Analysis Of Clinical Trial Data Research Articles

Development of normal reference intervals for renal function in pregnancy: a secondary analysis of clinical trial data

Background Due to its potential nephrotoxicity, screening for pre-existing renal function disorders has become a routine clinical assessment for initiating Tenofovir diphosphate fumarate (TDF)-containing antiretroviral treatment (ART) or pre-exposure prophylaxis (PrEP) in pregnant and non-pregnant adults. We aimed to establish reference values for commonly used markers of renal function in healthy pregnant women of African origin. Methods Pregnant women ≥18 years, not living with HIV, and at 14–28 weeks gestation were enrolled in a PrEP clinical trial in Durban, South Africa between September 2017 and December 2019. Women were monitored 4-weekly during pregnancy until six months postpartum. We measured maternal weight and serum creatinine (sCr) at each visit and calculated creatinine clearance (CrCl) rates using the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae. Reference ranges for sCr and CrCl by CG and MDRD calculations were derived from the mean ± 2SD of values for pregnancy and postdelivery. Results Between 14-–and 40 weeks gestation, 249 African women not exposed to TDF-PrEP contributed a total of 1193 renal function values. Postdelivery, 207 of these women contributed to 800 renal function values. The normal reference range for sCr was 30–57 and 32–60 umol/l in the 2nd and 3rd trimesters of pregnancy. Normal reference ranges for CrCl using the MDRD calculation were 129–282 and 119–267 ml/min/1.73m2 for the 2nd and 3rd trimesters, respectively. Using the CG method of calculation, normal reference ranges for CrCl were 120—304 and 123–309 ml/min/1.73m2 for the 2nd and 3rd trimesters respectively. In comparison, the normal reference range for sCr, CrCl by MDRD and CG calculations postpartum was 40–77 umol/l, 92–201, and 90–238 ml/min/1.73m2, respectively. Conclusions In African women, the Upper Limit of Normal (ULN) for sCr in pregnancy is approximately 20% lower than 6 months postnatally. Inversely, the Lower Limit of Normal (LLN) for CrCl using either MDRD or CG equation is approximately 35% higher than 6 months postnatally. We provide normal reference ranges for sCr and CrCl for both methods of calculation and appropriate for the 2nd and 3rd trimesters of pregnancy in African women.

Association between overweight and obesity with coronary artery bypass graft failure: an individual patient data analysis of clinical trials.

The association between obesity and graft failure after coronary artery bypass grafting has not been previously investigated. We pooled individual patient data from randomized clinical trials with systematic postoperative coronary imaging to evaluate the association between obesity and graft failure at the individual graft and patient levels. Penalized cubic regression splines and mixed-effects multivariable logistic regression models were performed. Six trials comprising 3928 patients and 12048 grafts were included. The median time to imaging was 1.03 (interquartile range 1.00-1.09) years. By body mass index (BMI) category, 800 (20.4%) patients were normal weight (BMI 18.5-24.9), 1668 (42.5%) were overweight (BMI 25-29.9), 983 (25.0%) were obesity class 1 (BMI 30-34.9), 344 (8.8%) were obesity class 2 (BMI 35-39.9) and 116 (2.9%) were obesity class 3 (BMI 40+). As a continuous variable, BMI was associated with reduced graft failure [adjusted odds ratio (aOR) 0.98 (95% confidence interval (CI) 0.97-0.99)] at the individual graft level. Compared to normal weight patients, graft failure at the individual graft level was reduced in overweight [aOR 0.79 (95% CI 0.64-0.96)], obesity class 1 [aOR 0.81 (95% CI 0.64-1.01)] and obesity class 2 [aOR 0.61 (95% CI 0.45-0.83)] patients, but not different compared to obesity class 3 [aOR 0.94 (95% CI 0.62-1.42)] patients. Findings were similar, but did not reach significance, at the patient level. In a pooled individual patient data analysis of randomized clinical trials, BMI and obesity appear to be associated with reduced graft failure at 1 year after coronary artery bypass grafting.

Longitudinal invariance of the Patient Health Questionnaire-9 among patients receiving pharmacotherapy for major depressive disorder: A secondary analysis of clinical trial data.

Comparing self-reported symptom scores across time requires longitudinal measurement invariance (LMI), a psychometric property that means the measure is functioning identically across all time points. Despite its prominence as a measure of depression symptom severity in both research and health care, LMI has yet to be firmly established for the Patient Health Questionnaire-9 depression module (PHQ-9), particularly over the course of antidepressant pharmacotherapy. Accordingly, the objective of this study was to assess for LMI of the PHQ-9 during pharmacotherapy for major depressive disorder. This was a secondary analysis of data collected during a randomized controlled trial. A total of 1,944 veterans began antidepressant monotherapy and completed the PHQ-9 six times over 24 weeks of treatment. LMI was assessed using a series of four confirmatory factor analysis models that included all six time points, with estimated parameters increasingly constrained across models to test for different aspects of invariance. Root-mean-square error of approximation of the chi-square difference test values below 0.06 indicated the presence of LMI. Exploratory LMI analyses were also performed for separate sex, age, and race subgroups. Root-mean-square error of approximation of the chi-square difference test showed minimal change in model fits during invariance testing (≤ 0.06 for all steps), supporting full LMI for the PHQ-9. LMI was also supported for all tested veteran subgroups. As such, PHQ-9 sum scores can be compared across extended pharmacotherapy treatment durations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Characterizing health-related quality of life and identifying disease predictors among patients suspected of having long COVID: an analysis of COMET-ICE clinical trial data.

Long COVID affects health-related quality of life (HRQoL). Here, we investigate the extent to which symptoms experienced during the acute phase of COVID-19 are significant predictors of the presence of long COVID at 12 weeks. Post-hoc analysis of COMET-ICE trial data, which assessed sotrovimab vs. placebo for treatment of mild-to-moderate COVID-19 among high-risk patients. Patient-reported outcome measures were completed during the trial, including the inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus), the 12-Item Short Form (SF-12) Hybrid questionnaire, and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH). COVID-19 symptoms and impacts (measured by the FLU-PRO Plus) and HRQoL (measured by SF-12 Hybrid and WPAI:GH) were compared between the acute phase (Days 1-21 and 29) and long-COVID phase (at Week 12) among patients with and without long COVID based on COMET-ICE data. Subgroups experiencing long COVID were derived using "All," "Returning," and "Persisting" symptomatic definitions. Long-COVID predictors were identified using a multivariate logistic regression model; odds ratios (ORs) and 95% CIs were calculated. Long-COVID subgroups had significantly higher baseline scores for most FLU-PRO Plus domains and Total Score compared with the non-long-COVID group. WPAI:GH and SF-12 Hybrid scores generally showed significantly more impairment for the long-COVID subgroups at baseline and Week 12 vs. the non-long-COVID group. In the univariate analyses, all FLU-PRO Plus domains were significant predictors of long COVID (all p < 0.05), with the exception of the Sense domain. Older age increased the risk of long COVID (OR 1.02, 95% CI 1.00-1.04, p < 0.05). Non-White patients were significantly less likely to have long COVID by the Returning and Persisting definitions vs. White patients (all p < 0.05). In the multivariate analysis, higher scores for the Nose domain (ORs 3.39-5.60, all p < 0.01) and having COPD (ORs 3.75-6.34, all p < 0.05) were significant long-COVID predictors. Patients who progressed to long COVID had higher symptom severity during the acute disease phase and showed significantly greater negative impact on HRQoL over an extended time period from initial infection through at least the subsequent 3 months. The FLU-PRO Plus Nose domain and having COPD were significant predictors of long COVID.

Abstract PO1-05-12: Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy

Abstract Background: Prior analyses of observational data suggest that for patients with metastatic breast cancer (MBC), tumor biology does not vary by HER2-low vs. HER2-0 expression given similar overall survival (OS) times after accounting for patients’ clinicopathologic features including hormone receptor (HR) status. We sought to evaluate potential differential biology by HER2-low status by (1) studying data pertaining to patients treated in historic clinical trials (i.e., data collected to measure associations between protocol defined treatments and outcomes) and (2) evaluating the endpoint of progression-free survival (PFS) in addition to OS following treatment with standard single agent chemotherapy for MBC. Methods: Pooling anonymized clinical trial data from studies within the Medidata Enterprise Data Store, we identified 142 women with HER2-negative MBC who received treatment with an NCCN recommended single agent chemotherapy in the context of a clinical trial. Using patient-level immunohistochemistry (IHC) results, we categorized patients as either HER2-low (IHC 1+/2+ and not amplified by in situ hybridization) or HER2-0 (IHC 0). We compared patients’ baseline demographic and clinicopathologic features according to HER2-low vs HER2-0 status. We used Cox proportional-hazard models stratified by HR status to estimate OS and PFS according to HER2-low vs HER2-0 classification while adjusting for patients' baseline demographic and clinicopathologic attributes. Results: Patients with HER2-low disease represented 20% (28/142) of the HER2-negative cohort. Twenty-five percent (7/28) of HER2-low patients had tumors that expressed hormone receptors compared with 17% (19/114) of HER2-0 patients (p=0.31). In this cohort, the maximum follow up time was 38.4 months. For HER2-low patients vs HER2-0 patients, the median OS was 10.7 vs. 12.7 months (p=0.37), and the median PFS was 3.5 vs. 2.9 months (log rank test, p=0.53) respectively. In Cox proportional-hazard models that adjusted for patient demographic and clinicopathologic features and were stratified by HR status, patients with HER2-low tumors had an 16% elevated (non-significant) hazard of death compared with patients with HER2-0 tumors (HR 1.16, 95% CI: 0.69-1.95) and a 22% reduced (non-significant) hazard of progression or death (HR 0.78, 95% CI: 0.45-1.35). Conclusions: Analyses of pooled historic clinical trial data pertaining to women with HER2-negative MBC who were treated with single agent chemotherapy revealed no meaningful clinical differences in either OS or PFS endpoints according to HER2-negative subtypes (i.e., HER2-low vs. HER2-0) after accounting for patient demographic and clinicopathologic features. These results support prior findings from observational research suggesting that there are no biological differences associated with HER2-negative subtypes. Table. Multivariable Cox Proportional Hazards Models for OS and PFS Stratified by Hormone Receptor Status, (N=134) Variable OS PFS HR* 95% CI HR* 95% CI Age (decade) 0.84 0.70-1.01 0.86 0.72-1.01 Race White 1.00 (referent) 1.00 (referent) Black 1.75 0.84-3.63 1.57 0.66-3.73 Asian 0.93 0.47-1.80 1.33 0.71-2.51 Other 1.69 0.45-6.38 2.10 0.62-7.15 Ethnicity Non-Hispanic or Latino 1.00 (referent) 1.00 (referent) Hispanic or Latino 2.10 0.95-4.64 1.02 0.44-2.35 HER2 Characterization HER2-0 1.00 (referent) 1.00 (referent) HER2-1+/2+ 1.16 0.69-1.95 0.78 0.45-1.35 Prior Lines of Chemotherapy for Metastatic Disease 0 1.00 (referent) 1.00 (referent) 1 0.82 0.46-1.46 1.13 0.65-1.95 2 0.69 0.35-1.36 1.00 0.52-1.93 3 0.59 0.10-3.42 2.18 0.45-10.50 ECOG Performance Status 0 1.00 (referent) 1.00 (referent) 1 1.65 1.07-2.54 1.57 1.02-2.43 Legend: OS=overall survival; PFS=progression-free survival; HR=hazard ratio; HER2=human epidermal group factor receptor 2; ECOG=Eastern Cooperative Oncology Group. *Analyses adjusted for clinical trial membership (coefficients not reported) Citation Format: Elizabeth Lamont, Emily Stein, Paolo Tarantino, Sara Tolaney, Corinne Ahlberg, Krishna Chinnathambu, Jiezhi Qi, Kala Tummagunta, Jackie Bilan, Ruthanna Davi, Lisa Ensign. Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-12.

Positive relationship between plant diversity dietary patterns and disease activity in Australian adults with Inflammatory Bowel Disease

Diet is implicated in the development of Inflammatory Bowel Disease (IBD). However, the role of diet in reducing inflammation and managing prevalent disease is unclear (1–3). Previous studies have analysed the relationship between dietary patterns and occurrence of flares or symptoms, but not disease activity or inflammation (4–5). It is important to explore the role of habitual diet in management of IBD to provide targeted dietary recommendations. We explored the relationship between dietary intake with disease activity and inflammation in an Australian adult cohort with and without IBD. We analysed dietary and clinical data from the Australian IBD Microbiome (AIM) study. AIM is a prospective longitudinal cohort study of adults and children with Crohn’s Disease (CD), Ulcerative colitis (UC) and healthy controls (HC). Habitual dietary intake of food groups, fibre, polyphenols and fermented foods was collected by merging dietary data from 3-day food records and food frequency questionnaires with PhenolExplorer and the Australian Fibre Categories Database. Dietary patterns were explored using Principal Component Analysis (PCA) and cluster analysis (CA) in IBM SPSS Statistics (V29). Associations between dietary intake, clinical disease activity categorised as remission or active, and faecal calprotectin (FCAL) were explored in adult participants. A total of 412 participants (IBD = 223, HC = 189) were included. FCAL data was available for 211 participants (HC = 100, CD = 49, UC = 62). Median (IQR) FCAL at baseline was 20 (20) mg/kg for HC and 33 (127) mg/kg for IBD, indicating clinically irrelevant inflammation (FCAL &gt;50mg/kg = clinical inflammation). PCA identified 7 distinct dietary patterns for adults with IBD. A dietary pattern of high plant diversity was associated with active CD. In the total IBD cohort, low association to a 'Prudent’ pattern was positively associated with low FCAL, and high association to a 'Meat-eaters’ dietary pattern was positively associated with moderate FCAL. CA revealed 3 distinct clusters amongst participants with IBD. No significant difference between diet cluster and disease activity or FCAL was seen. There were no significant differences in intake of fibre or polyphenols between remission vs active disease in participants with IBD. A significant difference between total, soluble and insoluble fibre and FCAL categories was seen with a higher fibre intake associated with lower FCAL. Higher plant-diversity and 'Prudent’ dietary patterns are associated with active disease and higher FCAL in Australian adults with IBD. Reverse causality cannot be ruled out, with analysis of larger cohorts and clinical trial data needed to clarify this.

Pharmacokinetic Profile of Brepocitinib with Topical Administration in Atopic Dermatitis and Psoriasis Populations: Strategy to Inform Clinical Trial Design in Adult and Pediatric Populations

IntroductionTopical brepocitinib, a tyrosine kinase (TYK)2/Janus kinase (JAK)1 inhibitor, is in development for psoriasis (PsO) and atopic dermatitis (AD). Quantitative analyses of prior clinical trial data were used to inform future clinical trial designs.MethodsTwo phase 2b studies in patients with AD and PsO were used to characterize the amount of topical brepocitinib and the resultant systemic trough concentration (CTrough) using a linear mixed-effects regression (LMER). This model was used to predict brepocitinib systemic CTrough for higher treated body surface areas (BSAs) in adults and children. Information from non-clinical and clinical trials with oral brepocitinib was leveraged to set safety thresholds. This combined approach was used to inform future dose-strength selection and treated BSA limits.ResultsData from 256 patients were analyzed. Patient type, dose strength, and frequency had significant impacts on the dose–exposure relationship. Systemic concentration in patients with PsO was predicted to be 45% lower than in patients with AD from the same dose. When topically applied to the same percentage BSA, brepocitinib systemic exposures are expected to be comparable between adults and children. The systemic steady-state exposure after 3% once daily and twice daily (2 mg/cm2) cream applied to less than 50% BSA in patients with AD and PsO, respectively, maintains at least a threefold margin to non-clinical safety findings and clinical hematologic markers.ConclusionThe relationship between the amount of active drug applied and brepocitinib systemic CTrough, described by LMER, may inform the development strategy for dose optimization in the brepocitinib topical program.

Abstract 2014: Tumor glycosylation impacts the efficacy of HER2 targeting therapies

Abstract Cancer progression remains a major obstacle to the successful treatment of cancer. In HER2+ breast cancer, targeting therapies against HER2 have revolutionized the treatment landscape. However, predictive factors for response are largely unknown and a significant number of patients develop resistance. An extensive body of work has revealed a plethora of mechanisms of resistance. However, a key aspect of cancer cells has been largely overlooked: their aberrant glycosylation profile. Aberrant glycosylation of proteins is a hallmark in cancer and has been linked to multiple processes such as invasion, angiogenesis and modulation of the immune response. Yet the influence of altered glycosylation on the efficacy of HER2-targeted therapies remains unknown. Therefore, here, we address this question using clinical data, 3D co-culture systems and advanced live microscopy. Bioinformatics analysis of SPY-2 clinical trial data reveals an association of specific glycogenes with response to HER2-targeting therapies in breast cancer patients. We validated these findings in resistance cell models generated in-vitro and in-vivo using gain and loss of function assays. Furthermore, to provide a more relevant cell model system, we implement the use of 3D co-cultures of cancer spheroids and immune cells. Thus, our research addresses a largely unexplored area in cancer biology combining clinical data from tumor biopsies, trastuzumab-resistant cancer cell models and, live imaging of 3D heterotypic cultures. This work holds the potential to identify new markers of response to therapies and highlights the importance of the interplay of cancer cells and their microenvironment on the efficacy of current treatments. Citation Format: Ana Ruiz-Saenz, Roos Vincken, Denise Wolf, Veronica Steri, Laura van't Veer, John Martens, Danny Huylebroeck, Mark M. Moasser. Tumor glycosylation impacts the efficacy of HER2 targeting therapies [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 2014.

Enhanced doubly robust estimation with concave link functions for estimands in clinical trials

ABSTRACT For observational studies or clinical trials not fully randomised, the baseline covariates are often not balanced between the treatment and control groups. In this case, the traditional estimates of treatment effects are biased, and causal inference method is needed to get unbiased estimate. The doubly robust estimator (DRE) is a recent popular development in casual inference. However, the unbiasedness of DRE relies on the correct specification of either propensity score or outcome models, which is hardly guaranteed. To overcome this issue, Yuan et al. [(2021), ‘Enhanced Doubly Robust Procedure for Causal Inference’, Statistics in Bioscience, 13(3), 454–478. https://doi.org/10.1007/s12561-021-09300-y.] proposed an enhanced doubly robust estimator which utilises semiparametric models and nonparametric monotone link functions for both propensity score and outcome models. In this article, we further develop an enhanced doubly robust estimator with concave link functions for both propensity score and outcome models. The asymptotic properties of the enhanced doubly robust estimator are studied. Simulation studies are conducted to evaluate the proposed method. A clinical trial data analysis is used to illustrate the method.

Dyspnea-Related Dimensions And Self-Efficacy: Associations With Well-Being in Advanced Lung Cancer

ContextDyspnea is a complex, multidimensional symptom comprising sensory-perceptual, affective, and functional domains that commonly persists in patients with lung cancer and impairs mental health and quality of life (QOL). However, data are lacking on how dyspnea's dimensions or self-efficacy to manage dyspnea are associated with patient outcomes. ObjectivesTo assess the associations of dyspnea dimensions (dyspnea-related sensory–perceptual experience, affective distress, and functional impact) and dyspnea self-efficacy with depression, anxiety, and QOL in patients with advanced lung cancer reporting dyspnea. MethodsWe conducted a secondary analysis of baseline clinical trial data testing a supportive care intervention for dyspnea. Patients with advanced lung cancer reporting at least moderate dyspnea (≥2 on the Modified Medical Research Council Dyspnea Scale) self-reported dyspnea and patient outcome measures. Hierarchical regressions tested the associations of the dyspnea dimensions with depressive and anxiety symptoms (Hospital Anxiety and Depression Scale) and QOL (Functional Assessment of Cancer Therapy-Lung) while adjusting for variables known to affect these outcomes. ResultsThe sensory–perceptual experience of dyspnea (effort) was associated with worse depressive symptoms (b = 0.21, P < 0.01) and QOL (b = −0.53, P = 0.01). Dyspnea self-efficacy was associated with improved depressive (b = −1.26, P < 0.01) and anxiety symptoms (b = −1.72, P < 0.01) and QOL (b = 3.66, P < 0.01). The affective and functional dimensions of dyspnea were not associated with the patient outcomes in the final models. ConclusionsDyspnea-related sensory–perceptual experience and self-efficacy were associated with mental health and QOL outcomes in patients with lung cancer. Examining the individual contributions of dyspnea's multiple dimensions provides a nuanced understanding of its patient impact.

Disparities in prostate cancer mortality and clinical trial availability across vulnerable populations.

24 Background: Clinical trials provide high-level evidence and test novel therapies that have significantly improved cancer outcomes. However, disparities in clinical trial participation and cancer mortality persist across race/ethnicity and vulnerable populations, notably in patients with prostate cancer (PCa). Adverse social determinants of health (SDOH) and systemic barriers may underlie these disparities. Identifying and overcoming these barriers may improve access to and representation in clinical trials, thereby promoting equitable advancement and applicability of science. For these reasons, we evaluate the association between clinical trial availability, cancer mortality, and population-level SDOH in PCa. Methods: Using custom data linkage from ClinicalTrials.gov, Surveillance Epidemiology and End Results (SEER) Registry, and the Centers for Disease Control and Prevention Social Vulnerability Index (SVI), we performed a cross-sectional analysis of county-level PCa clinical trial data, cancer incidence and mortality rates, and population-level SDOH. We included Phase 2 and Phase 3 interventional PCa clinical trials with start dates from 2007 to 2022. The total number of clinical trials over the study period was calculated per county and population-adjusted for 100,000 residents. Counties were stratified into quintiles based on SVI (i.e., least vulnerable to most vulnerable). Population-adjusted clinical trial availability, cancer incidence, and cancer mortality were compared across SVI quintiles. Multivariable logistic and linear regression analyses were performed to evaluate the association between SVI and clinical trial availability and cancer mortality, respectively. Results: The mean number of PCa trials per 100,000 residents was 25.6, with the most vulnerable counties having fewer clinical trials compared to the least vulnerable counties (mean 18.1 vs. 50.0, p&lt;0.05). Further, the most vulnerable counties had a lower PCa incidence rate per 100,000 residents (mean 393.8 vs. 411.7, p&lt;0.05), but a higher PCa mortality rate per 100,000 residents (mean 85.7 vs. 72.0, p&lt;0.05). On multivariable regression analysis, the most vulnerable counties were associated with significantly decreased odds of having any PCa clinical trial (OR 0.3, 95% CI 0.2 – 0.4) and significantly increased PCa mortality (10.8, 95% CI 7.4 – 14.3), while the presence of any PCa clinical trial was associated with significantly decreased PCa mortality (-6.9, 95% CI -9.1 – -4.7). Conclusions: The most vulnerable counties were far less likely to have any PCa clinical trials despite having a significantly higher PCa mortality rate. The presence of a PCa clinical trial was associated with a reduction in PCa mortality. These vulnerable counties represent scientifically underserved populations that may benefit from equity-driven clinical trial enrollment and cancer care infrastructure expansion.

Blue light cystoscopy versus white light cystoscopy for the detection of bladder cancer in China: An analysis of unpublished clinical trial and real-world data.

Blue light cystoscopy versus white light cystoscopy for the detection of bladder cancer in China: An analysis of unpublished clinical trial and real-world data.

Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101).

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

Clonal hematopoiesis of indeterminate potential (CHIP), treatment outcomes and adverse events in gastrointestinal cancers: A pooled analysis of clinical trial and real-world data.

169 Background: Clonal hematopoesis of indeterminate potential (CHIP) is the acquisition of somatic mutations leading to clonal expansion of hematopoietic stem cells and is a common incidental finding in circulating tumor DNA (ctDNA). Inflammation from these cells or a reduced marrow reserve may impact treatment outcomes or adverse events. We investigated the incidence of CHIP in ctDNA from patients with gastrointestinal (GI) cancers and explored its association with outcomes and adverse events (AEs). Methods: We collected ctDNA results from a local prospective metastatic colorectal cancer (mCRC) cohort (PREDICT-L) and ctDNA data from two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care [BSC] in mCRC) and CCTG PA.7 (gemcitabine and nab-paclitaxel [GN] with or without D+T in metastatic pancreatic adenocarcinoma [mPDAC]). CHIP+ was defined as the presence of a variant of ≥2% variant allele frequency annotated in the ctDNA report in any of the genes DNMT3A, TET2, ASXL1 and ATM, and not annotated as germline by respective sequencing platforms. The first line of treatment after ctDNA was reviewed, and grade ≥3 or dose-limiting adverse events were documented. Results: The prevalence of CHIP varied from 10% to 18% (see table). CHIP+ patients were older than CHIP- in the CO.26 cohort (p=0.011), and ECOG was higher in CHIP+ patients in the PREDICT-L cohort. There was no difference between CHIP+/- patients with regards to sex. DNMT3A was the gene most frequently mutated in all three cohorts. There was no significant difference in PFS or OS between the CHIP+/- groups, both in those treated with chemotherapy (Chemo) or immunotherapy (IO). The most common AEs were rash, GI toxicities and bleeding/clotting abnormalities. There was no significant difference in the rates of AEs between the CHIP+/- groups for those treated with Chemo or IO. Conclusions: CHIP is a common alteration in ctDNA but did not impact PFS, OS, or the chance of developing an AE. [Table: see text]

Testosterone nadir and clinical outcomes in patients with advanced prostate cancer: Post hoc analysis of triptorelin pamoate Phase III studies.

The objective of the study is to evaluate whether low nadir testosterone during treatment with triptorelin pamoate, a luteinising hormone-releasing hormone (LHRH) agonist, is associated with improved clinical outcomes in patients with advanced prostate cancer using a retrospective analysis of clinical trial data. Data were pooled from three prospective, 9-12-month Phase III studies of triptorelin monotherapy in patients with advanced prostate cancer (including NCT00751790). The serum testosterone concentration suppression targets evaluated were <0.35 nmol/L (<10 ng/dl), <0.7 nmol/L (<20 ng/dl), <1.7 nmol/L (<50 ng/dl) and ≥1.7 nmol/L. Overall survival (OS) and disease-specific survival (DSS) by testosterone suppression group were assessed by Kaplan-Meier analysis, with log-rank test. The time frame for the primary analysis was Days 1-518 (median OS follow-up 254 days [range, 29-518 days]) and for the sensitivity analyses was Days 1-262. Supplementary analyses combined the ≥0.7- to <1.7-nmol/L and ≥1.7-nmol/L groups. The sample size comprised 592 patients (most received triptorelin monotherapy; four reported concomitant androgen receptor-axis-targeted therapy). Nadir testosterones of <0.35, ≥0.35 to <0.7, ≥0.7 to <1.7 and ≥1.7 nmol/L were achieved by 96%, 3.2%, 0.34% and 0.17% of patients, respectively. Better OS with decreasing level of nadir testosterone was observed (p < 0.001) and this persisted after sensitivity/supplemental analyses (all p < 0.001). Differences in DSS with decreasing levels of nadir testosterone were not statistically significant in the primary analysis. Sensitivity/supplemental analysis showed better DSS with decreasing level of nadir testosterone (Days 1-262, p = 0.01; combined groups Days 1-518, p = 0.03; combined groups Days 1-262, p = 0.005). Low nadir testosterone achieved during treatment with the LHRH agonist triptorelin was associated with improved OS and DSS in patients with advanced prostate cancer.

Immune checkpoint inhibitors for patients with microsatellite instability-high colorectal cancer: protocol of a pooled analysis of clinical trials.

Colorectal cancer (CRC) is the third most common cause of cancer and the second leading cause of cancer-related deaths worldwide. Microsatellite instability-high (MSI-H) is a distinct molecular subtype of CRC that occurs in approximately 15% of all cases. Recently, immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic approach for patients with MSI-H colorectal cancer, exhibiting higher response rates than standard chemotherapies. To assess the effectiveness and safety of ICIs for the treatment of patients with MSI-H CRC, we propose a comprehensive pooled analysis of clinical trial data. A systematic search of multiple electronic databases, including PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov, will be conducted from their inception until September, 2023 to identify eligible randomized controlled trials (RCTs) and non-randomized studies. Inclusion criteria comprise studies of adult patients with histologically confirmed MSI-H CRC treated with immune checkpoint inhibitors, with a comparison to a control group receiving conventional therapies. Outcomes of interest will be overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and incidence of treatment-related adverse events (AEs). The Cochrane Risk of Bias tool and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool will be employed to evaluate the methodological quality of included studies. A random-effects model using the DerSimonian and Laird method will be applied for pooling the effect estimates, calculating hazard ratios (HRs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs). Heterogeneity will be assessed using I² statistics, and subgroup analysis and meta-regression will be performed to explore potential effect modifiers in case of substantial heterogeneity. Publication bias will be evaluated with funnel plots and Egger's test. Sensitivity analysis will be conducted to assess the robustness of the results. This meta-analysis will synthesize available evidence from clinical trials on immune checkpoint inhibitors in treating MSI-H colorectal cancer. The findings will offer valuable information about the effectiveness and safety of ICIs in this patient population, contributing to the refinement of clinical guidelines and enhancing the decision-making process for healthcare providers, policy-makers, and patients. The comprehensive analysis of subgroups and sensitivity allows for an in-depth understanding of potential effect modification, providing essential directions for future research. This study will involve the use of published data; hence, ethical approval is not required. The results of the study will be disseminated through publications in peer-reviewed journals and presentations at relevant conferences. The findings will potentially impact clinical decision-making and contribute to the development of evidence-based treatment recommendations for patients with MSI-H colorectal cancer. Open Science Framework identifier, 10.17605/OSF.IO/ZHJ85.

Medium-chain triglycerides (8:0 and 10:0) increase muscle mass and function in frail older adults: a combined data analysis of clinical trials.

Three clinical trials have examined the chronic effects of medium-chain triglycerides (MCTs) on muscle mass and function in frail older adults (mean age 85 years old). However, significant increases in muscle mass and some muscle function relative to long-chain triglycerides (LCTs) have yet to be shown, possibly due to the small number of participants in each trial. We re-analyzed these previous clinical trials to clarify whether MCT supplementation can increase muscle mass and function. After adding post hoc tests to the original report, we compared changes in measurement between the MCT and LCT groups in the first 2 trials and conducted a combined data analysis. In a combined data analysis, changes from baseline in measurements at the 3 months intervention in the MCTs- and LCTs-containing groups were assessed by analysis of covariance adjusted for baseline values of each measurement, age, sex, BMI, allocation to trial, habitual intakes in energy, protein, leucine, octanoic acid, decanoic acid, and vitamin D during the baseline period. The Mann-Whitney U test was used to analyze data on right and left knee extension times. MCT supplementation for 3 months increased muscle function relative to LCT supplementation with and without an L-leucine (1.2 g) and vitamin D (cholecalciferol, 20 μg)-enriched supplement. In a combined data analysis (n = 29 in MCTs, n = 27 in LCTs), relative to supplementation with 6 g LCTs/day, supplementation with 6 g MCTs/day at dinner for 3 months significantly increased body weight (adjusted mean change from baseline: MCTs 1.2 vs. LCTs 0.2 kg, p = 0.023), right arm muscle area (MCTs 1.4 vs. LCTs-0.7 cm2, p = 0.002), left calf circumference (p = 0.015), right-hand grip strength (MCTs 1.6 vs. LCTs 0.3 kg, p = 0.017), right knee extension time (p = 0.021), left knee extension time (p = 0.034), walking speed (p = 0.002), and number of iterations in leg open and close test (p < 0.001) and decreased right triceps skinfold thickness (p = 0.016). In frail older adults, supplementation for 3 months with a low dose (6 g/day) of MCTs (C8:0 and C10:0) increased muscle mass and function. These findings indicate the potential for the practical use of MCTs in daily life in treating sarcopenia.

Tailor: Interventional Study Evaluating Physician's Choice of Ibrutinib Monotherapy or Ibrutinib-Venetoclax Combination Using Dose Modifications and Alternate Dosing Approaches in Patients with Untreated Chronic Lymphocytic Leukemia

Background: Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor (BTKi) that has changed the treatment paradigm for patients with chronic lymphocytic leukemia (CLL) with durable responses and improved overall survival (OS). In the pivotal Phase 3 GLOW and Phase 2 CAPTIVATE trials, fixed-duration combination of ibrutinib-venetoclax (I+V) resulted in deep and sustained clinical responses, and a broadly manageable safety profile in patients with CLL. Several factors including genetic features, disease status, comorbidities, patient preferences, and safety profiles contribute to selection of the optimal therapeutic option for patients with CLL in the first-line setting. Adverse events (AEs), such as atrial fibrillation, bleeding, and hypertension, have been seen with the BTKi therapeutic class.Long-term clinical and real-world experience with ibrutinib has led to specific guidance regarding AE management, which has been included in the updated ibrutinib prescribing information (US PI, May 2022; EU SmPC, April 2023). Retrospective evidence, including post-hoc analyses of clinical trial data, demonstrates that dose reduction of ibrutinib mitigates recurrence or worsening of AEs while preserving efficacy. Thus, these findings together support the rationale to prospectively evaluate the impact of regimen and dosing flexibility of ibrutinib in patients with untreated CLL. Aim: The key objective of the TAILOR study (NCT05963074) is to assess the efficacy and safety of I+V and ibrutinib monotherapy regimens with both a proactive and reactive dose adjustment in patients with untreated CLL. Methods: TAILOR is a phase 2, two-arm, four-cohort interventional study designed to provide physicians the choice of ibrutinib monotherapy or I+V combination therapy for previously untreated patients with CLL and prospectively evaluate proactive and reactive dose adjustment approaches. Eligible patients will have previously untreated active CLL, needing therapy as per iwCLL 2018 criteria. Key exclusion criteria include significant active or history of cardiovascular disease, uncontrolled hypertension, and ECOG performance status &amp;gt; 2. Patients will be randomized after selection of regimen: I+V fixed-duration regimen (2 cohorts, 80 patients in each cohort) or ibrutinib monotherapy (2 cohorts, 80 patients in each cohort), as per physician's choice. Patients in the I+V arm will receive ibrutinib 420 mg QD as lead-in for 3 cycles plus 12 cycles of either ibrutinib 420 mg QD (Cohort 1a) or 280 mg QD (Cohort 1b) in combination with venetoclax, which will be initiated in cycle 4 with dose ramp-up per label over 5 weeks (20, 50, 100, 200, and 400 mg/day) and continued at 400 mg/day dose from cycle 5 onward. In addition, patients with deletion 17p and/or mutated TP53 will receive optional ibrutinib maintenance. Patients in the ibrutinib monotherapy arm will receive ibrutinib 420 mg QD (Cohort 2a) or 420 mg QD for 3 cycles, then 280 mg QD (Cohort 2b) until progressive disease or unacceptable toxicity ( Figure). All cohorts will follow the dose modification guidance as per protocol based on the US PI/ EU SmPC. The primary endpoint is best overall response rate as assessed by investigators and compared with historic controls. Secondary endpoints include: complete response rate, duration of response, PFS, and OS; undetectable minimal residual disease rate (I+V cohorts only); safety (AEs, discontinuation due to AEs, adherence rates); and patient reported outcomes. The study is currently recruiting patients.

Differing Definitions of Vaso-Occlusion in Clinical Studies of Sickle Cell Disease Can Result in Differing Outcomes

Background: Frequent episodes of vaso-occlusion are the hallmark of sickle cell disease (SCD), but the definition of what constitutes a vaso-occlusive episode is not consistently applied across clinical trials, creating challenges in evaluating and comparing efficacy results among different therapies. Here, we compare vaso-occlusion endpoint definitions from clinical trials for various therapies, including genetic therapies, and use clinical trial data to demonstrate the potential for outcomes differences based on differing definitions of vaso-occlusive episodes. Methods: We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Outcomes related to vaso-occlusion were compared across variables including care setting, care duration, treatments, and complications. Data from the CLIMB SCD-121 trial of exa-cel in patients aged 12 to 35 years with severe SCD (data cut as of 10 Feb 2023) were evaluated using different published definitions of vaso-occlusion. Results: The most substantial differences in vaso-occlusion endpoint definitions were associated with frequency and duration of visits to medical facilities for acute pain and inclusion of specific SCD specific complications. Definitions of vaso-occlusions for acute pain related events differed across studies. The definitions of severe vaso-occlusive crises for exa-cel (severe VOC; exa-cel), sickle cell pain-related crises (SCPC; crizanlizumab and L-glutamine), and VOC (VOC; voxelotor) include events with medical facility visits of any duration (severe VOC and SCPC) or medical records of a patient being seen or contacting a physician within 1 business day of an event (VOC), whereas the definition of severe vaso-occlusive events (severe VOE; lovo-cel) requires a ≥ 24-hour hospital or emergency room (ER) observation unit visit or ≥2 visits to a day unit or ER over 72 hours. Vaso-occlusion definition for HU (painful crisis) required a facility visit of ≥4 hours duration. All endpoints include acute chest syndrome and priapism; however, the definition of severe VOE requires ≥4 visits to a medical facility for priapism to meet criterion, while others require only a single visit. The exa-cel phase 3 trial in SCD employs a broad and inclusive definition for severe VOC which counts each individual medical facility visit, regardless of frequency or duration of hospitalization. Based on this, 19 out of 20 patients (95%) met the primary endpoint of freedom from severe VOCs for at least 12 consecutive months (95% CI, 75.1%, 99.9%; P&amp;lt;0.0001). However, when the primary endpoint was analyzed using the severe VOE definition, all patients (20/20; 100.0%) were free from severe VOEs for at least 12 consecutive months (95% CI: 83.2%, 100.0%; P&amp;lt;0.0001). Conclusions: Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion definitions have the potential to impact assessments of treatment efficacy across different SCD therapies.

Immune Checkpoint Inhibitors and the Risk of Cardiovascular Adverse Events: A Pooled Clinical Trial Database Analysis

Introduction Immune checkpoint inhibitors (ICIs) are a highly effective class of cancer immunotherapy, but their use has been limited by immune-related adverse events (irAEs) affecting various organ systems. Recent real-world studies have shown higher incidence rates of cardiovascular (CV) events in patients with cancer who are treated with ICIs compared to those treated with conventional chemotherapy (Laenens et al, J Clin Oncol 2022). Studies suggest that the underlying mechanism involves a pro-inflammatory response causing unintended vascular compromise, but there have been limited data on ICI-related cardiotoxicity across pooled datasets. Given that ICIs have been applied to lung cancer treatment in recent years, we use it as an example indication to study clinical trial (CT) patients with advanced non-small cell lung cancer (aNSCLC) randomized to either a first-line (1L) ICI-containing regimen or to 1L chemotherapy alone (chemo) to evaluate for potential differential rates of CV events. Methods We pooled patient-level, phase 3 CT data on aNSCLC patients treated with ICI or chemo from the Medidata Enterprise Data Store. Treatment assignment was the main variable of interest. The primary outcome was a composite CV event (acute coronary syndrome, heart failure, stroke, transient ischemic attack), occurring between the start of study treatment (index date) and 30 days following the last dose of study treatment. Incidence rates and the relative hazard of a CV event by treatment assignment were estimated. Additionally, the risk of CV event with non-CV death treated as a competing risk was estimated using the Fine-Gray model. In a post-hoc subgroup analysis we explored the impact of treatment assignment on overall survival (OS) among patients with and without baseline vascular disease. OS was defined as the time from the index date until the date of death (all-cause). Patients alive at the end of CT follow-up were censored. Results A total of 1862 patients were included in this analysis, with 1128 (60.6%) randomized to ICI and 734 (39.4%) to chemo. Baseline demographics and comorbidities were balanced across treatment groups. Forty-six (2.5%) patients experienced at least 1 CV event. The incidence rate of CV events was 2.48 times (95% CI: 1.10, 6.57) higher among patients treated with ICI compared to chemo. The unadjusted hazard of composite CV event, estimated using Kaplan-Meier, differed significantly by treatment assignment (p= 0.008) ( Figure 1). After adjusting for baseline demographics and comorbidities, the hazard of a composite CV event remained higher for patients treated with ICI compared to chemo (aHR 2.68, 95% CI: 1.19-6.06) ( Table 1). Baseline vascular disease history (N=359; 19.3%) was also associated with an increased hazard of a CV event (aHR: 2.40; 95% CI: 1.25-4.60). Similar results were found in the competing risk analysis. In the subgroup analysis, patients without baseline vascular disease history had a significant OS benefit from an ICI compared to chemo (aHR 0.84, 95% CI: 0.75-0.95), whereas patients with baseline vascular disease did not (aHR 1.00, 95% CI: 0.78-1.27). Conclusion Though ICIs enhance the body's immune responses against cancer, it is important to study the associated effect of irAEs on off-target tissues. These analyses of historical CT data suggest a positive association between 1L treatment of aNSCLC with ICI and subsequent composite CV events compared with chemo alone. Given the high prevalence of morbidity among patients with lung cancer, the use of concomitant cardioprotective therapies may be an important consideration when treating cancer populations with ICIs. Pooling CT data increases the power to detect clinically important differences in rare toxicities and may inform future research and patient-physician decision-making regarding the suitability of ICI use in aNSCLC treatment. Furthermore, this research highlights the potential clinical utility of drug repurposing: expanding the use of drugs approved to treat CV events and exploring their use in patients with vascular disease who are also being treated with ICIs. As cell-mediated immune responses play a key role in the potential CV effects of ICI treatments, future studies are needed to define the underlying mechanisms of ICI-related dysregulation of the immune system to better monitor patients and improve clinical outcomes in the context of immunotherapy for aNSCLC and other cancer types.