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Background Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation. Methods To address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints. Results We found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice. Conclusion These data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.

Interleukin-2 (IL-2) and its receptor (IL-2R) are essential in orchestrating immune responses. Their function and expression in the tumor microenvironment make them attractive targets for immunotherapy, leading to the development of IL-2/IL-2R-targeted therapeutic strategies. However, the dynamic interplay between IL-2/IL-2R and various immune cells and their dual roles in promoting immune activation and tolerance presents a complex landscape for clinical exploitation. This review discusses the pivotal roles of IL-2 and IL-2R in tumorigenesis, shedding light on their potential as diagnostic and prognostic markers and their therapeutic manipulation in cancer. It underlines the necessity to balance the anti-tumor activity with regulatory T-cell expansion and evaluates strategies such as dose optimization and selective targeting for enhanced therapeutic effectiveness. The article explores recent advancements in the field, including developing genetically engineered IL-2 variants, combining IL-2/IL-2R-targeted therapies with other cancer treatments, and the potential benefits of a multidimensional approach integrating molecular profiling, immunological analyses, and clinical data. The review concludes that a deeper understanding of IL-2/IL-2R interactions within the tumor microenvironment is crucial for realizing the full potential of IL-2-based therapies, heralding the promise of improved outcomes for cancer patients.

[This corrects the article DOI: 10.3389/fphar.2026.1741851.].

Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. Although there is much promise in this initiative, there are several challenges that need to be addressed, including multidimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long‐term tolerability beyond dose‐limiting toxicities, and the lack of reliable biomarkers for long‐term efficacy. Through the lens of Totality of Evidence and with the mindset of model‐informed drug development, we offer insights into dose optimization by building a quantitative knowledge base integrating diverse sources of data and leveraging quantitative modeling tools to build evidence for drug dosage considering exposure, disease biology, efficacy, toxicity, and patient factors. We believe that rational dose optimization can be achieved in oncology drug development, improving patient outcomes by maximizing therapeutic benefit while minimizing toxicity.

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).

Abstract Background Hyperthyroidism is the most common endocrinopathy in cats and is frequently managed using anti-thyroid medication. Hypothesis/Objectives To develop and validate an algorithm to predict the optimal starting daily dose of thiamazole required to control hyperthyroidism in cats. Animals One hundred eighty-eight client-owned cats with hyperthyroidism for algorithm development (2011-2021) and 45 hyperthyroid cats to validate the algorithm (2022-2024). Methods Retrospective case-control study. Cats with hyperthyroidism controlled medically using thiamazole within a year since diagnosis were enrolled. Controlled dose of thiamazole was categorized into “≤5 mg” or “>5 mg.” Binary logistic regression was performed to explore predictors associated with thiamazole dose. The performance of the final multivariable model in prediction was assessed by receiver operating characteristic (ROC) curve analysis. A cohort of cats subsequently diagnosed with hyperthyroidism and managed chronically with thiamazole were used to test algorithm performance. Results At hyperthyroidism diagnosis, baseline plasma total thyroxine (TT4); (odds ratio [OR] 1.29 [95% CI, 1.19-1.42] per 10 nmol/L; P < .001) and creatinine concentrations (OR 0.83 [95% CI, 0.7-0.96] per 0.1 mg/dL; P = .02) were independent predictors for higher thiamazole dose (>5 mg). The area under the ROC curve was 0.92 (95% CI, 0.88-0.96). In the test cohort, 26 cats controlled on ≤ 5 mg and 19 required >5 mg thiamazole. The predictive model had overall accuracy of 91.1%, sensitivity of 84.2%, and specificity of 96.2%. Conclusions and clinical importance Hyperthyroid cats with higher plasma TT4 and lower creatinine concentrations at diagnosis are likely to require >5 mg total daily dose of thiamazole to achieve euthyroidism.

A study was conducted to develop and validate the warfarin pharmacogenetic dose optimization algorithm considering the clinical pharmacogenetic implementation consortium (CPIC) recommendations for the Asian ethnicity population.The present prospective observational study recruited warfarin-receiving patients. We collected a three ml blood sample for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2 polymorphism assessment during the follow-up visits. Clinical history, sociodemographic and warfarin dose details were noted.The study recruited 300 patients (250 in derivation and 50 in validation timed cohort) receiving warfarin therapy. The baseline characteristics were similar in both cohorts. BMI, presence of comorbidity, VKORC1, CYP2C9*2, and CYP2C9*3 were identified as covariates significantly affecting the warfarin weekly maintenance dose (p<0.001 for all) and the same were included in warfarin pharmacogenetic dose optimization algorithm building. The algorithm built-in the present study showed a good correlation with Gage (r=0.57, p<0.0001), and IWPC (r=0.51, p<0.0001) algorithms, widely accepted in western side of the globe. The receiver operating characteristic curve analysis showed a sensitivity of 73 %, a positive predictive value of 96 %, and a specificity of 89 %. The algorithm correctly identified the validation cohort’s warfarin-sensitive, intermediate reacting, and resistant patient populations.Validation and comparisons of the warfarin pharmacogenetic dose optimization algorithm have made it ready for the clinical trial assessment.

Background Enzalutamide at standard doses (160 mg/day) is effective in advanced prostate cancer (PCa) but is associated with considerable adverse events (AEs) and high financial costs. Preliminary reports suggest that low/intermediate doses (≤80 mg/day) retain efficacy while reducing toxicity. This study evaluates the efficacy and safety of low/intermediate dose vs standard-dose enzalutamide in a real-world cohort. Methods This retrospective observational study included 140 assessable patients treated with enzalutamide for metastatic castration resistant (80%) or sensitive (20%) PCa. Patients were categorized by cumulative average daily dose relative to the standard dose (160 mg/day): low (≤50%, n = 11), intermediate (>50% and ≤80%, n = 16), and high (>80%, n = 113). The primary endpoint was the 12-month progression-free survival (PFS) by restricted mean time. Secondary endpoints included PSA response (decline ≥50% at 3 months), overall survival (OS) at 36 months and worsening of AEs of interest (fatigue, neurological disorders, hypertension). Results There were no significant differences in PFS at 12 months on high vs intermediate dose (10.4 vs 11.4 mo, p = 0.09) and high vs low dose (10.4 vs 9.2 mo, p = 0.37), nor was there on PSA response (70% vs 75% vs 60% on high, intermediate, low doses, respectively). Intermediate or low doses showed no evidence of adverse effects on OS at 36 months. The rate of fatigue worsening on high vs intermediate vs low dose was 61.1%, 63.0% and 27.3% ( p = 0.03 for high vs low). Conclusions Low/intermediate doses of enzalutamide show comparable efficacy than high dose while improving tolerability, indicating the need for further search of its optimal dose. Moreover, our findings prompt a study of the optimal dose in advanced disease and in the prevention/interception setting in patients with low/intermediate risk PCa under active surveillance.

Abstract Background Adalimumab (ADM) has been shown efficacious in ulcerative colitis (UC). In randomized controlled trials, dose escalation from 40 mg ADM every other week to 40 mg every week was required in 20%-25% of patients within 1 year. Real-life data suggest higher escalation rates. Attempts for dose de-escalation have not been studied yet. We assessed the need for, outcome of, and predictors of dose escalation and de-escalation in a large retrospective cohort of UC patients treated with ADM. Methods We included 231 consecutive patients from 10 Belgian centers initiating ADM treatment for active UC before September 1, 2015 (follow-up ≥1 year in each patient). We performed detailed chart review to identify variables associated with short-term clinical benefit (based on physician global assessment and absence of rectal bleeding at week 10), success of dose escalation, and dose de-escalation. Backward Cox regression and Wald Logistic regression were used to identify predictive variables. Results Short-term clinical benefit was achieved in 101 patients (44%) and was less frequent in infliximab failures [37% vs 50%, Odds ratio 0.57 (95% CI 0.34-0.97), P = 0.038]. After a median of 2.8 (1.7-5.1) months, 164 patients (71%) needed ADM discontinuation (n = 35, 15%) or dose escalation (n = 129, 56%). Dose escalation was successful in 77/129 (60%). Dose de-escalation was attempted in 71% (55/77) after a median of 4.3 (2.9-7.2) months and was successful in 80% (43/54). Conclusions In this cohort, 56% of patients with UC required ADM dose escalation with a 60% success rate. Of note, most patients could be successfully de-escalated later on.