Trial Of Combination Research Articles

Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria

BackgroundThe combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.MethodsTwenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study.ResultsFor a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28 in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively.ConclusionsThese results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.Trial registrationThis study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.

An investigation into the contributing factors to survival of ARDS patients supported by veno-venous ECMO.

This study aimed to identify characteristics associated with survival during and post Extra Corporeal Membrane Oxygenation (ECMO) therapy, in patients with acute respiratory distress syndrome (ARDS) during the COVID-19 pandemic. A retrospective observational study on 94 consecutive patients with confirmed COVID-19 induced ARDS supported by ECMO was carried out 49/94 (52.7%) patients survived to hospital discharge. Non-survivors were found to have significantly (p < .05) higher: Pre-ECMO International normalized ratios (INR), carbon dioxide partial pressure (pCO2), Acute Kidney Injury (AKI) scores and blood urea levels. Also, lower pre-ECMO peak inspiratory pressures (PIP), mean arterial pressure, saturation of arterial oxygen (SaO2), blood bicarbonate levels (HCO3), blood Ph and fewer trials off ECMO with shorter combined trial off times. Patients that did not survive were more likely to have renal impairment and have received peri-ECMO haemofiltration. Poor prognosis was significantly associated with: receiving pre-ECMO nitric oxide (HR = 3.047, CI = 1.247-7.447, p = .015), renal impairment (HR = 3.023, CI = 1.586-5.763, p < .001), AKI of 2 (HR = 3.611, CI = 1.382-9.441, p = .009) or 3 (HR = 3.275, CI = 1.235-8.685, p = .017), peri-ECMO haemofiltration (HR = 2.412, CI = 1.310-4.442, p = .005) and the ABO blood group B (HR = 3.103, CI = 1.335-7.212, p = .008). pre-ECMO high CO2 (HR = 1.134, CI = 1.031-1.248, p = .010), blood lactate (HR = 1.350, CI = 1.156-1.576, p < .001), INR (HR = 2.571, CI = 1.438-4.598, p=<0.001) and lower blood Ph (HR = 0.023, CI = 0.002-0.210, p < .001). Commonly used mortality scores may not be of use in a COVID-19 cohort of ECMO patients. The initiation of ECMO needs to be implemented prior to metabolic derangements, renal and fulminant respiratory failure.

APOE ε4 and Dietary Patterns in Relation to Cognitive Function: An Umbrella Review of Systematic Reviews.

Carrying the apolipoprotein ε4 allele (APOE ε4) is the strongest genetic risk factor for late-onset Alzheimer's disease. There is some evidence suggesting that APOE ε4 may modulate the influence of diet on cognitive function. This umbrella review of systematic reviews evaluates the existing literature on the effect of dietary interventions on cognitive and brain-imaging outcomes by APOE status. PubMed, EMBASE, Web of Science, and Scopus were searched using terms appropriate to each area of research, from their respective starting dates of coverage until March 2023. Two independent reviewers conducted data extraction and performed a quality appraisal using the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. Six total reviews were included in the final analysis. Four reviews evaluated randomized controlled trials on individuals aged 50-93 years ranging the entire cognitive continuum. One review combined observational studies and clinical trials conducted on both cognitively healthy and cognitively impaired individuals (age range: 50-90), and 1 review included observational studies of both cognitively healthy and cognitively impaired adults (age range: 50-75). Both observational studies and clinical trials yielded inconclusive results attributed to both practical limitations associated with longitudinal follow-up and issues of methodological quality. Except for the Mediterranean diet, dietary interventions, such as the ketogenic diet, nutraceuticals, and supplements, were generally not effective in older APOE ε4 carriers. This review considers plausible biological mechanisms that might explain why older and cognitively impaired APOE ε4 carriers were less likely to benefit. This review identifies notable gaps in the literature, such as a shortage of studies conducted in middle-aged and cognitively healthy APOE ε4 carriers assessing the impact of dietary interventions and provides suggestions for novel trial designs.

Research on safety control technology of high-speed railway combined test based on threatening event analysis

PurposeSafety management is a key point and poses a challenge in joint testing. To detect and address potential accidents' hidden dangers early, this paper conducts research on the safety control technology for high-speed railway joint tests by incorporating the concept of hazardous events.Design/methodology/approachAiming at ensuring the safety of high-speed railway combined inspections and trials, this paper starts from the dual prevention mechanism. It introduces the concept of threatening events, defines them and analyzes the differences between threatening events and railway accidents. The paper also proposes a cause model for threatening events in high-speed railway combined inspections and trials, based on three types of hazard sources. Furthermore, it conducts research on the control strategies for these threatening events.FindingsThe research on safety control technology for high-speed railway combined operation and testing, based on the analysis of threatened events, offers a new perspective for safety management in these operations. It also provides theoretical and practical support for the transition from passive prevention to active risk pre-control, which holds significant theoretical and practical value.Originality/valueThe innovation mainly includes the following three aspects: (1) Building on the traditional dual prevention mechanism, which includes risk hierarchical management and control as well as hidden danger investigation and management, a triple prevention mechanism is proposed. This new mechanism adds the management of threatening events as the third line of defense. The aim is to more comprehensively identify and address potential security risks, thereby enhancing the efficiency and effectiveness of security management. (2) In this paper, the definition of a railway threatening event is clarified, and the causative model of a high-speed railway threatening event based on three kinds of danger sources is proposed. (3) This paper puts forward the control strategy of the high-speed railway combined operation and trial, which includes five key links: identification, reporting, analysis, rectification and feedback, which provides a new perspective for the safety management of the high-speed railway combined operation and trial and has important theoretical and application value.

Combined Phase 1/2a Initial Clinical Safety Trials and Proof-of-Concept Assessment of a Novel Antimicrobial Peptide KSL-W Anti-Plaque Chewing Gum.

The effective control of dental plaque is crucial for oral health, given that pathogenic bacteria in plaque are the primary cause of dental caries. Current antimicrobial agents, although effective, disrupt the oral microbiome and lead to oral dysbiosis, hindering efforts to curb dental caries. Novel antimicrobial peptides offer a promising solution due to their selective bactericidal activity against cariogenic bacteria. This study explores the initial safety and efficacy of KSL-W formulated into chewing gum through a Phase 1 and 2a clinical trial. The combined trial, approved by the FDA, follows a double-blind, randomized, placebo-controlled design. Phase 1 assessed safety with single doses (2-100 mg), whereas Phase 2a explored both safety and proof of concept in reducing oral bacteria with multiple doses (4-75 mg). Besides adverse events (Phase 1), outcome measures included whole-mouth plaque and gingival index scores and bleeding on probing (Phase 2a). KSL-W demonstrated safety in both phases, with no severe adverse events. The proof-of-concept analysis revealed a decrease in plaque and gingival inflammation, particularly at doses ≥ 20 mg. The 30 mg dose appeared to yield optimal effects without any adverse reactions in subjects. Results from this study indicate that KSL-W is safe for use in humans and provides initial evidence of its potential efficacy in reducing plaque and gingival inflammation. Further research is essential to determine optimal usage and ultimate safety, and to assess its potential in diverse populations. The trial is registered with the FDA (Trial Registration Number: NCT01877421). The clinical trials were registered in the clinicaltrials.gov database under the title "Safety and Tolerability of Antiplaque Chewing Gum in a Gingivitis Population" and the identifier number is NCT01877421. The URL for accessing the study in clinicaltrials.gov is https://clinicaltrials.gov/study/NCT01877421?intr=Antiplaque%20chewing&rank=1.

HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

Toxicity Adaptive Lists Design: A Practical Design for Phase I Drug Combination Trials in Oncology.

We introduce a novel algorithmic approach to design phase I trials for oncology drug combinations. Our proposed Toxicity Adaptive Lists Design (TALE) is straightforward to implement, requiring the prespecification of a small number of parameters that define rules governing dose escalation, de-escalation, or reassessment of previously explored dose levels. These rules effectively regulate dose exploration and control the number of toxicities. A key feature of TALE is the possibility of simultaneous assignment of multiple-dose combinations that are deemed safe by previously accrued data. A numerical study shows that TALE shares comparable operative characteristics, in terms of identification of the maximum tolerated dose (MTD), to alternative approaches such as the Bayesian optimal interval design, the COPULA, the product of independent beta probabilities escalation, and the continual reassessment method for partial ordering designs while reducing the risk of overdosing patients. The proposed TALE design provides a favorable balance between maintaining patient safety and accurately identifying the MTD. To facilitate the use of TALE, we provide a user-friendly R Shiny application and an R package for computing relevant operating characteristics, such as the risk of assigning highly toxic dose combinations.

Immune checkpoint inhibitor combinations for patients with advanced endometrial cancer: a network meta-analysis and cost-utility analysis

BackgroundImmune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.ObjectiveTo compare the efficacy, safety, and cost-effectiveness of different immunotherapy combinations for clinician and...

Prospective Evaluation of Supplemental External Beam Radiation Therapy With Palladium-103 Prostate Brachytherapy: Long-Term Results of the 44/20/0 Trials

PurposeThe 44/20 and 20/0 randomized trials evaluated whether different external beam radiation therapy (EBRT) dosing regimens prior to brachytherapy impacted biochemical failure (BF). We report long-term outcomes of both trials, and evaluate whether biological equivalent dose (BED) was associated with reduced BF in the combined trial cohort. Materials/methodsBoth trials enrolled patients with clinical T1c-T2b, Gleason score 7-9 and/or a pre-treatment prostate-specific antigen (PSA) 10-20 ng/ml disease. The 44/20 trial randomized patients to 44Gy EBRT with 90Gy palladium (Pd)-103 versus 20Gy EBRT with 115Gy Pd-103. The subsequent 20/0 trial randomized patients to the 20Gy arm versus monotherapeutic 125Gy Pd-103. For each trial, univariate Fine-Gray analysis evaluated whether treatment arm was associated with BF for the entire cohort and the unfavorable intermediate risk (UIR) subgroup. For the combined trial cohort, multivariate Fine-Gray analysis evaluated whether BED was associated with BF, while adjusting for clinical factors. ResultsThere were 247 analyzable patients in the 44/20 trial. At a median follow-up of 13.7 years, there were no differences in BF for the entire cohort (sub-distribution hazard ratio (sHR) 0.99; 95% CI: 0.43, 2.276; p = 0.97) or the UIR subgroup (sHR 0.72; 95% CI: 0.25, 2.08; p = 0.55). There were 383 analyzable patients in the 20/0 trial. At a median follow-up of 10.4 years, there were no differences in BF for the entire cohort (sHR 0.42; 95% CI: 0.13-1.80; p = 0.15) or the UIR subgroup (sHR 0.81; 95% CI: 0.16-4.03; p = 0.80). For the combined cohort (630 patients), BED was not associated with BF (1.00; 95% CI: 0.98-1.02; p = 0.88) on multivariate analyses, while adjusting for androgen deprivation therapy utilization, 4-tiered National Comprehensive Cancer Network category, and year of treatment. ConclusionsBrachytherapy monotherapy should be a standard-of-care treatment for clinically localized, intermediate risk prostate cancer, including UIR disease.

Thirty-five Years of Reporting of Sex and Race in Clinical Studies of U.S. FDA-Authorized Orthopaedic Devices.

At the U.S. Food and Drug Administration (FDA), the mission of the Center for Devices and Radiological Health (CDRH) is to ensure that all patients and providers have timely and continued access to safe, effective, and high-quality medical devices and safe radiation-emitting products. Although the CDRH has observed enrollment differences in some clinical trials, no systematic analysis has been conducted regarding enrollment differences in baseline demographics, to our knowledge. The CDRH has summarized information on study participants and their baseline demographics in public-facing documentation for all authorized medical devices that involved orthopaedic clinical studies from 1985 to 2020. Descriptive analyses and exploratory statistical testing have been conducted to investigate the reported percentages by sex and race compared with those reported in the U.S. National Census and the American Joint Replacement Registry (AJRR), respectively. We identified 94 submissions and corresponding combined clinical trials from 261 original clinical study arms with 34,193 participants. Most of the submissions reported age and sex, while only 36 submissions (38.3%) reported racial demographics. Among the 88 trials providing enrollment by sex, the female enrollment percentage ranged from 22.2% to 88.7%, with a mean of 55.0%. In the submissions that reported racial data (38.3%), White and Black patients had a mean enrollment of 89.2% (range, 64.8% to 98.7%) and 6.2% (range, 0.4% to 20.7%), respectively. The enrollment for other minority groups ranged from 0% to 3.0%. These clinical trials have shown numerically lower female representation (55.0%) but higher White representation (89.2%) than what has been reported in the AJRR. The other racial groups have participated much less than their corresponding percentages in the U.S. population, but they are similarly represented in the AJRR. The clinical trials supporting the FDA's authorization of orthopaedic devices had a wide range of sex and racial enrollments. It appears that female enrollment mirrors the percentage of women in the U.S. population. However, despite prior efforts, some racial groups are still underrepresented. The FDA has made a commitment to advancing health equity as part of the 2022-2025 Strategic Priorities of the CDRH. We hope that the results of this study will help health-care professionals make informed clinical decisions when using medical devices.

Modelling The Effects of Multi-Indication Treatment for Multiple Long-Term Conditions Using Population-Scale Linked Electronic Health Records To Inform Healthcare Policy

Background and ObjectivesHealthcare decision-making has previously focused on developing recommendations for single conditions. This research aimed to develop a modeling framework to estimate the effects of multi-indication treatment in people living with multiple long-term conditions. ApproachUsing a case study in type 2 diabetes mellitus [T2DM], chronic kidney disease [CKD], and heart failure [HF], age-adjusted multistate models were used to estimate the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors as a multi-indication treatment. Baseline hazards were estimated using population-scale, individual-level, linked anonymized electronic health record (EHR) data for 613,195 individuals aged 55 to 85 years in Wales over a 20-year period. Hazard ratios for treatment effects compared to standard of care were obtained from randomized controlled trials for combinations of multiple-long term conditions and incorporated in a patient-level simulation. ResultsSGLT2 inhibitors increased the estimated mean life expectancy from 0.02 (95% Confidence Interval (CI): -0.02, 0.05) to 1.44 (95% CI: 1.12, 1.74) years in people living with coexisting T2DM, CKD, and HF. The estimated gain in life expectancy was less than 0.5 years for individuals with T2DM, CKD, and HF in different temporally ordered sequences. The estimated mean time to develop HF increased by 3.1 (95% CI: 3.00, 3.24) and 1.34 (95% CI: 1.12, 1.56) years in individuals with CKD, and in those with CKD followed by T2DM. Conclusions and ImplicationsThere is an ever increasing need to appraise interventions in people living with multiple long-term conditions to identify optimal treatment strategies and reduce polypharmacy. Multistate models applied to linked EHRs allow for a more rigorous assessment of treatment effects to inform healthcare policy.

Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH

MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron-corrected T1 (cT1) of ≥80ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these non-invasive biomarkers with histological improvement, specifically the resolution of steatohepatitis. We performed a retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders were assessed. Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119ms vs. -49ms) and LFC (-65% vs. -29%) in responders compared to non-responders (p <0.001), respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82ms and for liver fat was a 58% relative reduction. Those achieving a ≥80ms reduction in cT1 were 5-fold more likely to achieve histological response (sensitivity 0.68; specificity 0.70). Those achieving a 30% relative reduction in liver fat were ∼4-fold more likely to achieve a histological response (sensitivity 0.77; specificity 0.53). These results, from a pooled analysis of three drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and LFC) can predict histological response for steatohepatitis following therapeutic intervention. We investigated the utility of two MRI-derived non-invasive tests, iron-corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for metabolic dysfunction-associated steatohepatitis. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis on histology. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health. NCT02443116, NCT03976401, NCT03551522.

618MO Phase Ib/II first-in-class novel combination trial of next generation CDK4-selective inhibitor PF-07220060 and next generation CDK2-selective inhibitor PF-07104091 in HR+ HER2- metastatic breast cancer and advanced solid tumors

618MO Phase Ib/II first-in-class novel combination trial of next generation CDK4-selective inhibitor PF-07220060 and next generation CDK2-selective inhibitor PF-07104091 in HR+ HER2- metastatic breast cancer and advanced solid tumors

Spotlight on polatuzumab vedotin: new standards for diffuse large B-cell lymphoma?

Despite continuous improvements in the management and treatment of diffuse large B-cell lymphoma (DLBCL), approximately 35% of affected patients experience relapse or are refractory to frontline chemotherapy. For these patients, outcomes are far from satisfactory, and a real unmet need exists both to improve frontline treatment and to create better options for relapsed/refractory disease. Polatuzumab vedotin is an anti-CD79b antibody conjugated to the monomethyl auristatin E microtubule inhibitor. The molecule has recently been under the spotlight for the promising results of the frontline combination with rituximab, cyclophosphamide, doxorubicin and prednisone in the phase III POLARIX study, demonstrating improved progression-free survival over standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Remarkable improvements in terms of complete response rate and overall survival have also been achieved with polatuzumab vedotin by combining the antibody with the standard rituximab and bendamustine regimen for relapsed/refractory patients. Based on the results of these studies, health authorities in several countries granted approval for polatuzumab vedotin to be used as treatment both for patients with previously untreated DLBCL and for those with relapsed/refractory DLBCL. In this review, we summarize the data of major studies recently concluded with polatuzumab vedotin, and we provide an overview of the ongoing combination trials for frontline and relapsed/refractory DLBCL, outlining reported toxicities.

Efficacy and Safety of a Novel Low-Dose Triple Single-Pill Combination Compared With Placebo for Initial Treatment of Hypertension

BackgroundSingle-pill combinations of 3 or more low-dose blood pressure (BP)–lowering drugs hold promise for initial or early treatment of hypertension. ObjectivesThe authors conducted a placebo-controlled trial of a new single-pill combination containing low doses of telmisartan, amlodipine, and indapamide in 2 dose options to assess efficacy and safety. MethodsThis international, randomized, double-blind, placebo-controlled, parallel-group trial enrolled adults with hypertension receiving 0 to 1 BP-lowering drugs. After a 2-week placebo run-in during which any BP-lowering medication was stopped, participants were eligible if home systolic BP (SBP) was 130 to 154 mm Hg. Participants were randomized in a 2:2:1 ratio to GMRx2 ¼ dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), GMRx2 ½ dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The primary efficacy outcome was difference in change in home SBP from randomization to week 4, and primary safety outcome was treatment discontinuation due to an adverse event. ResultsFrom June 14, 2021 to October 18, 2023, a total of 295 participants (mean age: 51 years; 56% female) were randomized and 96% completed the trial. Baseline mean home BP was 139/86 mm Hg and clinic BP was 138/86 mm Hg after placebo run-in. The placebo-corrected least square mean differences in home SBP at Week 4 were −7.3 mm Hg (95% CI: −4.5 to −10.2) for GMRx2 ¼ dose and −8.2 mm Hg (95% CI: −5.2 to −11.3) for GMRx2 ½ dose; reductions for clinic BP were 8.0/4.0 and 9.5/4.9 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37%, 65%, and 70% for placebo, GMRx2 ¼ dose, and GMRx2 ½ dose, respectively (both doses P < 0.001 vs placebo). Placebo, GMRx2-triple ¼, and GMRx2 ½ treatment discontinuation due to an adverse event occurred in 1 (1.6%), 0, and 6 (5.1%), respectively; out of normal range serum sodium or potassium was observed in 4 (6.3%), 12 (10.6%), and 12 (10.1%), respectively, but no participant had a serum sodium <130/>150 mmol/L or potassium <3.0/>6.0 mmol/L. Serious adverse events were reported by 2 participants in the placebo and GMRx2 ½ groups and none in the GMRx2 ¼ group. ConclusionsIn a population with mild-to-moderate BP elevation, both dose versions of the novel low-dose triple single-pill combination showed good tolerability and clinically relevant BP reductions compared with placebo. (Efficacy and Safety of GRMx2 Compared to Placebo for the Treatment of Hypertension: NCT04518306)

Comparative Meta-Analysis of Triplet vs. Quadruplet Induction Regimens in Newly Diagnosed, Treatment Naïve, Multiple Myeloma.

The use of 4-drug induction regimens for treatment naïve newly diagnosed multiple myeloma (NDMM) is associated with improved depth of response and progression-free survival (PFS). However, head-to-head trials of 4-drug combinations are lacking, and instead, these regimens are typically compared to 3-drug backbones; limiting the ability to discern whether any additional benefit (or toxicity) is simply additive or represents a synergy (or interaction). We conducted a meta-analysis of phase 2 and phase 3 clinical trials that randomized treatment naïve NDMM patients to either a 4-drug or 3-drug induction regimen. We included 11 trials which represented 6509 unique patients. PFS for all trials in the meta-analysis was 54 months with a 4-drug induction and 8.9 months with a 3-drug induction (HR: 0.49; 95% CI: 0.45; 0.54), but there was no benefit to using a 4-drug induction that did not include an anti-CD38 antibody (PFS 4-drug 8.1 months, PFS 3-drug 8.0 months; HR 0.95; 95% CI 0.86; 1.06). Adverse events were more frequent with the quadruplet regimens but were predominately mild. High-grade (≥3) adverse events (AEs) that were more common with 4-drug regimens were infections (RR: 1.34; 95% CI 1.17; 1.54) and thrombocytopenia (RR: 1.39; 95% CI 1.12; 1.74). This study suggests that 4-drug induction regimens which include an anti-CD38 antibody improve efficacy although with additional toxicity in NDMM patients.

Harnessing the CD44-targeted delivery of self-assembled hyaluronan nanogel to reverse the antagonism between Cisplatin and Gefitinib in NSCLC cancer therapy

The combination of the standard platinum-based chemotherapy with EGFR-tyrosine kinase inhibitor Gefitinib (Gef) principally boosts the anticancer efficacy of advanced non-small cell lung cancer (NSCLC) through non-overlapping mechanisms of action, however the clinical trials of cisplatin (Cis) and Gef combination failed to show a therapeutic improvement likely due to compromised cellular influx of Cis with the Gef interference. To overcome the antagonism between Cis and Gef in anti-NSCLC therapy, here we demonstrated a self-targeted hyaluronan (HA) nanogel to facilitate the anticancer co-delivery by utilizing the HA's intrinsic targeting towards CD44, a receptor frequently overexpressed on lung cancer cells. The co-assembly between HA, Cis and Gef generated a HA/Cis/Gef nanogel of 177.8 nm, featuring a prolonged drug release. Unlike the Gef inhibited the Cis uptake, the HA/Cis/Gef nanogel efficiently facilitated the drug internalization through CD44-targeted delivery as verified by HA competition and CD44 knocking down in H1975 NSCLC model both in vitro and in vivo. Moreover, the HA/Cis/Gef nanogel significantly improved the anticancer efficacy and meanwhile diminished the side effects in reference to the combination of free Cis and Gef. This CD44-targeted HA/Cis/Gef nanogel provided a potent strategy to advance the platinum-based combination therapy towards optimized NSCLC therapy.

Outcomes Among Racial and Ethnic Minority Patients With Advanced Cancers in Phase 1 Trials

Patients from racial and ethnic minority groups (eg, Asian, Hispanic, and non-Hispanic Black patients) have low representation in clinical trials, especially in phase 1 trials in cancer. These trials represent valuable options for patients with advanced cancer who experience disease progression with standard therapy. To determine whether the benefit of enrollment to phase 1 cancer trials extends to Asian, Hispanic, and non-Hispanic Black patients as much as it does for non-Hispanic White patients. Patient records at a single institution from January 1999 to December 2016 were reviewed. Treatment-related responses, toxic effects, and deaths were recorded. All phase 1 studies were included. Data underwent independent extraction by multiple observers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The primary outcome was overall survival (OS), assessed using univariate and multivariable time-to-event analyses. A total of 738 patients (median [range], 60 [22-93] years; 467 [63.3] female) including 197 Hispanic patients (26.7%), 238 non-Hispanic Black patients (32.2%), and 282 non-Hispanic White patients (38.2%), were enrolled in 64 phase 1 trials, including 33 cytotoxic trials (51.5%), 21 biologic trials (32.8%), and 10 combined therapy trials (15.6%). The primary cancer diagnoses were colorectal (187 patients [25.3%]), ovarian (141 patients [19.1%]), lung (58 patients [7.9%]), uterine (49 patients [6.6%]), and breast (41 patients [5.6%]). Patients underwent a median (range) of 3 (0-13) therapies prior to trial enrollment. Among 558 patients evaluated for response, the clinical benefit rate (ie, stable disease plus response rates) was 49.1%, and the overall response rate was 6.5%. Grade 3 or 4 nonhematological toxic effects were observed in 27.8% (95% CI, 24.6%-31.3%) of patients and grade 3 or 4 hematological toxic effects were observed in 19.7% (95% CI, 17.0%-22.8%) of patients. The treatment-related mortality rate was 0.9% (95% CI, 0.4%-1.9%). Median OS was 9.6 (95% CI, 8.2-11.0) months among Hispanic patients, 8.3 (95% CI, 6.7-10.4) months among non-Hispanic Black patients, and 9.8 (95% CI, 8.5-11.4) months among non-Hispanic White patients (P = .13). In a multivariable analysis, age older than 60 years, Eastern Cooperative Oncology Group performance status score of 2 or greater, more than 2 metastatic sites, lactate dehydrogenase grade 1 or 2, grade 2 or greater low albumin, grade 1 or greater total bilirubin, and grade 2 or greater anemia were associated with worse prognosis, whereas leukocytosis greater than grade 1 was associated with better OS. In this meta-analysis assessing outcomes in phase 1 cancer trials among patients from racial and ethnic minority groups, Hispanic and non-Hispanic Black patients had benefits similar to those of non-Hispanic White patients.

A phase 1 clinical trial of NKTR-255 with CD19-22 CAR T-cell therapy for refractory B-cell acute lymphoblastic leukemia

AbstractAlthough chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease–negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854.