Advancing patient-centric care: integrating patient reported outcomes for tolerability assessment in early phase clinical trials - insights from an expert virtual roundtable.

Early phase clinical trials provide an initial evaluation of therapies' risks and benefits to patients, including safety and tolerability, which typically relies on reporting outcomes by investigator and laboratory assessments. Use of patient-reported outcomes (PROs) to inform risks (tolerability) and benefits (improvement in disease symptoms) is more common in later than early phase trials. We convened a two-day expert roundtable covering: (1) the necessity and feasibility of a universal PRO core conceptual model for early phase trials; (2) the practical integration of PROs in early phase trials to inform tolerability assessment, guide dose decisions, or as real-time safety alerts to enhance investigator-reported adverse events. Participants (n = 22) included: patient advocates, regulators, clinicians, statisticians, pharmaceutical representatives, and PRO methodologists working across diverse clinical areas. In this manuscript, we report major recommendations resulting from the roundtable discussions corresponding to each theme. Additionally, we highlight priority areas necessitating further investigation.

Distinct cellular uptake patterns of two anticancer unsymmetrical bisacridines and their metabolic transformation in tumor cells.

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents. Their high cytotoxicity towards multiple human cancer cell lines and inhibition of human tumor xenograft growth in nude mice signal their potential for cancer treatment. Therefore, the mechanism of their strong biological activity is broadly investigated. Here, we explore the efflux and metabolism of UAs, as both strongly contribute to the development of drug resistance in cancer cells. We tested two highly cytotoxic UAs, C-2028 and C-2045, as well as their glucuronic acid and glutathione conjugates in human cancer cell lines (HepG2 and LS174T). As a point of reference for cell-based systems, we examined the rate of UA metabolic conversion in cell-free systems. A multiple reaction monitoring (MRM)-mass spectrometry (MS) method was developed in the present study for analysis of UAs and their metabolic conversion in complex biological matrices. Individual analytes were identified by several features: their retention time, mass-to-charge ratio and unique fragmentation pattern. The rate of UA uptake and metabolic transformation was monitored for 24 h in cell extracts and cell culture medium. Both UAs were rapidly internalized by cells. However, C-2028 was gradually accumulated, while C-2045 was eventually released from cells during treatment. UAs demonstrated limited metabolic conversion in cells. The glucuronic acid conjugate was excreted, whereas the glutathione conjugate was deposited in cancer cells. Our results obtained from cell-free and cell-based systems, using a uniform MRM-MS method, will provide valuable insight into the mechanism of UA biological activity in diverse biological models.

Efficacy and safety in early-phase clinical trials for refractory colorectal cancer: A meta-analysis.

BACKGROUND: Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. METHODS: The PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2021. Trials reporting on new therapies for treatment-refractory mCRC were included. RESULTS: The search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 % and 36 % in phase 2 trials. CBR increased from 23 % in 2010-2012 to 42 % in 2019-2021. Compared to 2010-2012, trials in 2019-2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments. CONCLUSIONS: Treatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies.

Midostaurin added to 10-day decitabine, for patients unfit for intensive chemotherapy with AML and higher risk MDS, irrespective of FLT3 mutational status, does not improve outcome.

The treatment of older patients with acute myeloid leukemia (AML) considered unfit for receiving intensive chemotherapy is challenging. Based on the hypothesis that addition of the broad tyrosine kinase inhibitor (TKI) midostaurin could improve the response to hypomethylating agents, irrespective of FLT3 gene mutational status, we conducted a randomized phase II multicenter study to assess the tolerability and efficacy of the addition of midostaurin to a 10-day schedule of decitabine in unfit (i.e. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) ≥ 3) AML and higher risk myelodysplasia (MDS) patients (HOVON155 trial). In total, 140 eligible patients were randomly (1:1) assigned to treatment with 10-days of decitabine alone (N = 70) or combined with midostaurin (50 mg bid;starting the day following the last dose of decitabine), (N = 70). Addition of midostaurin was well tolerated and the number of AEs was comparable for both treatment arms. Early death rates (< 30 days) were similar as well (10%). In the decitabine plus midostaurin arm 24% reached CR/CRi, the median OS was 4.8 months and 1-yrs OS was 31% which compared with 34% CR/CRi, median OS of 7.4 months and 1-yrs OS of 37% for the decitabine alone group (NS). Thus, while the addition of midostaurin appears safe, it does not enhance therapeutic efficacy of decitabine in unfit AML patients.

Efficacy and safety of anlotinib plus penpulimab as second-line treatment for small cell lung cancer: A multicenter, open-label, single-arm phase II trial.

Background: Currently, the need for new therapeutic strategies involving programmed cell death protein-1 (PD-1) monoclonal antibodies in the second-line setting of small cell lung cancer (SCLC) is urgent. This study aimed to evaluate the efficacy and safety of anlotinib plus penpulimab as a second-line treatment for patients with SCLC who progressed after first-line platinum-based chemotherapy. Methods: This study included the patients from Cohort 4 of a single-arm, open-label, multicenter, phase II clinical trial. A safety run-in phase was performed under anlotinib (10/12 mg quaque die [QD], days 1-14) plus penpulimab (200 mg intravenously [IV], day 1) in a 21-day cycle, followed by the formal trial in which the patients received anlotinib (12 mg QD, days 1-14) plus penpulimab (200 mg IV, day 1) in a 21-day cycle. The primary endpoint of the safety run-in phase was safety. The primary endpoint of the formal trial phase was the objective response rate (ORR). Results: From April 28, 2020, to November 24, 2020, 21 patients were enrolled from 11 hospitals, including 2 in the safety run-in phase and 19 in the formal trial phase. In the formal trial phase, the ORR was 42.1% (8/19; 95% confidence interval [CI]: 17.7-66.6%). The median progression-free survival was 4.8 months (95% CI: 2.9-11.3 months), and the median overall survival was 13.0 months (95% CI: 4.6-not applicable [NA] months). The incidence of ≥grade 3 treatment-related adverse events (TRAEs) was 52.4% (11/21), and the incidence of treatment-related serious adverse events (AEs) was 28.6% (6/21). Two AE-related deaths occurred. The most common AEs were hypertension (57.1%, 12/21), hypothyroidism (42.9%, 9/21), and hypertriglyceridemia (38.1%, 8/21). Conclusions: In patients with SCLC who progressed after first-line platinum-based chemotherapy, the second-line anlotinib plus penpulimab treatment demonstrates promising anti-cancer activity and a manageable safety profile, which warrants further investigation. Trial registration: No. NCT04203719, https://clinicaltrials.gov/.

Monoclonal antibodies in phase II and III trials for moderate to severe atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease that significantly affects quality of life and mental health, especially in children. Traditional treatments include chemotherapeutics, topical corticosteroids, and immunomodulatory agents, but recent advances have introduced novel monoclonal antibody therapies. Through this comprehensive review paper, we aim to discuss these therapeutic options and their role in treating atopic dermatitis. AREAS COVERED: A comprehensive search of the NIH Clinical Trials database was conducted from September 2023 to January 2024, focusing on phase 2 and 3 trials for AD treatments. Trials were filtered using keywords such as 'atopic dermatitis,' 'monoclonal antibody,' and 'phase 2/3.' Out of 25 trials analyzed, 11 were in phase 2 and 14 in phase 3. Only U.S.-based trials comparing novel therapies to placebo were included. In addition to the clinical trial database, we utilized the companies' websites and relevant abstracts to gather the latest results. EXPERT OPINION: Currently investigated monoclonal antibodies have the ability to transform management by targeting specific mediators implicated in the inflammatory pathway of AD. The results of Phase II and III trials for monoclonal antibodies demonstrated strong therapeutic potential with significant reductions in EASI scores and represent a promising new targeted treatment option.

Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). METHODS: This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125 mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60 mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130 mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. RESULTS: Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. CONCLUSION: The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).

Antiviral agents and therapeutics against respiratory viruses.

INTRODUCTION: Respiratory viruses are responsible for significant worldwide morbidity and mortality. While vaccines are highly effective at reducing the morbidity and mortality associated with viral infections, this protection is incomplete. It requires a high degree of compliance, which is hindered by vaccine hesitancy. To address these gaps, antiviral agents and therapeutics are crucial in combating diseases caused by respiratory viruses. Antiviral agents are broadly classified into two groups: 1) direct-acting antivirals (DAA) and 2) host-directed antivirals (HDA). AREAS COVERED: This review comprehensively examines Phase II FDA-approved antiviral drugs for influenza virus, SARS-CoV-2, and RSV as published in clinicaltrials.gov. It focuses on DAAs and various monoclonal antibodies (mAbs) that have been approved for the prevention and treatment of viral respiratory tract infections. EXPERT OPINION: Antiviral drugs being developed assess different mechanisms of action to combat viruses and other delivery routes (i.e. oral, inhalation, or parenteral). The associated clinical trials address the impact on disease while determining the appropriate dosage levels for further investigation in Phase III. A robust pipeline of agents is necessary to meet the global need for effective antiviral therapeutics.

Phase II control charts for monitoring the depth-ratio of ball-bearings involving three normal variables.

This paper investigates the problem of monitoring the ratio involving three variables, jointly distributed as trivariate normal. The Shewhart-type and two exponentially weighted moving average (EWMA) type schemes for monitoring depth ratio are proposed. The ratio of a normal variable to the average of two other normal variables has wide applications in natural science, production, and engineering. It is defined with slightly different terminology in various contexts, such as depth or aspect ratios. In modern bearing manufacturing, the aspect ratio of width to the average of inner and outer diameters can be an essential indicator of product quality and process stability. While there are many helpful existing charts for monitoring the three components separately or jointly when these characteristics follow a normal distribution, the ratio aspect is often ignored. The Shewhart-type schemes' exact and approximated control limits are considered and analyzed. Numerical results based on Monte-Carlo are conducted using the average run length as a metric with different values of in-control ratio and correlation between the three variables. An application based on the parts manufacturing data illustrates the implementation design of the two control charts. The real-life data analysis shows the efficacy of the proposed monitoring schemes in practice.

Preoperative stereotactic radiosurgery for patients with 1-4 brain metastases: A single-arm phase 2 trial outcome analysis (NCT03398694).

Background: Stereotactic radiosurgery (SRS) following surgical resection is the standard of care for patients with symptomatic oligo brain metastasis (BM), however, it is associated with 10-15% local failure. Targeting a resection cavity is imprecise, thus preoperative radiosurgery where the target is well-defined may be superior, however, the efficacy of preoperative SRS has not yet been tested in a clinical trial. Methods: We conducted a phase 2, single-arm trial of preoperative SRS followed by surgical resection in patients with 1-4 symptomatic oligo BMs (NCT03398694) with the primary objective of measuring 6-month local control (LC). SRS was delivered to all patients utilizing a gamma knife or linear accelerator as per RTOG-9005 dosing criteria [Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291-298] based on tumor diameter with the exception that the largest lesion diameter treated was 5 cm with 15 Gy with all SRS treatment given in single fraction dosing. Results: The trial screened 50 patients, 48 patients were treated under the protocol and 32 patients completed the entire follow-up period. Of all the patients who completed the follow-up period, the primary endpoint of 6-month LC was 100% (95% CI: 0.891-1.000; P = .005). Secondary endpoints, presented as medians, were overall survival (17.6 months), progression-free survival (5.3 months), distant in-brain failure (40.8% at 1 year), leptomeningeal failure (4.8% at 1 year), and radiation necrosis (7.7% at 1 year). Conclusions: Our data confirms superior local control in patients who received preoperative SRS when compared to historical controls. Further study with a larger randomized cohort of patients is warranted to fully understand the benefits of preoperative SRS.

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). RESULTS: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. CONCLUSION: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.

SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer.

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

A meta-epidemiological analysis of post-hoc comparisons and primary endpoint interpretability among randomized non-comparative trials in clinical medicine.

OBJECTIVE: Randomized non-comparative trials (RNCT) promise reduced accrual requirements versus randomized controlled comparative trials because RNCTs do not enroll a control group, and instead compare outcomes to historical controls or prespecified estimates. We hypothesized that RNCTs often suffer from two methodological concerns: (1) lack of interpretability due to group-specific inferences in non-randomly selected samples and (2) misinterpretation due to unlicensed between-group comparisons lacking pre-specification. The purpose of this study was to characterize RNCTs and the incidence of these two methodological concerns. STUDY DESIGN AND SETTING: We queried PubMed and Web of Science on September 14, 2023, to conduct a meta-epidemiological analysis of published RNCTs in any field of medicine. Trial characteristics and the incidence of methodological concerns were manually recorded. RESULTS: We identified 70 RNCTs published from 2002 through 2023. RNCTs have been increasingly published over time (slope=0.28, 95% CI 0.17 to 0.39, P<0.001). Sixty trials (60/70, 86%) had lack of interpretability for the primary endpoint due to group-specific inferences. Unlicensed between-group comparisons were present in 36 trials (36/70, 51%), including in the primary conclusion of 31 trials (31/70, 44%), and were accompanied by significance testing in 20 trials (20/70, 29%). Only 5 (5/70, 7%) trials were found to have neither of these flaws. CONCLUSION: Although RNCTs are increasing published over time, the primary analysis of nearly all published RNCTs in the medical literature were unsupported by their fundamental underlying methodological assumptions. RNCTs promise group-specific inference, which they are unable to deliver, and undermine the primary advantage of randomization, which is comparative inference. The ongoing use of the RNCT design in lieu of a traditional RCCT should therefore be reconsidered.

Phase II study of carboplatin plus weekly paclitaxel with bevacizumab for non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia (Hanshin Cancer Group IP002).

BACKGROUND: There is an increased risk of acute exacerbation of idiopathic interstitial pneumonia when treating patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. There is no standard optimal treatment regimen for patients with lung cancer complicated with idiopathic interstitial pneumonia. We aimed to evaluate the efficacy and safety of carboplatin (CBDCA), bevacizumab (Bmab) and weekly paclitaxel (PXT) in patients with idiopathic interstitial pneumonia. METHODS: This phase 2 study involved chemotherapy-naïve patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. Patients received CBDCA (area under the curve: 5 on day 1), PXT (70 mg/m2 on days 1, 8 and 15) and Bmab (15 mg/kg on day 1) every 4 weeks. The primary endpoint was the overall response rate. RESULTS: Twenty-one patients were enrolled between January 2013 and October 2018 and received at least one course of the protocol treatment. The study was terminated before enrolling the planned number of patients because of poor accrual. The median patient age was 69 (range: 62-79) years, and 19 (90.5%) patients were men. The overall response rate was 61.9% (95% confidence interval [CI], 38.4-81.9), meeting the primary endpoint. The median progression-free survival, time to treatment failure, and overall survival were 9.69 (95% CI, 5.78-11.63), 8.21 (95% CI, 3.75-11.63) and 20.93 (95% CI, 13.17-29.83) months, respectively. There was no acute exacerbation or treatment-related death during protocol treatment. CONCLUSION: The results indicate that patients with advanced non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia could be effectively and safely treated using a combination of CBDCA, PXT and Bmab.

AB052. A multicenter prospective exploratory phase II study of neoadjuvant bevacizumab for newly diagnosed malignant glioma.

BACKGROUND: We conducted a multicenter study for neoadjuvant bevacizumab (neoBev) for newly diagnosed glioblastoma (nGB). In this study, median overall survival (mOS) related to radiological response, of which reliability as a prediction of overall survival (OS) was explored. METHODS: A total of 15 patients with nGB were enrolled, and given ring enhancement and perifocal edema on magnetic resonance imaging (MRI). Two weeks after neoBev, the tumor volumes on T1 weighted image with contrast medium (T1CE) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev, surgery was performed. Clinical outcomes including mOS as well as the safety of neoBev were evaluated. RESULTS: Severe adverse events were observed in two of 15 patients as one postoperative hematoma and one wound infection. The average volume decrease rates on T1CE and FLAIR were -37% and -54%, respectively. The decrease rate on T1CE was not correlated with that on FLAIR. Based on MRI, good (GR) and poor responders (PR) on T1CE were defined as more or less of the average volume reduction rate, respectively. In addition, there was a case with discordance in tumor volume changes between T1CE and FLAIR. And OS in a discordant case was 20.4 months, which was not unfavorable. mOS of GR and PR on T1CE were 19.8 and 12.9 months, respectively. In contrast, mOS of GR and PR on FLAIR were 16.0 and 17.0 months, respectively. CONCLUSIONS: Preoperative neoBev was confirmed a safe procedure. mOS in the present cohort was not significantly prolonged. Early tumor volume regression on T1CE but not FLAIR after neoBev therapy has a significant prognostic indicator for mOS in nGB.

Bayesian Optimal Designs for Multi-Arm Multi-Stage Phase II Randomized Clinical Trials with Multiple Endpoints.

There is a growing need to evaluate of multiple competing drugs in phase II trials where the number of patients is often limited, and simultaneous assessment of both efficacy and toxicity is crucial. To avoid the waste of research resources, it is indeed more efficient to screen multiple drugs at once in a platform phase II setting. We aim to adapt the Bayesian optimal phase II (BOP2) design to multi-arm trials for both uncontrolled and controlled settings. The binary efficacy and toxicity endpoints are modeled by a Dirichlet distribution as a vector of four outcomes. Posterior marginal distributions at each analysis are used to derive the monitoring threshold that varies during the trial. We control the family-wise Type I error rate for multiple comparison against a common reference value or a shared control. We conduct simulation studies under both uncontrolled and controlled settings to evaluate the operating characteristics of the proposed design. Our simulations demonstrate that the design exhibits better operating characteristics compared to a design using a constant threshold and is less sensitive to changes in accrual rate relative to what was planned. The design had promising operating characteristics and could be used in phase II oncology clinical trials for evaluating multiple drugs at a time.

A randomized, active-controlled, multi-centric, phase-II clinical study to assess safety and immunogenicity of a fully liquid DTwP-HepB-IPV-Hib hexavalent vaccine (HEXASIIL®) in Indian toddlers.

BACKGROUND: Combination vaccines are effective in simplifying complex vaccination schedules involving multiple vaccines. A fully liquid hexavalent diphtheria (D)-tetanus (T)-whole-cell pertussis (wP)- hepatitis B (HepB)-inactivated poliovirus (IPV)-Haemophilus influenzae b (Hib) vaccine (HEXASIIL®), manufactured by Serum Institute of India Pvt. Ltd. was tested for safety and immunogenicity following booster vaccination. METHODS: This was a phase-II/III, open label, multicentric, controlled trial in toddlers (phase II) and infants (phase III) in India. This manuscript presents results of phase II. Healthy toddlers aged 12-24 months were randomized (1:1) to receive a 0.5 ml booster dose of HEXASIIL® or comparator Pentavac SD + Poliovac, intramuscularly and followed for 28 days for safety assessment. Blood samples were collected pre-vaccination and 28 days post-vaccination to assess immunogenicity. Descriptive summary statistics were provided for safety and immunogenecity analyses. RESULTS: A total of 223 subjects were randomized. One subject droped out prior to dosing, due to consent withdrawal. Thus, 222 subjects received study vaccine (110 HEXASIIL® and 112 comparator). Frequency of solicited adverse events was comparable between HEXASIIL® and comparator (85.5 % vs 90.2 %). Most local and systemic solicited AEs were mild to moderate in severity. All events resolved completely without any sequelae and none led to subject discontinuation. No vaccine related serious AE was reported. Post vaccination, seroprotection rates against tetanus, Hib and polio type 1 and 3 were 100 % in both the groups. Seroprotection rates for diphtheria (99.1 % vs 100 %) and polio type 2 (98.2 % vs 100 %) were observed in HEXASIIL® and comparator group, respectively. For Hepatitis B, seroprotection was >99 % in both groups. Seroconversion observed for Bordetella Pertussis (94.5 % vs 95.4 %) and Pertussis Toxin (77.1 % vs 87.2 %) in HEXASIIL® and comparator group, respectively. CONCLUSION: HEXASIIL® vaccine was found to be safe and immunogenic in toddlers and supported its further clinical development in infants. Clinical Trial Registration - CTRI/2019/11/022052.

Dietary protein affects tissue accumulation of mercury and induces hepatic Phase I and Phase II enzyme expression after co-exposure with methylmercury in mice.

Methylmercury (MeHg) is a ubiquitous environmental contaminant, well known for its neurotoxic effects. MeHg can interact with several nutrients in the diet and affect nutrient metabolism, however the interaction between MeHg and dietary proteins has not been thoroughly investigated. Male BALB/c mice were fed diets based on either casein, cod or chicken as protein sources, which were or were not spiked with MeHg (3.5 mg Hg kg-1). Following 13 weeks of dietary exposure to MeHg, the animals accumulated mercury in a varying degree depending on the diet, where the levels of mercury were highest in the mice fed casein and MeHg, lower in mice fed cod and MeHg, and lowest in mice fed chicken and MeHg in all tissues assessed. Assessment of gut microbiota revealed differences in microbiota composition based on the different protein sources. However, the introduction of MeHg eliminated this difference. Proteomic profiling of liver tissue uncovered the influence of the dietary protein sources on a range of enzymes related to Phase I and Phase II detoxification mechanisms, suggesting an impact of the diet on MeHg metabolism and excretion. Also, enzymes linked to pathways including methionine and glycine betaine cycling, which in turn impact the production of glutathione, an important MeHg conjugation molecule, were up-regulated in mice fed chicken as dietary protein. Our findings indicate that dietary proteins can affect expression of hepatic enzymes that potentially influence MeHg metabolism and excretion, highlighting the relevance of considering the dietary composition in risk assessment of MeHg through dietary exposure.

Adenosine protects cardiomyocytes against acrolein-induced cardiotoxicity by enhancing mitochondrial homeostasis, antioxidant defense, and autophagic flux via ERK-activated FoxO1 upregulation.

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5'-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection.

Tazemetostat for relapsed/refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan: 3-year follow-up for a phase II study.

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%-88.6%) and 64.1% (95% CI 33.7%-83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1-2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726.