Chemotherapy remains a cornerstone of cancer treatment, yet its lack of tumor specificity often leads to systemic toxicity and limits the maximum tolerable dose. To address these limitations, drug-loaded nanocarriers responsive to ionizing radiation have emerged as a promising strategy to achieve localized drug release within irradiated tumor regions, thereby enhancing therapeutic efficacy while minimizing off-target effects. However, current radiation-responsive nanosystems often exhibit limited drug release at clinically relevant radiation doses. In our previous work, we evaluated liposomal formulations varying lipid composition, sensitizers, and particle size. While these systems demonstrated moderate immediate release upon irradiation followed by sustained passive leakage, they were incompatible with remote drug loading and failed to achieve rapid release. In the present study, we optimized the liposomal membrane composition through modulation of polyunsaturated and saturated phospholipids to enhance radiation sensitivity and colloidal stability. Furthermore, we introduced a radiosensitization mechanism based on the encapsulation of Fe³+ ions, which are reduced to Fe2+ upon γ-irradiation. This redox transition triggers a Fenton-like reaction that catalyzes the degradation of lipid hydroperoxides, leading to localized lipid peroxidation and membrane disruption. This dual strategy, membrane composition tuning and iron-mediated oxidative activation, resulted in significantly enhanced drug release upon exposure to low-dose radiation.

Phase I study of ABM-1310 as monotherapy and in combination with cobimetinib for BRAF-mutated advanced solid tumors: safety, efficacy, and dose expansion

Emerging long-term data indicates relapse rates of over 50% after CD19 redirected chimeric antigen receptor (CAR) T cell therapy in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen we conducted a first-in-human phase I clinical trial of zamtocabtagene autoleucel (zamto-cel) - a non-cryopreserved tandem CD20-CD19-directed CAR-T cell therapy. Two predefined dose levels (DL1=1x106 and DL2=2.5x106 CAR+ T cells/kg body) were applied. The primary endpoint (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events (AEs), best overall response (BOR) and biomarker assessments. A total of 12 patients, 6 per dose level were treated. No DLT and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75% with 5/12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with higher mean Cmax and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ TCM cells in patients with CR, thus facilitating persistence and improved outcomes in r/r B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal Phase II clinical trials for patients with r/r aggressive B-NHL. This trial was registered at www.clinicaltrials.gov as #NCT03870945.

The single-agent pediatric maximum tolerated dose (MTD) of nab-paclitaxel is significantly higher than adult dosing. We conducted a Phase I trial to establish the MTD/recommended Phase 2 dose (RP2D) of nab-paclitaxel with gemcitabine in children with relapsed/refractory solid tumors. Nab-paclitaxel was administered intravenously with fixed-dose gemcitabine on days 1, 8, and 15 of 28-day cycles. Three dose levels (DL) of nab-paclitaxel, 180, 210, and 240mg/m2, were evaluated using a rolling six design. Toxicity, nab-paclitaxel pharmacokinetics (PK), and radiologic responses were evaluated. Pretreatment tumor tissue was assessed for SPARC and CAV-1. Twenty-four patients enrolled, 22 received therapy, and 20 were evaluable for dose-limiting toxicity (DLT): 17 during dose escalation and 3 in dose expansion at the MTD. Median age was 12.5 years. Diagnoses included osteosarcoma (n = 11), neuroblastoma (n = 4), and rhabdomyosarcoma (n = 4). At the starting dose level (gemcitabine 1000mg/m2, nab-paclitaxel 180mg/m2), two of five patients experienced DLT, prompting an amendment lowering gemcitabine to 675mg/m2/dose. Post-amendment, nab-paclitaxel 240mg/m2/dose with gemcitabine 675mg/m2/dose was identified as the MTD. Grade ≥3 hematologic toxicities were common. Two patients experienced a partial response (Wilms tumor and osteosarcoma), and PK exhibited linearity across DL. SPARC immunoreactivity was present in most tumors, while CAV-1 immunoreactivity was infrequent. The MTD/RP2D of nab-paclitaxel with gemcitabine in patients with relapsed/refractory pediatric solid tumors is nab-paclitaxel 240mg/m2/dose and gemcitabine 675mg/m2/dose on days 1, 8, and 15 of 28-day cycles; responses were limited in this patient population.

Local therapy with hypoxia-targeting radiopharmaceutical [64Cu]Cu-ATSM in high-grade glioma patient-derived xenograft models.

Safety assessment of Zhibo Qingliang extract derived from a clinical experience formula: Single and 13-week repeated-dose studies in rats.

PurposeCombinations of immune checkpoint inhibitors and cytokine therapies have shown promise in cancer immunotherapy. We aimed to evaluate the safety, tolerability, and preliminary efficacy of recombinant human interleukin-15 (rhIL-15) in combination with nivolumab and ipilimumab in patients with advanced, refractory cancers.MethodsThis open-label, non-randomized study employed a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of rhIL-15 combined with fixed doses of nivolumab and ipilimumab. Safety and tolerability were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) criteria, and preliminary efficacy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related RECIST (iRECIST) criteria. Pharmacodynamic studies evaluated changes in immune cell populations in peripheral blood and paired baseline and on-treatment tumor biopsies.ResultsThirty-one patients were enrolled, with a median age of 56 years (range: 24–81 years). Five patients received rhIL-15 with either nivolumab or ipilimumab in safety run-in cohorts, 26 patients received rhIL-15 with nivolumab plus ipilimumab. The most common cancer types were gastrointestinal (n=7) or gynecologic (n=5). The MTD was 1 µg/kg/day rhIL-15, 240 mg nivolumab, and 1 mg/kg ipilimumab. The triplet combination showed a manageable safety profile; the most common treatment-related adverse events (trAEs) were chills (20/26, 77%), fever (18/26, 69%), injection site reaction (15/26, 58%), anemia (14/26, 54%), and fatigue (14/26, 54%). Lymphopenia (4/26, 15%) was the most common grade 3/4 trAE. Pharmacodynamic analysis of tumor biopsies revealed increases in CD8+, CD8+CD3ζpY142+ (ie, activated CD8+T cells), PD-1+CD3+, and CD45RO+CD3+ (ie, memory T cells) in some patients. Tumor infiltration of natural killer (NK) and γδ T cells was also observed. NK cell populations in peripheral blood were modulated by rhIL-15. 11 of 26 patients (42%) had stable disease as a best response on the triplet regimen. A partial response was measured after cycle 1 in one patient (4%) with cholangiocarcinoma and confirmed after cycle 2; this patient completed 16 cycles.ConclusionsThe combination of rhIL-15 with nivolumab and ipilimumab was safe and induced changes in immune cell populations in some patients. However, preliminary signs of efficacy were limited. Pharmacodynamic findings may support further clinical development of this combination with alternative dosing regimens or combinations of rhIL-15 with other therapeutic modalities.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, largely due to its dense stromal architecture and poor intratumoral drug penetration. To address this challenge, IMP305 was developed as an ultrasound-sensitive liposome for tumor-localized drug release. In particular, IMP305 is dominantly capable of release by ultrasound-mediated cavitation. Methods: This ultrasound-sensitive liposome integrates tumor-specific drug delivery with cavitation-induced loosening of the stromal architecture in PDAC, thereby enabling more efficient intratumoral drug release using PANC-1 xenografted mouse. Results: The maximal tolerance dose of exatecan was increased by encapsulation into IMP305. Cavitation-triggered structural disruption of IMP305 was 84.68 ± 6.21%, which resulted in a robust release of approximately 84.4 ± 1.95% of the encapsulated exatecan. In PANC-1 xenograft models, IMP305 exhibited a maximal tolerance dose approximately four times higher than that of free exatecan and demonstrated markedly superior antitumor ability. Especially, IMP305 combined with focused ultrasound achieved the most pronounced therapeutic benefit, demonstrating a 49.17 ± 9.00% reduction in tumor volume at day 48 and an 80% survival rate at day 60. Conclusions: In conclusion, these findings demonstrate that ultrasound-activated IMP305 significantly enhances intratumoral accumulation and release of exatecan, resulting in superior tumor suppression while mitigating systemic toxicity.

Probiotics are living microorganisms that, when given in sufficient quantities, boost the host's health. Probiotics have been used more often in recent years as dietary supplement to prevent illnesses, including diarrhea, obesity, and constipation. The probiotic strain Bacillus subtilis BSP110 is being developed as a dietary supplement. In this work, we assessed the in vivo safety of the probiotic strain Bacillus subtilis BSP110 in rats as per OECD-423 and 407 guidelines. Female rats were given a single oral (gavage) dosage of 2000mg/kg (4 × 1011 CFU/g) to assess the maximum tolerated dose (MTD). This was followed by a 28-day sub-acute toxicity study in which Bacillus subtilis BSP110 was given orally (gavage) once daily to male and female rats at dose levels of 250, 500, and 1000mg/kg/day. No effects of Bacillus subtilis BSP110 were noted at any of the dosage levels given over the course of 28 days. Between the control and test groups, there was no discernible difference in body weight, clinical symptoms, urinalysis, hematological tests, clinical biochemistry, gross pathology, or histopathological evaluation. Additionally, in vitro cytotoxicity was evaluated using the MTT assay with the VERO cell line, and Bacillus subtilis BSP110 was found to be non-cytotoxic at 4 × 1011 CFU/kg. The single dose MTD was ≥2000mg/kg, and the NOAEL was 1000mg/kg/day.

Background: the primary challenge with implant infections is the formation of biofilm, which harbors dormant bacteria that reduce the effectiveness of antibiotics and amplify antibiotic resistance, exacerbating the global antimicrobial resistance crisis. A potential novel treatment strategy is radioimmunotherapy, which uses antibodies linked to radioisotopes to deliver targeted radiation to the bacteria and biofilm. We describe the first in vivo use of targeted radiation therapy, employing Actinium-225 (α-radiation) and Lutetium-177 (β-radiation) labeled antibodies to treat a Staphylococcus aureus biofilm-associated intramedullary implant infection. Untargeted radiation in the form of unbound radionuclide treatment was also evaluated. Methods: to assess therapeutic efficacy, bacterial counts were performed on implant and surrounding bone after seven days of follow-up. Biodistribution was evaluated using SPECT/CT and ex vivo gamma counting. Results: radioimmunotherapy using an antibody against wall teichoic acid which was labeled with Actinium-225 and Lutetium-177 achieved bacterial reductions between 45% and 93% on the implant and surrounding bone. Surprisingly, a similar antimicrobial effect was observed with unbound Actinium-225 treatment reducing the bacterial load by 80% on the implant and 98% in the surrounding bone. Indications of maximum tolerated dose (MTD) with Lutetium-177 labeled antibodies were observed through hepatic and renal function evaluations. Conclusions: These results should be interpreted in the context of the study’s constraints, particularly the limited animal sample size. Nonetheless, the results suggest that in vivo applied radiation may help reduce a biofilm-associated infection at the implant site as well as in the surrounding bone. These findings encourage further investigation into the use of targeted and non-targeted radiation, potentially combined with antibiotics, to develop effective strategies for eradicating biofilm-associated implant infections.

ABSTRACTIntroductionBI 891065, a second mitochondria‐derived activator of caspases mimetic targets the inhibitor of apoptosis (IAP) family member cIAP1. We describe two first‐in‐human phase 1 trials assessing BI 891065 ± the anti‐programmed cell death protein‐1 (PD1) antibody, ezabenlimab, in advanced solid tumors.MethodsTrials were conducted in the USA (NCT03166631) and Japan (NCT04138823). Dose escalation of BI 891065 monotherapy (part A) and combined with ezabenlimab (part B) was guided by a Bayesian Logistic Regression Model with overdose control. Primary endpoints were maximum tolerated dose (MTD) and number of patients with dose‐limiting toxicities (DLTs) in Cycle 1. Other endpoints included objective response (RECIST v 1.1), pharmacokinetics, and changes in peripheral blood mononuclear cell (PBMC) and tumor cIAP1 levels.ResultsTwenty‐five patients (USA study) received 5–400 mg daily BI 891065 monotherapy; 12 patients (Japan study) received 100 mg daily, 200 mg daily, or 200 mg twice‐daily BI 891065 monotherapy. No DLTs occurred in the USA study; three occurred in the Japan study: grade 3 increased bilirubin (n = 2) and maculopapular rash (n = 1). Neither study reached MTD for monotherapy. Treatment‐related adverse events (TRAEs) occurred in 52% and 75% of patients, respectively. BI 891065 plus ezabenlimab combination (USA study part B only) was received by 37 patients (50–400 mg daily, 200 mg twice‐daily) plus ezabenlimab (240 mg fixed‐dose, Day 1 of 21‐day cycles). One DLT occurred (grade 2 pneumonitis). MTD was not reached. TRAEs occurred in 81% of patients. Neither study reported objective responses; 25%–40% and 35% of patients achieved stable disease with BI 891065 monotherapy and the combination, respectively. cIAP1 levels were reduced in PBMCs and biopsies.ConclusionsBI 891065 was tolerable in patients with advanced solid tumors, demonstrating target engagement as monotherapy and combined with ezabenlimab. Both studies ended early due to efficacy data that were insufficiently promising to justify continuation.Trial RegistrationNCT03166631, NCT04138823

Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of SLC-391 in patients with advanced solid tumours. Methods: Using a 3 + 3 design, SLC-391 was administered orally, either once daily (from 25 mg up to 175 mg QD) or twice daily (from 75 mg to 200 mg BID) in 21-day cycles. Results: Following single and repeated dosing, SLC-391 was generally well tolerated by subjects. The maximum tolerated dose (MTD) was not reached in this study. A total of 34/35 subjects experienced at least one TEAE. Three (8.6%) subjects experienced Grade 3 TRAEs that were considered related to SLC-391. Eight SAEs were reported in five (14.3%) subjects (seven Grade 3 SAEs and one Grade 2 SAE), in 150 mg QD (3/6, 50%), 175 mg QD (1/2, 50%), and 110 mg BID (1/3, 33.3%) cohorts. Four SAEs in three (8.6%) subjects led to dose interruption, drug withdrawal, or study discontinuation. Three DLTs were reported in two subjects: one subject experienced Grade 3 hematochezia (SUSAR/DLT) at 175 mg QD, and another subject experienced Grade 3 thrombocytopenia associated with Grade 1 hematuria at 200 mg BID. The median Tmax was 2.0 h. Plasma concentrations following multiple doses generally increased with higher doses and appeared to reach steady state by Day 21 and were generally dose-proportional. Twelve (12) out of 35 subjects with solid tumours achieved stable disease according to RECIST or mRECIST (mesothelioma), with durations of stable disease lasting up to 318 days on SLC-391 monotherapy. The clinical benefit rate was 34.3%. Conclusions: This first study of SLC-391 in adult subjects with advanced solid tumours demonstrated that a total daily dose of 300 mg (150 mg BID) of SLC-391 monotherapy was generally well tolerated, with no DLTs or SAEs observed at this dose. The drug’s promising safety profile, along with stable disease reported for several subjects with advanced solid tumours, provides a strong rationale for the phase 1b/2a clinical investigation of SLC-391 in combination with pembrolizumab in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) (NCT05860296).

Thymol is an antimicrobial terpene with potential as a feed additive for cattle; however, in vivo data describing the response of forage-fed beef cattle to the increasing provision of thymol is limited. As thymol may affect palatability and exert antimicrobial effects on rumen microbes, defining its effects in vivo is critical to inform adoption. Accordingly, the objectives of this study were to evaluate cattle acceptance of thymol and characterize the effects of increasing thymol doses on diet utilization and ruminal fermentation, with the overarching goal of identifying a maximum tolerable dose for beef cattle. Two 4 × 4 Latin Square experiments were conducted using beef steers consuming forage and providing thymol dosed on alfalfa. Experiment 1 assessed acceptance of thymol at increasing concentrations (0, 110, 220, and 330 mg/kg intake), and experiment 2 assessed diet utilization and fermentation in response to one of four thymol doses: 0, 120, 240, and 480 mg/kg intake. For experiment 1, thymol dose did not affect treatment or forage intake (p ≥ 0.17). For experiment 2, thymol did not linearly or quadratically affect (p ≥ 0.28) forage organic matter (OM) intake or OM digestibility. There were also no linear or quadratic effects (p ≥ 0.09) on ruminal ammonia-N, volatile fatty acids, or pH. These data indicate that thymol can be provided to beef cattle at up to 330 mg/kg intake and 480 mg/kg intake without negatively impacting acceptance and diet utilization, respectively.

Introduction. Cell cycle dysregulation associated with errors in the CDK4 / 6-pRb signaling pathway is characteristic of many oncological diseases. The MM-D37K drug is an innovative chimeric peptide imitating endogenous inhibitor p16INK4a. Unlike traditional ATP-competitive (adenosine triphosphate) inhibitors, MM-D37K is highly selective. It consists of p16INK4a cytotoxic fragment and pANTP transport peptide promoting effective intracellular delivery. Results of preclinical studies showed high cytotoxic effect of MM-D37K in a wide variety of tumor cells and synergy with chemotherapeutic drugs. Aim. To evaluate the effect of MM-D37K drug on biochemical characteristics of blood and to determine dose-limiting toxicity and maximal tolerable dose in patients with advanced solid tumors. Materials and methods. The study was performed in accordance with the 3 + 3 escalation dose scheme. Starting MM-D37K dose was 7.5 mg / m2, further dose escalation for MM-D37K drug in the clinical trial was two-fold at each dosing level (7.5; 15; 30; 60; 120 and 240 mg / m2). The drug was administered intravenously 3 times a week for 2 weeks. Dose-limiting toxicity was evaluated according to the hematological and non-hematological toxicity criteria per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 classification. Results. Intravenous administration of MM-D37K in the dose range between 7.5 and 240 mg / m2 did not show signs of dose-limiting toxicity. There were no statistically significant differences in the analyzed laboratory, instrumental and diagnostic parameters during intravenous administration of the drug which allowed to conclude that the maximal tested dose of the MM-D37K drug 240 mg / m2 is safe and has satisfactory tolerability profile. Conclusion. First clinical use of the new antitumor drug – targeted inhibitor of cyclin-dependent kinases 4 / 6 – MM-D37K in humans confirmed its safety and possibility of further clinical trials with the selected dose 240 mg / m2.

Bevacizumab and temsirolimus target angiogenic and mTOR pathways in cancer progression. This phase I study enrolled 48 heavily pretreated patients with advanced solid tumors, including an ovarian cancer expansion cohort. Patients received bevacizumab biweekly plus temsirolimus weekly in a 3 + 3 design to assess safety, maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Exploratory analyses included tumor genomic profiling and dynamic contrast-enhanced MRI (DCE-MRI). Patients had a median age of 59 and median four prior therapies. Common tumor types were ovarian (27%) and head and neck (15%). Treatment-related adverse events occurred in 93.8%, with 31.2% ≥grade 3. Five patients experienced DLTs, including grade 3 enteritis, fatigue, bowel obstruction/abdominal ileus/pulmonary embolism, bowel perforation and grade 3/4 elevated liver enzymes. MTD was bevacizumab 10 mg/kg biweekly plus temsirolimus 20 mg weekly. Overall, objective response rate (ORR) was 7.3% and 19.5% achieved stable disease ≥6 months (clinical benefit rate [CBR] 26.8%). In ovarian cohort, ORR was 16.7% and CBR 33.3%. Patients with tumor regression on DCE-MRI had lower ΔKtrans values. Combination therapy showed acceptable safety and modest activity. Molecular and imaging findings were exploratory and limited. These preliminary observations could inform future biomarker studies. (ClinicalTrials.gov Identifier: NCT01552434).

This clinical case demonstrates a severe, highly active form of psoriatic arthritis with pronounced peripheral arthritis, dactylitis, enthesitis, and widespread skin lesions. The patient had radiographically confirmed signs of sacroiliitis, spondylitis, and significant structural changes (stage III–IV according to the Steinbrocker classification). The course of the disease was complicated by multiple comorbid conditions, including metabolic syndrome with morbid obesity (BMI 46 kg/m²), hyperuricemia, and subsequently clinically established diabetes insipidus. An additional factor that significantly limited the effectiveness of treatment was the patient's low adherence to therapy and repeated refusals to undergo the recommended examinations by related specialists. There was marked resistance of the disease to both the maximum tolerable doses of basic anti-inflammatory drugs and various groups of genetically engineered biological therapies. Despite repeated attempts to optimise treatment, it was not possible to achieve sustained control of the disease: only partial effectiveness of therapy was recorded, accompanied by periodic exacerbations and persistent high activity of the pathological process.

WP1066 is an orally bioavailable, small molecule inhibitor of activated p-STAT3 that has demonstrated preclinical efficacy in pediatric brain tumor models. In a first-in-child, single-center, single-arm 3+3 design Phase I clinical trial, ten patients were treated with WP1066 twice daily, Monday-Wednesday-Friday, for 14 days of each 28-day cycle to determine the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066. Compassionate use treatment with WP1066 in three pediatric patients with H3.3 G34R/V-mutant high-grade glioma (HGG) is also described. There was no significant toxicity and the MFD was determined to be 8 mg/kg. Treatment-related adverse events were Grade 1-2 (diarrhea and nausea most common); there were no dose-limiting toxicities. Median progression-free and overall survival were 1.8 months and 4.9 months, respectively. One partial response was observed in a patient with pontine glioma. Among the H3.3 G34R/V-mutant HGG patients not on study, WP1066 was administered after upfront radiation to one patient for 17 months. At all dose levels tested, WP1066 suppressed p-STAT3 expression by peripheral blood mononuclear cells (PBMCs). Single cell RNA-seq analysis of PBMCs demonstrated increased CD4+ and CD8+ T cells, pro-inflammatory TNFA signaling, differentiation activity in myeloid cells, and downregulation of Tregs after WP1066 treatment, consistent with systemically inhibited STAT3 activity. WP1066 is safe, has minimal toxicity, and induces anti-tumor immune responses in pediatric brain tumor patients. Phase II investigation of WP1066 at the MFD in this patient population is warranted. gov NCT04334863. CURE Childhood Cancer (TJM) and Peach Bowl, Inc. (TJM).

Cancer cachexia, a multifactorial debilitating syndrome, highly impacts the quality of life, treatment tolerance, and survival among the cancer patients. Mainly characterized by progressive weight loss, skeletal muscle atrophy, and metabolic dysregulation, it is essentially an unmet medical need. This review explores the roles of metronomic chemotherapy (mCT) and drug repurposing as innovative strategies for cachexia prevention and management. Metronomic chemotherapy, a low-dose chemotherapeutic drug administration, shows reduced toxicity, anti-angiogenic, and immunomodulatory effects over Maximum Tolerated Dose (MTD), potentially mitigates chemotherapy-induced cachexia, and improves treatment tolerability. Drug repurposing, in which an existing drug is utilized for a new indication, has the advantages of rapid development, reduced costs, and established safety profiles. It provides targeted interventions against the complex inflammatory and metabolic pathways underlying cachexia. A good number of preclinical and early clinical studies have shown evidence for both approaches, particularly for Ponsegromab, a Growth Differentiation Factor-15 (GDF-15) inhibitor. Due to the multifactorial nature of cachexia, a multimodal, integrated intervention is a good substitute for the maximum tolerated dose, which can be effective against it. Future directions in cancer therapy should emphasize the development of robust clinical trial designs with cachexia-specific endpoints to advance precision prevention strategies.

ABSTRACT Oncology dose-finding trials are shifting from identifying the maximum-tolerated dose (MTD) to determining the optimal biological dose (OBD), driven by the need for efficient methods that consider both toxicity and efficacy. This is particularly important for novel therapies, such as immunotherapies and molecularly targeted therapies, which often exhibit non-monotonic dose–efficacy curves. The Simple Toxicity and Efficacy Interval (STEIN) design has demonstrated strong performance in accommodating diverse dose-efficacy patterns and incorporating both toxicity and efficacy outcomes to select the OBD. However, the rapid accrual of patients and the often-delayed onset of toxicity and/or efficacy pose challenges to timely adaptive-dose decisions. To address these challenges, we propose TITE-STEIN, a model-assisted design that incorporates time-to-event (TITE) outcomes for toxicity and/or efficacy, by extending STEIN. In this article, we demonstrate that TITE-STEIN significantly shortens the trial duration compared to STEIN. Furthermore, by integrating an OBD verification procedure during OBD selection, TITE-STEIN effectively mitigates the risk of exposing patients to inadmissible doses when the OBD does not exist. Extensive simulations demonstrate that TITE-STEIN outperforms existing TITE designs, including TITE-BONI12, TITE-BOIN-ET, LO-TC, and Joint TITE-CRM, by selecting the OBD more accurately, allocating more patients to it, and improving overdose control.

Cabazitaxel (CTX) is primarily used in the clinical treatment of prostate cancer. The clinical CTX injection (Jevtana®) contains the solubilizer Tween 80, which can lead to serious toxic side effects during intravenous injection. This study developed a novel nanodelivery system for encapsulating CTX, eliminating the need for Tween 80 and addressing current clinical challenges associated with CTX use. The nanodelivery system uses the hydrophilic polymer polyvinylpyrrolidone K12 (PVP K12) as a dispersing agent and a small amount of highly biocompatible sodium cholesteryl sulfate (SCS) as a stabilizer, forming a cabazitaxel nanodispersion (CTX-NP) through the water dispersion method. The CTX-NP exhibited a spherical shape, uniform distribution, a particle size of 128.90 ± 0.42nm, a PDI of 0.14 ± 0.01, a zeta potential of -65.88 ± 1.23mV, and a drug encapsulation efficiency of 97.58 ± 0.58%. Furthermore, hemolysis, vascular irritation, and maximum tolerated dose (MTD) experiments indicated that CTX-NP has good biocompatibility compared to cabazitaxel-Tween injection (CTX-TW). The pharmacokinetic studies in rats revealed that, compared to CTX-TW, CTX-NP had an extended half-life (T1/2), mean residence time (MRT), and a larger area under the drug concentration-time curve (AUC). In the RM-1 prostate cancer mouse model, compared with CTX-TW, the high-dose CTX-NP group showed better tumor inhibition with an inhibition rate of 79.48%, indicating that CTX-NP could achieve superior anti-tumor effects by increasing the administered dose.