized, Open-Label, Single-Dose, Crossover Study.

Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR® XR in healthy Chinese volunteers under fed conditions. A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) and the maximum observed concentration (Cmax). A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC0-t and Cmax of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80-125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity. Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied. This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn/index.html ) with registration number CTR20211243, date: June 1, 2021.

Factor XI as a new target for prevention of thromboembolism in cardiovascular disease: a meta-analysis of randomized controlled trials.

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease. The use of conventional anticoagulants carries potential side effects, mainly bleeding. Drugs targeting Factor XI (FXI) have been investigated in randomized controlled trials as a new option with more favorable outcomes. A comprehensive literature search was conducted to identify relevant studies comparing FXI inhibitors to placebo or standard therapy. The primary outcomes were incidence of all bleeding events, major bleeding, and thromboembolism. Secondary outcomes included incidence of all adverse events (AE), serious AE, and all-cause mortality. A total of 11 studies involving 10,536 patients were included. FXI inhibitors were associated with a trend toward reduction of bleeding events and incidence of thromboembolism compared to the control group (placebo/standard therapy). There was no statistically significant difference between both groups in terms of adverse events and all-cause mortality. When compared to enoxaparin, FXI inhibitors significantly reduced the risk of bleeding events (RR = 0.42, 95% CI: 0.23-0.76, P = 0.004) and thromboembolism (RR = 0.59, 95% CI: 0.44-0.77, P = 0.001). On the other hand, when compared to DOACs, FXI inhibitors were associated with a significant reduction in bleeding events but not thromboembolism. Whereas, compared to placebo, FXI inhibitors did not increase the risk of bleeding events, adverse events, or all-cause mortality (P > 0.05). FXI inhibitors could be a safer and more potent option for prevention of thromboembolism than conventional therapy.

A single-dose, randomized, open-label, four-period, crossover equivalence trial comparing the clinical similarity of the proposed biosimilar rupatadine fumarate to reference Wystamm® in healthy Chinese subjects.

The aim of this study was to evaluate the bioequivalence of two formulations of rupatadine (10-mg tablets) under fasting and fed conditions in healthy Chinese subjects. A total of 72 subjects were randomly assigned to the fasting cohort (n = 36) and fed cohort (n = 36). Each cohort includes four single-dose observation periods and 7-day washout intervals. Blood samples were collected at several timepoints for up to 72h post-dose. The plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC-MS/MS method. The non-compartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation of the reference formulation, a reference-scaled average bioequivalence or average bioequivalence method was used to evaluate the bioequivalence of the two formulations. For the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of the maximum observed rupatadine concentration (Cmax; subject standard deviation > 0.294), while the average bioequivalence method was used to evaluate the bioequivalence of the area under the rupatadine concentration-time curve from time 0 to the last detectable concentration (AUC0-t) and from time 0 to infinity (AUC0-∞). The geometric mean ratio (GMR) of the test/reference for Cmax was 95.91%, and the upper bound of the 95% confidence interval was 95.91%. For AUC0-t and AUC0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%-103.90%) and 98.71% (93.93%-103.75%), respectively. For the fed status, the subject standard deviation values of Cmax, AUC0-t, and AUC0-∞ were all <0.294; therefore, the average bioequivalence method was used. The GMR and 90% CI for Cmax, AUC0-t, and AUC0-∞ were 101.19% (91.64%-111.74%), 98.80% (94.47%-103.33%), and 98.63% (94.42%-103.03%), respectively. The two-sided 90% CI of the GMR for primary pharmacokinetic endpoints of desloratadine and 3-hydroxydesloratadine was also within 80%-125% for each cohort. These results met the bioequivalence criteria for highly variable drugs. All adverse events (AEs) were mild and transient. The test drug rupatadine fumarate showed a similar safety profile to the reference drug Wystamm® (J. Uriach y Compañía, S.A., Spain), and its pharmacokinetic bioequivalence was confirmed in healthy Chinese subjects based on fasting and postprandial status. http://www.chinadrugtrials.org.cn/index.html, identifier CTR20213217.

Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program

BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII.MethodsThis disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022.ResultsAs of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and − 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died.ConclusionsTo date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.

Efficacy and tolerability of tirbanibulin 1% ointment in the treatment of cancerization field: a real-life Italian multicenter observational study of 250 patients.

Tirbanibulin 1% ointment is approved for the field treatment of Olsen grade I actinic keratoses (AKs) of the face and scalp. We performed a multicenter retrospective study involving 15 dermatologic units in Italy to investigate the efficacy and tolerability of tirbanibulin in a real-life setting. 250 patients were enrolled. Tirbanibulin, 1% ointment, was applied daily for five consecutive days. The efficacy of treatment was measured with modifications of the Actinic Keratosis Area and Severity Index (AKASI). A satisfactory response was defined by complete (100% reduction in the number of lesions) or partial clearance (75-99%) of treated AKs. Overall, the AKASI score was significantly reduced in the studied population (mean, from 4.1 ± 2.7 to 1.4 ± 1.5; P < 0.001). A satisfactory response was observed in 222 (88.8%) cases. The proportion of satisfactory responses was higher when follow-up was performed after 8 weeks (34/35, 97.1%). The reduction in AKASI was significant in patients with Olsen grade II or III lesions (from 5.3 ± 2.8 to 1.6 ± 1.6; P < 0.001). A satisfactory response was observed in 91/104 (87.5%) cases. AKASI reduction was also significant in patients with trunk or limb AKs (from 7.0 ± 1.3 to 2.0 ± 1.6; P = 0.018) since a satisfactory response was observed in 7/8 (87.5%) cases. Tirbanibulin was well tolerated; all adverse events (AEs) included transient local reactions at the site of treatment. Overall, 231 patients had at least one AE. Only 7 (2.8%) grade 4 AEs were recorded. Our retrospective study confirmed that tirbanibulin 1% ointment is effective and well tolerated in a real-life setting and is also promising for Olsen grade II and grade III AKs and AKs localized on difficult-to-treat areas.

Abstract CT260: A phase II trial of defactinib combined with avutometinib in patients with metastatic uveal melanoma

Abstract Background: Outcomes remain poor for patients with metastatic uveal melanoma (MUM). Therapies targeting commonly mutated G-protein pathway-associated GNAQ and GNA11 have not been met with clinical success. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single-arm, single-institution, phase II study evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (avutometinib, VS-6766) for the treatment of MUM [NCT04720417]. Defactinib was given 200mg twice daily and avutometinib was given 3.2mg twice a week. Both drugs were given for 3 weeks on and 1 week off (28-day cycle). The primary endpoint of the study is disease control rate (DCR) including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST version 1.1 after two cycles. Secondary endpoints include progression free survival (PFS), overall survival (OS), and safety. The trial was designed using a Simon’s two stage design where in stage I, a total of 8 patients would be accrued and if there are ≤2 overall responses, further enrollment would be stopped with the conclusion that DCR cannot be ≥50%. An additional 10 patients would be accrued in stage II, resulting in a total sample size of 18 patients. Results: Twelve patients with MUM were treated with the combination. Median lines of prior therapy was 2 (range 0-7), with 3 patients (25%) being treatment naïve. After 2 cycles, 6 patients achieved SD (50%) while the other 6 patients developed PD. No patients achieved CR or PR. Median duration of treatment was 2.6 months for all patients, and 5.6 months for patients with SD. With a median follow up of 16.5 months, the median PFS was 2.6 months and median OS was 18.4 months. All adverse events (AE) were Grade 1-2 except one Grade 3 AE of asymptomatic elevated CPK that resolved with holding treatment and did not recur upon restarting. Most common AEs were rash (100%), diarrhea (66.7%), peripheral edema (50%), nausea (50%), fatigue (50%), and blurred vision (41.7%). No dose reductions were required for any patients. Reduction of active ERK (pERK) was observed in 2 patients that achieved SD, but not in 2 patients that had PD. Trial enrollment was stopped early by study sponsors before the anticipated accrual of 18 patients due to no patients having significant reduction in disease. Conclusions: In this phase II study of the combination regimen of FAK and RAF/MEK inhibitors, stable disease was achieved in half of patients with MUM. Treatment was well tolerated with only one transient asymptomatic grade 3 CPK elevation. Further research should seek to elucidate an optimal combination treatment strategy such as FAK and PKC inhibitors for improved blocking of the downstream pathways of GNAQ/GNA11 driver mutations. Citation Format: Rino S. Seedor, Mizue Terai, Amry Majeed, Ryota Tanaka, Andrew E. Aplin, Marlana Orloff, Alfredo A. Molinolo, J Silvio Gutkind, Takami Sato. A phase II trial of defactinib combined with avutometinib in patients with metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT260.

Abstract 5005: Safety and tolerability of multi-epitope HER2 peptide vaccines in combination with trastuzumab emtansine in HER2-positive breast cancer patients with residual disease after neoadjuvant chemotherapy

Abstract Background: Residual disease after neoadjuvant chemotherapy (NAC) in breast cancer (BC) confers poor outcomes. Trastuzumab emtansine (T-DM1) is approved for HER2+ patients with residual disease after NAC. However, many patients still develop recurrence. H2NVAC is a multi-epitope CD4 helper T cell activating vaccine that includes a pool of 4 degenerate HER2-derived HLA-DR epitopes admixed with GM-CSF. Our previous phase I trial showed that this vaccine was safe and generated robust, long-lasting T and B cell immune responses. Method: We conducted a safety run-in phase of H2NVAC in combination with T-DM1 in stage II-III HER2+ BC with residual disease after NAC. Patients were treated with H2NVAC and T-DM1 for 6 cycles, followed by 2 boosters at 3 and 12 months. Dose-limiting toxicity (DLT) was defined as any grade (G) ≥ 3 toxicity occurring within 21 days after the first vaccination. Results: 20 patients were enrolled (median age 51; 27-69 years), including 80% White and 15% Black. 90% had hormone receptor-positive disease. There was no DLT observed in the safety run-in cohort. All adverse events (AEs) during the DLT period were grades 1 and 2, with fatigue being the most common (60% G1, 5% G2), followed by peripheral sensory neuropathy (55% G1, 5% G2), and injection site reaction (50% G1). Across all treatment cycles, the 10 most common AEs that were at least possibly related to treatment in all cycles are summarized in the table below. The injection site reaction was the most common AE, with 85% G1 and 15% G2. Conclusion: H2NVAC, in combination with T-DM1, was safe, with a favorable side effect profile. There was no DLT observed. The most common AE was injection site reaction, with the majority being G1. A multicenter, randomized, placebo-controlled, phase II trial of H2NVAC vs. placebo in combination with trastuzumab emtansine is currently ongoing through the ACCRU consortium (NCT04197687). Adverse Events Grades 1 2 N % N % Injection site reaction 17 85.0 3 15.0 Aspartate aminotransferase increase 13 65.0 Alanine aminotransferase increase 9 45.0 Fatigue 7 35.0 2 10.0 Peripheral sensory neuropathy 7 35.0 2 10.0 Alkaline phosphatase increase 8 40.0 Nausea 7 35.0 1 5.0 Arthralgia 7 35.0 Myalgia 5 25.0 1 5.0 Platelet count decrease 6 30.0 Citation Format: Saranya Chumsri, Sharmila Giri, Andy J. Ness, David W. Hillman, Nadine Norton, Davitte Cogen, Brian M. Necela, Aziza Nassar, Donald W. Northfelt, Pooja Advani, Rohit Rao, Kostandinos Sideras, Alvaro Moreno-Aspitia, Brenda J. Ernst, Kathryn J. Ruddy, Matthew P. Goetz, Keith L. Knutson. Safety and tolerability of multi-epitope HER2 peptide vaccines in combination with trastuzumab emtansine in HER2-positive breast cancer patients with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5005.

Targeting histamine receptor 4 in cholinergic urticaria with izuforant (LEO 152020): results from a phase IIa randomized double-blind placebo-controlled multicentre crossover trial.

Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects. To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability. Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R. This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU.

Real-World Outcomes of Lip Augmentation Using a Hyaluronic Acid-Based Filler With Low 1,4-Butanediol Diglycidyl Ether Content: A Prospective, Open-Label, Multicenter, Post-marketing Study.

Background 1,4-butanediol diglycidyl ether (BDDE) is the most common cross-linker used to produce hyaluronic acid (HA)-based dermal fillers. However, BDDE may have cytotoxic and potentially mutagenic effects, raising safety concerns. Consequently, manufacturers are developing new HA filler formulations with reduced BDDE levels to mitigate potential biological risks. Here, we sought to evaluate the clinical outcomes of lip augmentation performed using an HA-based filler with a reduced BDDE content (Agex Fill Volume®; Biodue SpA, Barberino Tavarnelle, Italy) in a real-world clinical setting. Methods This was a prospective, open-label, multicenter, post-marketing study conducted over six months. Thirty adult subjects (29 women and one man) who desired a ≥1-point improvement on the validated Lip Fullness Scale 2 (LFS2) were enrolled. The primary efficacy endpoint was the post-procedural increase in the investigator-reported LFS2 compared to baseline. Other endpoints included self-perceived happiness assessed using the Happiness Measure Scale (HMS) and safety. Results Of the study participants, 73% (22/30) demonstrated an improvement of at least one point in their LFS2 scores immediately after treatment compared to baseline, thus qualifying as responders. Six months later, the responder rate, based on LFS2 scores, remained steady at 66.7% (20/30). Importantly, these aesthetic improvements were consistently associated with a positive impact on subject-reported HMS, with a significant difference (p < 0.001) between post-treatment and baseline scores. All adverse events (AEs) reported after treatment were mild. Conclusions Agex Fill Volume®, a HA filler with low BDDE content, provides a safe and effective option for enhancing lip volume in real-world aesthetic settings.

No drug-drug interactions between selective prolyl-tRNA synthetase inhibitor, bersiporocin, and pirfenidone or nintedanib in healthy participants.

Bersiporocin, a potent and selective prolyl-tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open-label, two-part, one-sequence, three-period, three-treatment study was designed to evaluate the effect of drug-drug interactions (DDI) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated, enteric-coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses, and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose of nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. Forty-six participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs, suggesting bersiporocin alone or in combination therapy were well-tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there are no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib.

Homoeopathic eye drops in the treatment of mild-to-moderate dry eye disease: Randomised, prospective, multicentre, single-masked study.

To compare the efficacy and safety of a homeopathic eye drop medicinal product (Homeoptic®) with 0.9% sodium hydrochloride eye drops (Larmabak®) in patients with mild-to-moderate dry eye disease (DED). Prospective, single-masked, observer-blinded, multicentre study on adult patients. Non-inferiority primary endpoint of the relative change between treatment groups in a composite Visual Analogue Scale (VAS) score covering five symptoms of DED, namely pain, itching, sensation of dry eye, impression of foreign body presence and burning, after 30 days of treatment. Details of all Adverse Events (AEs) were recorded and analysed. Ninety three patients were randomised to each treatment arm. At Day 30, the mean VAS symptom score was 26.0 ± 18.8 in the Homeoptic® group and 32.8 ± 21.2 Larmabak® group. Homeoptic® was demonstrated to be non-inferior to Larmabak®: the mean treatment difference of -7 being below the 10 mm upper limit of the 95% CI ([-12.9; -1.0]) pre-set as significant. The superiority of Homeoptic® over Larmabak® was then established with detection of a significant difference between the two treatment groups (p = 0.022). Significant differences between the treatment groups in favour of Homeoptic® were also detected in isolated VAS scores for the symptoms dry eye sensation (p = 0.009) and burning (p = 0.004). Results of ocular surface staining tests to estimate corneal and conjunctival damage as well as patient satisfaction were also significantly in favour of Homeoptic®. No new safety concerns were identified. Homeoptic® is more effective than Larmabak® at relieving the symptoms of DED and constitutes an effective treatment for mild-to-moderate DED.