First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the \"3 + 3\" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.

OBJECTIVE: Intravenous (IV) racemic ketamine and intranasal (IN) esketamine have demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). This systematic review aims to evaluate the efficacy and safety of ketamine and esketamine at various dosages for depression.
METHODS: We included randomized controlled trials (RCTs) with parallel group dose comparison of ketamine and esketamine for depression/TRD. Ovid Medline, Embase, PsycINFO, Scopus and Cochrane databases were searched. Standardized mean differences were calculated using Hedges\'-g to complete random effects meta-analysis. The efficacy outcomes were changes in depression outcomes for IV ketamine and IN esketamine respectively. Safety was assessed by reported adverse effects.
RESULTS: A random effects meta-analysis of studies (n = 12) showed efficacy in reducing depression symptoms with IV ketamine (Hedges\'g = 1.52 [0.98-2.22], Z = 4.23, p < 0.001) and IN esketamine (Hedges\' g = 0.31 [0.18-0.44], Z = 4.53, P < 0.001) compared to control/placebo. Treatment response was observed at IV ketamine doses ≤0.2 mg/kg, >0.2-0.5 mg/kg and > 0.5 mg/kg. Higher IV ketamine doses (>0.5 mg/kg) did not lead to greater treatment response. Esketamine doses of 56-84 mg were superior to 28 mg dose.
CONCLUSIONS: Overall quality of evidence was low and limited by small number of studies. Publication bias was high.
CONCLUSIONS: This meta-analysis suggests that IV ketamine may be efficacious at doses as low as 0.2 mg/kg, with increasing dose response at 0.5 mg/kg, without demonstrable increased benefit at 1 mg/kg, based on a small number of studies. Efficacy for IN esketamine increases with doses above 28 mg with best response being found between 56 and 84 mg for reducing depressive symptoms.

The aim of this review is to highlight key published oral immunotherapy (OIT) protocols and post-desensitization strategies for the major food allergens and to cover important concepts to consider when evaluating OIT for food-allergic patients. Shared decision-making should help identify patient and family values which will help influence the type of evidence-based protocol and maintenance strategy to use.
With food OIT emerging as a treatment option, there is a pressing need for patients, physicians, and other providers to have a nuanced understanding of the management choices available to them. There are now randomized controlled trials (RCT) of OIT for peanut, egg, milk, and wheat, and reports of cohorts of patients who have undergone OIT for tree nuts and sesame clinically. The current published protocols contain significant diversity in terms of starting dose, build-up schedule, maintenance dose, and even the product used for desensitization. Emerging data can help direct the long-term maintenance strategy for patients on OIT. Based on patient and family values elicited through the shared decision-making process, an OIT protocol may be selected that balances the level of desensitization, potential side effects, frequency of clinic visits, and potential to induce sustained unresponsiveness, among other factors. Once maintenance dosing is reached, most patients will need to maintain regular exposure to the food allergen to remain desensitized. The option to transition to commercial food products with equivalent amounts of food protein as the OIT maintenance dose would simplify the dosing process and perhaps improve palatability as well. Less frequent or decreased OIT dosing can provide practical benefits but may affect the level of desensitization and safety for some patients.

Esophageal cancer, ranked as the eighth most prevalent cancer globally, is characterized by a low survival rate and poor prognosis. Concurrent chemoradiation therapy (CCRT) is the standard therapy in the non-surgical treatment of localized carcinoma of the esophagus. Nevertheless, the radiation doses employed in CCRT remain notably lower compared to the curative definite chemoradiation therapy utilized in the management of other carcinomas. In order to increase the local control rates and enhance the treatment outcomes, several clinical trials have used high-dose radiation to analyze the effect of dose escalation. Despite the integration of technically advanced RT schemes such as intensity-modulated radiation therapy (IMRT), the results of these trials have failed to demonstrate a significant improvement in overall survival or local progression-free survival. In this review, we investigated previous clinical trials to determine the ineffectiveness of radiation dose escalation in the context of CCRT for esophageal cancer. We aim to clarify the factors contributing to the limited efficacy of escalated radiation doses in improving patient outcomes. Furthermore, we delve into recent research endeavors, exploring prospective radiation dose modifications being altered based on the histological characteristics of the carcinoma. The exploration of these recent studies not only sheds light on potential refinements to the existing treatment protocols but also seeks to identify novel approaches that may pave the way for more efficacious and personalized therapeutic strategies for esophageal cancer management.

Dose escalation is one of the treatment approaches studied and suggested in advanced therapies for Crohn\'s disease (CD) and ulcerative colitis (UC). This study aimed to identify and characterize the dosing escalation patterns of advanced therapies in CD and UC.
Two systematic literature reviews (SLRs) were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE®, Embase®, and Cochrane Library were searched for articles published between January 2011 and October 2021 and limited to non-interventional studies in English language. Congress and bibliographic searches were also conducted. Articles were screened by two independent researchers. Dose escalation patterns were described and summarized considering the regional regulatory label recommendation (in North America [NA] or outside of North America [ONA]).
Among 3190 CD and 2116 UC articles identified in the Ovid searches, 100 CD and 54 UC studies were included in the SLR, with more studies conducted ONA. Most studies reported an initial maintenance dose pattern aligned with the lower starting dose per local regulatory label; however, several ONA studies (n = 13 out of 14) reported ustekinumab every 8 weeks as starting maintenance pattern in CD. In ONA studies, the median within-guideline escalation rates in CD and UC were 43% in ustekinumab (CD only), 33% and 32% for vedolizumab; 29% and 39% for adalimumab; and 14% and 10% for infliximab. Evidence regarding dose escalation patterns for tofacitinib, certolizumab pegol, and golimumab was limited. Some dose escalation patterns outside of label recommendations were observed including ustekinumab every 8 weeks to every 4 weeks and vedolizumab every 8 weeks to every 6 weeks.
Dose escalation strategies are widely documented in the literature. The reported dose escalation patterns and escalation rates vary by region and by CD and UC. Most escalation patterns reported were aligned with regulatory recommendations while some reported more diverse or aggressive dose escalation.
CRD42021289251.

UNASSIGNED: Vedolizumab is a gut-selective anti-lymphocyte trafficking agent approved for the treatment of moderate to severely active inflammatory bowel disease (IBD: ulcerative colitis [UC] and Crohn\'s disease [CD]).
UNASSIGNED: A systematic literature review (SLR) of real-world studies was conducted to assess the effectiveness of dose escalation of vedolizumab every 8 weeks (Q8W) during maintenance treatment to achieve a response in patients who were either vedolizumab responders experiencing secondary loss of response (SLOR) or non-responders. MEDLINE and EMBASE databases were searched from January 2014 to August 2021.
UNASSIGNED: Screening of SLR outputs identified 72 relevant real-world study publications featuring dose escalation of vedolizumab maintenance therapy. After qualitative review, ten eligible studies (9 articles, 1 abstract) were identified as reporting clinical response and/or clinical remission rates following escalation of intravenous vedolizumab 300 mg Q8W maintenance dosing to every 4 weeks (Q4W) maintenance dosing in adult patients with UC/CD (≥10 patients per study). Overall, 196/395 (49.6%) patients with IBD had a response within 54 weeks of vedolizumab maintenance dose escalation. Although definitions for clinical response/remission varied across the 10 studies, clinical response rates after escalated vedolizumab Q8W maintenance dosing ranged from 40.0% to 73.3% (9 studies) and from 30.0% to 55.8% for remission (4 studies) over a range of 8 to <58 weeks\' follow-up.
UNASSIGNED: This synthesis of real-world effectiveness data in vedolizumab-treated patients with IBD indicates that approximately half were able to achieve or recapture clinical response after escalating vedolizumab maintenance dosing.

OBJECTIVE: Chimeric antigen receptor (CAR) T cells with tumor specificity are being increasingly investigated. Phase I trials are the first step of testing for safety of novel CAR-T therapy to determine the maximum tolerated dose (MTD). Several dose escalation methods have been developed over time including rule-based, model-based, and model-assisted designs. The goal of this project is to overview the phase I designs used in current CAR-T trials.
METHODS: We searched PubMed for peer-reviewed literature published between January 1, 2015 and December 31, 2021. The search was limited to human studies in the English language using the keywords \"CAR-T phase I\", \"clinical trials\", and \"full text\".
RESULTS: One hundred nine papers with at least partial phase I components were included for analysis. 31.2% of the trials used the traditional 3+3 or a variation of said design, and 60.6% did not mention the dose escalation design. The majority of the manuscripts (59.6%) did not report cohort size while 19.3% did not specify the timing of evaluation. Although most of the studies were registered with CT.gov, only 33.9% had any results submitted or posted to CT.gov These trends persisted even in manuscripts published in journals with high impact factors.
CONCLUSIONS: Standardizing the publication criteria and providing basic elements of phase I clinical trials are critical to ensure high quality of manuscripts. With the quick development and high costs of CAR-T cell therapy, adoption of advanced designs such as model-based and model-assisted should increase to improve efficiency of clinical trials.

Loss of response to infliximab or adalimumab in ulcerative colitis occurs frequently, and dose escalation may aid in regaining clinical benefit. This study aimed to systematically assess the annual loss of response and dose escalation rates for infliximab and adalimumab in ulcerative colitis.
A systematic search was conducted from August 1999 to July 2021 for studies reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response. Annual loss of response, dose escalation rates, and clinical benefit after dose escalation were calculated. Subgroup analyses were performed for studies with 1-year follow-up or less.
We included 50 unique studies assessing loss of response (infliximab, n = 24; adalimumab, n = 21) or dose escalation (infliximab, n = 21; adalimumab, n = 16). The pooled annual loss of response for infliximab was 10.1% (95% confidence interval [CI], 7.1-14.3) and 13.6% (95% CI, 9.3-19.9) for studies with 1-year follow-up. The pooled annual loss of response for adalimumab was 13.4% (95% CI, 8.2-21.8) and 23.3% (95% CI, 15.4-35.1) for studies with 1-year follow-up. Annual pooled dose escalation rates were 13.8% (95% CI, 8.7-21.7) for infliximab and 21.3% (95% CI, 14.4-31.3) for adalimumab, regaining clinical benefit in 72.4% and 52.3%, respectively.
Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively. Uniform definitions are needed to facilitate more robust evaluations.
Annual loss of response in ulcerative colitis was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation was higher than loss of response, with clinical benefit for 72% (infliximab) and 52% (adalimumab).

UNASSIGNED: The long-term efficacy and safety of infliximab (IFX) in children with ulcerative colitis (UC) have not been well-evaluated. Here, we reviewed the long-term durability and safety of IFX in our single center pediatric cohort with UC.
UNASSIGNED: This retrospective study included 20 children with UC who were administered IFX.
UNASSIGNED: For induction, 5 mg/kg IFX was administered at weeks 0, 2, and 6, followed by every 8 weeks for maintenance. The dose and interval of IFX were adjusted depending on clinical decisions. Corticosteroid (CS)-free remission without dose escalation (DE) occurred in 30% and 25% of patients at weeks 30 and 54, respectively. Patients who achieved CS-free remission without DE at week 30 sustained long-term IFX treatment without colectomy. However, one-third of the patients discontinued IFX treatment because of a primary nonresponse, and one-third experienced secondary loss of response (sLOR). IFX durability was higher in patients administered IFX plus azathioprine for >6 months. Four of five patients with very early onset UC had a primary nonresponse. Infusion reactions (IRs) occurred in 10 patients, resulting in discontinuation of IFX in four of these patients. No severe opportunistic infections occurred, except in one patient who developed acute focal bacterial nephritis. Three patients developed psoriasis-like lesions.
UNASSIGNED: IFX is relatively safe and effective for children with UC. Clinical remission at week 30 was associated with long-term durability of colectomy-free IFX treatment. However, approximately two-thirds of the patients were unable to continue IFX therapy because of primary nonresponse, sLOR, IRs, and other side effects.

BACKGROUND: The use of modern radiotherapy techniques (MRTs) has contributed to reduced treatment-related toxicities through better avoidance of normal structures and dose tapering, and has enabled the delivery of higher doses continuously. The purpose of this study was to review retrospectively (1) outcomes for anal cancer treated at BC Cancer (Canada) using MRT, and (2) the utilization and effect of dose escalation on cancer-related outcomes.
METHODS: Patients between 2010 and 2016 with biopsy-proven anal cancer, aged >18 years, and treated with primary curative-intent chemoradiation using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) were included. Primary end points included overall survival (OS), relapse-free survival (RFS), and colostomy-free survival (CFS). Kaplan-Meier curves were created for prognostic factors, as well as dose escalation (>54 Gy vs. ≤54 Gy). Univariate and multivariate analyses were performed to evaluate predictors of the outcome.
RESULTS: A total of 273 patients were assessed. The median age was 61 years with 70% being female, 6% HIV positive, and 68% with locally advanced cancer (T3-4, or node positive). The median follow-up time was 41.3 months. Time from diagnosis to treatment was 60 days, and treatment duration 42 days. Dose escalation was prescribed for 22, of whom 15 were locally advanced cases. A total of 97% completed their radiation, including all who were dose-escalated; 11% required unplanned treatment breaks, with over half of breaks <5 days. More than 90% completed at least half of their chemotherapy; 41% had pre-treatment, and 34% post-treatment positron emission tomography (PET) scans. For primary tumor response, 88% were complete and 10% partial; 23% relapsed, with 15% locoregional, 5% distant, and 3% both, and 12% had salvage surgery. The colostomy rate was 15%, with 4% pre-treatment, 10% relapse related, and only 1% treatment-toxicity related. On univariate analysis, male sex was associated with a higher risk of death (p=0.02) and relapse (p=0.041). Non-squamous histology was consistently a strong predictor of all outcomes (OS, p=0.0089; RFS, p<0.0001; CFS, p<0.0001) as was advanced T stage (OS, p=0.0075; RFS, p=0.0019; CFS, p=0.0099), and node positivity (OS, p=0.0014; RFS, p=0.001; CFS, p=0.0071). Age, HIV status, grade, longer treatment times (>42-day median), and lack of a pre- or post-treatment PET scan were not associated with the outcome. Dose escalation beyond 54 Gy was not significant, even among locally advanced tumors. On multivariate analysis, non-squamous histology (OS, p=0.043; RFS, p<0.001; CFS, p=0.01), T4 (OS, p=0.049; RFS, p=0.026; CFS, p=0.042) and node positivity (OS, p=0.05; RFS, p=0.006) remained significant predictors of the outcome, although node positivity was no longer significant for CFS (p=0.10).
CONCLUSIONS: BC Cancer outcomes for anal cancer treated with MRTs are comparable to what has been previously reported. Unplanned breaks were notably few, and short. Treatment-related colostomies were rare. Dose-escalated regimens were infrequently prescribed, appeared tolerable, but more often required a break. Prospective trials are needed to clarify efficacy of such regimens.