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PurposeMethodsResultsConclusionThis study explores the geographic distribution and ethnicity of Iranian patients with Thyroid Eye Disease (TED). It also analyzes semiology, the temporal relationship between thyroid dysfunction and TED, and concomitant diseases. An analysis of ocular visual and motility function in Iranian patients with TED at their initial presentation was also conducted.Data from the Iran TED Registry (IrTED) was extracted and analyzed to examine the demographics, clinical features, severity, and activity of TED. The study included patients who presented to the Rassoul Akram Hospital oculoplastic clinic in Tehran, Iran, between March 2020 and March 2023.The database (https://orc.iums.ac.ir) included 685 patients (66.56% female), with congenital or acquired thyroid dysfunction/disease diagnosed with a mean age of 34.68 years (SD: 13.95, Range 0–78) and TED onset in the mean age of 37.79 years (SD: 14.06, Range: 2–78). Notably, 10.95% of patients developed TED before thyroid dysfunction, while 62.77% were diagnosed with thyroid dysfunction before the onset of TED. Elevated intraocular pressure (≥21 mmHg) in either eye was observed in 49 (7.15%) of participants, with 32 (4.67%) patients bilaterally involved. The distribution of registered patients by province of birth and ethnicity was also graphed. Semiology, coexisting health conditions, and visual and motility functions of patients were presented in a tabular format.The successful implementation of IrTED contributes to a better understanding of TED epidemiology and semiology within the Iranian population. [ABSTRACT FROM AUTHOR]

AbstractThere are Phase II monitoring schemes for linear profiles with between-profile autocorrelation that assume known parameters. However, their performance under parameter estimation has not been evaluated. This study fills this gap by assessing Phase II monitoring schemes for autocorrelated simple linear profiles with estimated parameters and recommending Phase I sample sizes. We evaluate four schemes: T2, EWMA/R, and EWMA3 proposed by Noorossana, Amiri, and Soleimani and VEWMA3 proposed by Wang and Huwang. Simulations show that as the number of in-control Phase I profiles increases, the in-control ARL approaches the target, and the Standard Error of ARL decreases for all schemes. VEWMA3 is the most effective in detecting parameter shifts but requires a larger dataset of in-control profiles to stabilize performance, especially at higher autocorrelation. This study provides practical Phase I sample size guidelines to enhance statistical process control reliability. [ABSTRACT FROM AUTHOR]

Introduction: Uveal melanoma remains a disease with aggressive behavior and poor prognosis despite advances in clinical management. Because monotherapy with immune checkpoint inhibitors has led to limited improvement in response rates, combination with other agents that act on the biological basis of oncogenesis has been proposed as a possible therapeutic strategy. Methods: We designed a phase 1b trial to test the safety and tolerability of selinexor in combination with immune checkpoint inhibitors in patients with advanced uveal melanoma. Patients received selinexor 60 mg PO twice weekly with standard of care, commercially available immune checkpoint inhibitor of the investigator's choice. In one patient receiving nivolumab and ipilimumab as the immunotherapy backbone, selinexor 60 mg PO was given once weekly. Results:We included 10 patients with uveal melanoma who received treatment with either selinexor plus pembrolizumab (n = 9) or selinexor plus nivolumab and ipilimumab (n = 1). The most common adverse events of any grade were neutropenia, thrombocytopenia, leukopenia, and anemia. Additional common nonhematological toxicities included hyponatremia, nausea, and vomiting. Dose reductions were required in six patients (60%). Among nine patients with evaluable disease, eight had stable disease as the best response. The median progression-free and overall survival were 6 months (95% CI: 4, not reached and 17 months (95% CI: 7, not reached), respectively. Conclusion: The combination of selinexor and immunotherapy was safe and showed a side effect profile consistent with previous reports. Clinical benefit was achieved in most patients and should be validated in larger phase 2 trials. [ABSTRACT FROM AUTHOR]

Pirfenidone is an inhibitor of transforming growth factor-beta 1 (TGF-β1) and is being developed for the treatment of diabetic kidney disease (DKD). We assessed the pharmacokinetics (PK) and safety of a single dose of pirfenidone in individuals with CKD stages G2/G3a. In this phase I bridging study, patients with CKD stages G2 or G3a, aged 18–70 years, with a body mass index of 18–26 kg/m2, and glomerular filtration rate (eGFR) ranging from 45 to 89 ml/min/1.73 m2, received a single oral dose of 400 mg pirfenidone capsules 30 min after a standard breakfast. The pharmacokinetic parameters of the two groups were measured and compared after blood and urine collection. The co-primary endpoints were the area under the plasma concentration-time curve from time zero to 36 h (AUC 0 – 36) and the maximum observed plasma concentration (C max) of pirfenidone. Safety was a secondary endpoint. The trial has been registered on ClinicalTrials.gov (ChiCTR2300077297). A total of 20 subjects participated in this study. There were no significant differences between the control group and the patient group (CKD stages G2/G3a) in terms of plasma C max , the time to reach the maximum observed concentration (T max), and elimination half-life(t 1/2). However, the Vz/F of the patient group (CKD G2 stage) was significantly higher than that of the control group. Renal accumulation rate, renal clearance rate (CLr), and urine drug concentration also showed no significant differences. No severe adverse events occurred during the trial. These results indicate that the PK and safety of pirfenidone are not influenced by renal function. Individuals with renal impairment may not require dose adjustments. [ABSTRACT FROM AUTHOR]

Aims: Bronchiectasis patients face an unmet need for treatment options that reduce inflammation. Cathepsin C inhibition is expected to achieve this by reducing the activation of neutrophil‐derived serine proteases. Here, we present safety and pharmacokinetic (PK) data from a Phase I trial evaluating the novel cathepsin C inhibitor BI 1291583 in healthy Japanese male subjects. Methods: This randomized, double‐blind, placebo‐controlled, parallel‐group study investigated BI 1291583 in healthy Japanese male subjects (jRCT2071210111) and consisted of a single‐rising‐dose (SRD) part and a multiple‐dose (MD) part. The primary endpoint was the percentage of subjects with drug‐related treatment‐emergent adverse events (AEs). Secondary PK endpoints (SRD: AUC0‐∞ and Cmax; MD: AUCτ,1 and Cmax,1 after first dose and AUCτ,ss and Cmax,ss after last dose), as well as further safety and PK endpoints, were also assessed. Results: Overall, 36 subjects (n = 24 for SRD part; n = 12 for MD part) entered this Phase I trial. BI 1291583 was safe and well tolerated across the doses tested. All AEs were of mild intensity, with no drug‐related treatment‐emergent AEs, deaths, serious AEs or AEs of special interest reported in either part of the trial. Following both SRD and MD administration, BI 1291583 was readily absorbed, and PK was supraproportional over the doses assessed. Conclusion: The results show that BI 1291583 has an appropriate benefit–risk ratio for Japanese patients, with no safety or exposure concerns at the doses studied. Japanese patients with bronchiectasis can be safely integrated into future global clinical trials of BI 1291583, with no dose adjustment required. [ABSTRACT FROM AUTHOR]

ABSTRACT Conventional Phase I trial designs assign a single dose to each patient, necessitating a minimum number of patients per dose to reliably identify the maximum tolerated dose (MTD). However, in many clinical trials, such as those involving pediatric patients or patients with rare cancers, recruiting an adequate number of patients can pose challenges, limiting the applicability of standard trial designs. To address this challenge, we propose a new Phase I dose‐finding design, denoted as IP‐CRM, that integrates intra‐patient dose escalation with the continual reassessment method (CRM). In the IP‐CRM design, intra‐patient dose escalation is allowed, guided by both individual patients' toxicity outcomes and accumulated data across patients, and the starting dose for each cohort of patients is adaptively updated. We further extend the IP‐CRM design to address carryover effects and/or intra‐patient correlations. Due to the potential for each patient to contribute multiple data points at varying doses owing to intra‐patient dose escalation, the IP‐CRM design offers the advantage of determining the MTD with a considerably reduced sample size compared to standard Phase I dose‐finding designs. Simulation studies show that our IP‐CRM design can efficiently reduce sample size while concurrently enhancing the probability of identifying the MTD when compared with standard CRM designs and the 3 + 3 design. [ABSTRACT FROM AUTHOR]

Broadening eligibility criteria in cancer trials has been advocated to represent the intended patient population more accurately. The advantages are clear in terms of generalizability and recruitment, however there are some important considerations in terms of design for efficiency and patient safety. While toxicity may be expected to be homogeneous across these subpopulations, designs should be able to recommend safe and precise doses if subpopulations with different toxicity profiles exist. Dose‐finding designs accounting for patient heterogeneity have been proposed, but existing methods assume that the source of heterogeneity is known. We propose a broadened eligibility dose‐finding design to address the situation of unknown patient heterogeneity in phase I cancer clinical trials where eligibility is expanded, and multiple eligibility criteria could potentially lead to different optimal doses for patient subgroups. The design offers a two‐in‐one approach to dose‐finding by simultaneously selecting patient criteria that differentiate the maximum tolerated dose (MTD), using stochastic search variable selection, and recommending the subpopulation‐specific MTD if needed. Our simulation study compares the proposed design to the naive approach of assuming patient homogeneity and demonstrates favorable operating characteristics across a wide range of scenarios, allocating patients more often to their true MTD during the trial, recommending more than one MTD when needed, and identifying criteria that differentiate the patient population. The proposed design highlights the advantages of adding more variability at an early stage and demonstrates how assuming patient homogeneity can lead to unsafe or sub‐therapeutic dose recommendations. [ABSTRACT FROM AUTHOR]

The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345). [ABSTRACT FROM AUTHOR]

HSK21542 injection is a new peripheral kappa opioid receptor (KOR) agonist. To evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics, this study was conducted in healthy volunteers, consisting of two parts: a single ascending dose (0.2–3.375 μg/kg, 15‐min infusion) and different infusion durations (0.2 and 1 μg/kg, 2‐ or 15‐min infusion). The area under the plasma concentration‐time curve (AUC) and peak concentration (Cmax) of HSK21542 were dose‐linear among 0.2–3.375 μg/kg. After intravenous injection, HSK21542 was rapidly eliminated with a half‐life (t1/2) of 1.5 h, and the majority (48.02%) of the dose was excreted unchanged in urine. Pharmacodynamic results showed that HSK21542 increased prolactin release and reached a peak at 1–2 h after administration but had no significant effect on vasopressin levels. There was a brief increase in urine volume within the initial 2 h after administration. HSK21542 was well tolerated; most of the adverse effects (AEs) in the trial group were grade 1, and only 2 cases (4.0%) were grade 2. The main AE was paresthesia, which appeared in 42% (21/50) in the trial group. No serious adverse event (SAE) was observed. No subject withdrew early due to AEs. These results suggest that HSK21542 may be a potential treatment for pain and pruritic conditions. [ABSTRACT FROM AUTHOR]

Background: Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence. Methods: Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing. Results: Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4–20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7–100%) in the cohort of vaccinated patients. Conclusion: Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses. Clinical trial registration number: NCT02348320. [ABSTRACT FROM AUTHOR]

The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single‐blinded, placebo‐controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1–3 h and 4–6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose‐proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose‐dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1–4 h and 2–6 days after IV and SC administration, respectively. Anti‐drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose‐proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated. [ABSTRACT FROM AUTHOR]

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia‐reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N‐acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90‐minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N‐acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P <.05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric‐reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P <.001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy. [ABSTRACT FROM AUTHOR]

Unexpected metabolism could lead to the failure of many late-stage drug candidates or even the withdrawal of approved drugs. Thus, it is critical to predict and study the dominant routes of metabolism in the early stages of research. We describe the development and validation of a 'WhichEnzyme' model that accurately predicts the enzyme families most likely to be responsible for a drug-like molecule's metabolism. Furthermore, we combine this model with our previously published regioselectivity models for Cytochromes P450, Aldehyde Oxidases, Flavin-containing Monooxygenases, UDP-glucuronosyltransferases and Sulfotransferases – the most important Phase I and Phase II drug metabolising enzymes – and a 'WhichP450' model that predicts the Cytochrome P450 isoform(s) responsible for a compound's metabolism. The regioselectivity models are based on a mechanistic understanding of these enzymes' actions and use quantum mechanical simulations with machine learning methods to accurately predict sites of metabolism and the resulting metabolites. We train heuristics based on the outputs of the 'WhichEnzyme', 'WhichP450', and regioselectivity models to determine the most likely routes of metabolism and metabolites to be observed experimentally. Finally, we demonstrate that this combination delivers high sensitivity in identifying experimentally reported metabolites and higher precision than other methods for predicting in vivo metabolite profiles. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). Methods: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. Discussion: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. Trial registrations: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022). [ABSTRACT FROM AUTHOR]

Outlier detection is an important aspect of statistical process monitoring (SPM) because outliers affect the performance of control charts. SPM researchers study the negative impact of outliers on control charts for monitoring location parameters. However, there is little research on outlier detection in multivariate charts for monitoring process dispersion. This study aims to investigate the impact of outliers in multivariate control charts for monitoring covariance matrix of a process, and then to recommend techniques for detecting potential outliers present from Phase I samples. We propose a new multivariate dispersion chart that employs the determinant of logarithm of estimated covariance matrix as the monitoring statistic. Through Monte Carlo simulations, the results show how outliers from the first phase affect the overall performance of multivariate charts. The results also demonstrate that the minimum volume ellipsoid (MVE) estimator is effective in reducing the effect of outliers on the proposed control scheme than the other compared estimators. [ABSTRACT FROM AUTHOR]

Control charts are useful to monitor if a process is in a state of statistical control (in-control) or if changes have occurred due to the presence of any assignable causes. To this end, the pattern of points displayed on a control chart plays an important role. A process is declared as in-control when the plotted points display a random pattern. On the other hand, when the points display a nonrandom pattern, with or without one or more points falling beyond the control limits, the process may be declared out-of-control. Thus, the constellation of points, along with the type of the displayed pattern in a control chart can provide useful clues about the possible presence and diagnosis of assignable causes, which can then be dealt with in an appropriate manner. In this work, we propose a methodology using randomness tests based on the theory of runs that can be applied in a supplementary manner in order to assess the statistical significance of a pattern on a Phase I Shewhart X ¯ chart in an objective way. Five common nonrandom patterns with corresponding tests are considered. The performance of the tests is evaluated in terms of their false alarm rate and power, via simulation. An illustration based on some real data is provided. Conclusions and practical recommendations are offered. [ABSTRACT FROM AUTHOR]

Background: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours. Study design: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1). Results: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days. Conclusions: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings. [ABSTRACT FROM AUTHOR]

Aims: CG‐750 is an oral formulation of ivaltinostat, a newly developing histone deacetylase (HDAC) inhibitor. This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of an oral formulation (CG‐750) of ivaltinostat compared to an intravenous (IV) formulation (CG‐745). Methods: A randomized, double‐blind, placebo‐controlled study was conducted in three cohorts. Subjects received either CG‐745 (Cohorts 1 and 3: 125 mg; Cohort 2: 250 mg) or placebo followed by CG‐750 (Cohort 1: 125 mg; Cohort 2: 375 mg; Cohort 3: 750 mg) or placebo. Blood samples for PK and PD assessment were collected up to 72 h post‐dose. Histone H3 acetylation at sites K9, K9/K14 and K27 was assessed for area under the % acetylation induction versus time curve (AUEC). Results: A total of 25 subjects were randomized, and 23 subjects completed the study (Cohort 1, n = 6; Cohort 2, n = 6; Cohort 3, n = 6; placebo, n = 5). The mean bioavailability of CG‐750 was 10.6% (range: 4.18%–21.33%) and displayed linear PK in the dose range of 125–750 mg. The comparison of AUEC between formulations and the evaluation of the dose–AUEC relationship were inconclusive, due to the small sample sizes and significant variability observed in PD markers. All adverse events (AEs) were transient and of mild or moderate intensity. Conclusions: The oral formulation of ivaltinostat (CG‐750) was generally well tolerated after a single dose. CG‐750 displayed a mean bioavailability of 10.6%. [ABSTRACT FROM AUTHOR]

Control charts play a crucial role in industry, facilitating retrospective analysis of process data during its initial phase (Phase I) and monitoring its behavior over time once a chart is set (Phase II). This study introduces four novel Phase I nonparametric control charts based on combined forms of sequential normal scores. An adequate combination of characteristics from these statistics helps address early-stage data analysis challenges, including potential contamination and lack of normality. Their performance, evaluated by empirical alarm probability, was compared, and the preferred option was later tested against parametric approaches and available nonparametric alternatives across various practical scenarios. Previous Phase I charts have demonstrated difficulties handling specific out-of-control patterns and sample size restrictions. The results of this research indicate that the SNSmax statistic exhibits superior detection power compared to existing nonparametric methods, particularly when dealing with skewed distributions. Furthermore, it demonstrates robustness against isolated and certain types of sustained changes. This positions the SNSmax statistic as a reliable and powerful tool for quality assurance practitioners dealing with the assessment of independent batches of observations. [ABSTRACT FROM AUTHOR]

Background: Recruitment of cancer clinical trial (CCT) participants, especially participants representing the diversity of the US population, is necessary to create successful medications and a continual challenge. These challenges are amplified in Phase I cancer trials that focus on evaluating the safety of new treatments and are the gateway to treatment development. In preparation for recruitment to a Phase I recurrent head and neck cancer (HNC) trial, we assessed perceived barriers to participation or referral and suggestions for recruitment among people with HNC and community physicians (oncologist, otolaryngologist or surgeon). Methods: Between December 2020 and February 2022, we conducted a qualitative needs assessment via semistructured interviews with a race and ethnicity‐stratified sample of people with HNC (n = 30: 12 non‐Hispanic White, 9 non‐Hispanic African American, 8 Hispanic and 1 non‐Hispanic Pacific Islander) and community physicians (n = 16) within the University of Florida Health Cancer Center catchment area. Interviews were analyzed using a qualitative content analysis approach to describe perspectives and identify relevant themes. Results: People with HNC reported thematic barriers included: concerns about side effects, safety and efficacy; lack of knowledge and systemic and environmental obstacles. Physicians identified thematic barriers of limited physician knowledge; clinic and physician barriers and structural barriers. People with HNC and physicians recommended themes included: improved patient education, dissemination of trial information and interpersonal communication between community physicians and CCT staff. Conclusions: The themes identified by people with HNC and community physicians are consistent with research efforts and recommendations on how to increase the participation of people from minoritized populations in CCTs. This community needs assessment provides direction on the selection of strategies to increase CCT participation and referral. Patient or Public Contribution: This study focused on people with HNC and community physicians' lived experience and their interpretations of how they would consider a future Phase I clinical trial. In addition to our qualitative data reflecting community voices, a community member reviewed the draft interview guide before data collection and both people with HNC and physicians aided interpretation of the findings. [ABSTRACT FROM AUTHOR]

Aims: This phase I study investigated potential drug–drug interactions of the maturation inhibitor GSK3640254 (GSK'254) with darunavir/ritonavir (DRV/RTV) and/or etravirine (ETR). Methods: In this randomized, open‐label, single‐sequence, multiple‐dose study, healthy participants received GSK'254 200 mg once daily alone or coadministered with DRV/RTV 600/100 mg twice daily (BID; n = 19), ETR 200 mg BID (n = 19) or DRV/RTV 600/100 mg + ETR 200 mg BID (n = 16) under fed conditions. Primary endpoints were steady‐state area under the plasma concentration–time curve from time 0 to the end of the dosing interval (AUC0‐τ) and maximum observed concentration (Cmax). Secondary endpoints included trough concentration (Cτ), safety and tolerability. Pharmacokinetic parameters were calculated using standard noncompartmental analysis, and geometric least‐squares mean ratios were derived from linear mixed‐effects models. Results: GSK'254 AUC0‐τ (geometric least‐squares mean ratio [90% confidence interval], 1.14 [1.00–1.29]), Cmax (1.07 [0.92–1.24]) and Cτ (1.17 [1.01–1.35]) were similar when administered alone and with DRV/RTV. Etravirine coadministration decreased GSK'254 AUC0‐τ (0.53 [0.48–0.59]), Cmax (0.60 [0.53–0.68]) and Cτ (0.51 [0.39–0.66]). Similar reductions were not observed with GSK'254 + DRV/RTV + ETR (AUC0‐τ, 0.94 [0.82–1.09]; Cmax, 0.89 [0.75–1.07]; Cτ, 1.02 [0.89–1.18]). GSK'254 had no meaningful effect on DRV/RTV or ETR concentrations. All reported adverse events (AEs) were grade 1; 3 led to withdrawal and resolved (rash, asymptomatic electrocardiogram T‐wave inversion, periorbital oedema). Most common AEs were diarrhoea (n = 9) and headache (n = 7). No deaths or serious AEs occurred. Conclusion: GSK'254 pharmacokinetics was not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but were reduced with only ETR; no new tolerability concerns were observed. [ABSTRACT FROM AUTHOR]

GSK3640254 (GSK'254) is a novel HIV‐1 maturation inhibitor with pharmacokinetics supporting once‐daily (QD) therapy for HIV‐1 treatment. This thorough QT/corrected QT (QTc) study evaluated the effect of GSK'254 on cardiac repolarization. In this two‐part, randomized study, healthy participants received GSK'254 or placebo QD for 7 days (part 1) to determine safety and pharmacokinetics of a 500‐mg supratherapeutic dose. Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400‐mg moxifloxacin dose on Day 7 (all with a moderate‐fat meal). Concentration‐QTc analyses modeled the relationship between GSK'254 plasma concentrations and placebo‐adjusted change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF). Of 50 participants enrolled, 48 completed the study (part 1, 8/8; part 2, 40/42). Least‐squares (LS) mean change from baseline in QTcF for GSK'254 100 mg followed the placebo pattern across time points (maximum LS mean ΔΔQTcF, 1.7 ms); the upper bound of the 90% CI remained <10 ms. Maximum LS mean ΔΔQTcF for GSK'254 500 mg exceeded the 10‐ms threshold: 10.6 ms (90% CI 7.75–13.38). Neither GSK'254 dose had clinically relevant effects on heart rate or cardiac conduction. By concentration‐QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL−1. No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100‐mg dose. [ABSTRACT FROM AUTHOR]

In most real‐world applications, such as production and manufacturing processes, the underlying process distribution does not always follow a normal distribution. In such cases, statistical process control literature recommends the use of nonparametric (or distribution‐free) control charts. This paper introduces a new distribution‐free precedence chart using repetitive sampling. The performance of the proposed chart is investigated in terms of the average run‐length (ARL) profile. The expressions of the in‐control process probability and ARL of the proposed chart are introduced using integral formulas. The out‐of‐control performance of the new chart is compared to that of the existing precedence charts with and without runs‐rules. A numerical example is provided using real‐life data to demonstrate the application and implementation of the new chart. [ABSTRACT FROM AUTHOR]

Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs. • r/r PTCLs are rare and aggressive diseases with poor clinical outcome. • Golidocitinib is the first JAK1 inhibitor for treating r/r PTCLs at the stage of pivotal clinical development. • In a phase I clinical study, golidocitinib demonstrated an acceptable safety profile in patients with r/r PTCLs. • An objective response rate of 39.2% and a complete response rate of 21.6% were achieved in heavily pretreated patients. • Tumor response was durable, and irrespective of PTCL subtypes and prior treatment history. [ABSTRACT FROM AUTHOR]

Background: The development of triplet regimens for advanced gastric cancer is challenging. The aim of this phase I dose-escalation study was to determine the maximum tolerated dose and recommended dose of the combination of irinotecan, cisplatin, and S-1 in chemotherapy-naïve patients with HER2-negative advanced gastric cancer. Methods: The 3 + 3 design was adopted. Every 4 weeks, patients received an escalating dose of intravenous irinotecan (100–150 mg/m2) on day 1 and fixed doses of intravenous cisplatin (60 mg/m2) on day 1 and oral S-1 (80 mg/m2) on days 1 to 14. Results: Twelve patients were enrolled in two dose level cohorts. In the level 1 cohort (irinotecan 100 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicity including grade 4 neutropenia and febrile neutropenia occurred in one of six patients, whereas in the level 2 cohort (irinotecan 125 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicities including grade 4 neutropenia developed in two of six patients. Thus, the level 1 and 2 doses were determined to be the recommended and maximum tolerated doses, respectively. Common grade 3 or higher adverse events were neutropenia (75%; n = 9), anemia (25%; n = 3), anorexia (8%; n = 1), and febrile neutropenia (17%; n = 2). Irinotecan, cisplatin, and S-1 combination therapy achieved an overall response rate of 67% with a median progression-free survival and overall survival of 19.3 and 22.4 months, respectively. Conclusions: The potential treatment efficacy of this triplet regimen in HER2-negative advanced gastric cancer warrants further evaluation, especially in patients requiring intensive chemotherapy. [ABSTRACT FROM AUTHOR]

Phase I and Phase II metabolic reactions are involved in the pharmacokinetic properties of drugs after administration. These reactions mainly aim to make drugs more polar and eliminate them safely. However, some of these metabolites have the potential to exhibit a toxicological effect. Industry and/or academia have to consider these metabolites in terms of their pharmacodynamic and pharmacokinetic properties. These metabolites are not only residual intermediates from the synthetic process of the main drug but also unique structures produced by metabolic enzymes in the human organism. Thus, metabolite synthesis by synthetic or semi-synthetic methods is a key feature in the pharmaceutical industry. In this review, synthetic methods of the metabolites from all known metabolic pathways are reviewed from the literature. It was observed that both synthetic and semi-synthetic methods require more attention as they are as important and complex as drug synthesis. Moreover, it showed that there was much more research available for Phase I than Phase II in the literature. [ABSTRACT FROM AUTHOR]

Adapted from the acceptance sampling field, the double sampling monitoring schemes implement a two-stage strategy to decide whether the process being monitored is in-control or out-of-control. That is, a master sample is split into two separate subgroup samples, with the first subgroup sample used in the first stage and, depending on which type of double sampling method is used, either only the second or the combined first and second, subgroup sample(s) are used in the second stage. This strategy has been proven to effectively decrease the sampling effort and, at the same time, to decrease the time to detect potential out-of-control situations. For these reasons, it has received some attention in the statistical process monitoring (SPM) literature and, in this review paper, all 92 existing publications on the basic double sampling monitoring schemes and other different schemes that are integrated with the basic double sampling schemes are reviewed. The double sampling schemes are categorized and summarized so that any research gaps in the SPM literature can easily be identified. Finally, concluding remarks and some directions for future research ideas are given. [ABSTRACT FROM AUTHOR]

Background: RLS-0071 is a dual-targeting peptide developed for the regulation of humoral and cellular inflammation via inhibition of neutrophil effectors, including myeloperoxidase and neutrophil extracellular trap formation (NETosis). The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of RLS-0071 were evaluated in a first-in-human clinical trial in healthy volunteers. Myeloperoxidase is the major peroxidase enzyme present in neutrophilic granules and contributes to cellular inflammation. Extracellular myeloperoxidase has been associated with chronic inflammation in a variety of diseases, including atherosclerosis. RLS-0071 has previously been shown to inhibit extracellular myeloperoxidase function both in vitro and in vivo in animal disease models. Case Report: Healthy subjects participating in the RLS-0071-101 study were screened for baseline myeloperoxidase level, leading to the identification of a 21-year-old woman with elevated baseline levels. After randomization, the subject received 9 intravenous infusions of 10 mg/kg RLS-0071. The subject tolerated the peptide infusions well with no adverse changes in vital signs, significantly abnormal clinical laboratory results, or severe adverse events. Analysis of this subject's myeloperoxidase plasma concentrations demonstrated that her myeloperoxidase levels decreased by 43% and myeloperoxidase activity levels decreased 49% after infusions of RLS-0071. The reduction in the patient's plasma myeloperoxidase levels demonstrated a partial return to baseline levels 24 hours after cessation of dosing. There were no other clinically meaningful safety observations for this subject. Conclusions: This observation suggests RLS-0071 has the therapeutic potential to moderate plasma myeloperoxidase levels and activity and modulate diseases in which myeloperoxidase contributes to pathogenesis. [ABSTRACT FROM AUTHOR]

We performed a phase I study of weekly selinexor, carfilzomib, and dexamethasone (wSKd) in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to identify the maximum tolerated dose (MTD) of wSKd. Secondary endpoints included overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Prior exposure/refractoriness to carfilzomib was permitted. Thirty patients were enrolled; 26 (87%) had triple‐class exposed disease and 6 (20%) received chimeric antigen receptor (CAR) T‐cell therapy. Dose level 2 (carfilzomib 70 mg/m2 Intravenous [IV] on Days 1, 8, and 15; selinexor 100 mg PO on Days 1, 8, 15, 22; dexamethasone 40 mg on Days 1, 8, 15, 22 of 28‐day cycles) was chosen as the MTD, with no DLTs having occurred. The most common hematologic adverse events (AE) were thrombocytopenia (83%), anemia (70%), lymphopenia (50%), and neutropenia (50%). The most common nonhematologic AE were fatigue (70%), nausea (70%), diarrhea (53%), and anorexia (47%). The ORR was 21/30 (70%) overall and 18/23 (78%) at the MTD. At a median follow‐up of 12.3 months, the median PFS was 5.3 months and median OS 23.3 months. Responses were similar in carfilzomib naïve and exposed patients. Long‐term efficacy of wSKd is modest; wSKd could be employed as a bridging strategy to immunotherapies. [ABSTRACT FROM AUTHOR]

Compared to pelubiprofen, a cyclooxygenase-2-selective inhibitor, pelubiprofen tromethamine has been reported to exhibit improved solubility and absorption. Pelubiprofen tromethamine combines the anti-inflammatory effect of pelubiprofen with the gastric protective function of tromethamine salt, making it a relatively safe class of non-steroidal anti-inflammatory drugs with low levels of gastrointestinal side effects in addition to its original analgesic, anti-inflammatory, and antipyretic effects. This study assessed the pharmacokinetic and pharmacodynamic characteristics of pelubiprofen and pelubiprofen tromethamine in healthy subjects. Two independent clinical trials were performed in healthy subjects using a randomized, open-label, oral, single-dose, two-sequence, four-period, crossover design. In Study I and Study II, subjects received 25 mg of pelubiprofen tromethamine and 30 mg of pelubiprofen tromethamine, respectively, with 30 mg of pelubiprofen being the reference. Study I fell within the bioequivalence study criteria. A trend of increased absorption and exposure for 30 mg of pelubiprofen tromethamine vs. the reference in Study II was observed. The maximum cyclooxygenase-2 inhibitory effect of 25 mg of pelubiprofen tromethamine was approximately 98% compared to the reference, showing no significant pharmacodynamic variation. It is thus predicted that 25 mg of pelubiprofen tromethamine would show no clinically significant discrepancies in clinical analgesic and antipyretic effects from 30 mg of pelubiprofen. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti‐cancer activity through multiple pathways. Methods: The objective of this Phase I trial was to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of metformin in combination with VIT in children with relapsed and refractory solid and CNS tumors. A 3 + 3 design was used to test the addition of metformin at five dose levels (666, 999, 1333, 1666, and 2000 mg/m2/day). Therapy toxicity, pharmacokinetics, and radiologic response to treatment were evaluated. Results: Twenty‐six patients (median age 13 years, range 2–18 years) were enrolled with 22 evaluable for toxicity. The most common diagnoses were Ewing sarcoma (n = 8), rhabdomyosarcoma (n = 3) and atypical teratoid/rhabdoid tumor (n = 3). The MTD was exceeded at Dose Level 5 due to two dose‐limiting toxicities; both were Grade 3 diarrhea requiring prolonged hospitalization and intravenous fluids. The MTD was not determined due to study closure with less than six patients enrolled at Dose Level 4. Frequently observed toxicities were gastrointestinal (most notably diarrhea) and hematologic. Amongst 16 patients evaluable for best overall response, there was one complete response (Ewing sarcoma), three partial responses (Ewing sarcoma, glioblastoma multiforme, and alveolar rhabdomyosarcoma), and five patients with stable disease. Conclusions: The MTD of VIT with metformin was not determined due to premature study closure. We recommend an RP2D of Dose Level 4, 1666 mg/m2/day. Radiographic responses were seen in multiple tumor types. Further evaluation for efficacy could be investigated in a Phase II trial. [ABSTRACT FROM AUTHOR]

This study assessed the safety, tolerability, and pharmacokinetics of single and multiple oral doses of DA‐8010, a muscarinic M3 receptor antagonist, in healthy subjects. This was a randomized, double‐blind, placebo‐controlled, ascending single (Part A: 1, 2.5, 5, 20, and 40 mg QD fasted and 10 mg QD fasted and fed) and multiple doses (Part B: 5, 10, and 20 mg QD from Days 1 to 7 fasted), sequential‐group study. Safety data were analyzed descriptively, time to maximum plasma concentration (tmax) nonparametrically, and pharmacokinetic parameters using power and mixed models and ANOVA. Of 109 subjects randomized (Part A = 69 and Part B = 40; each part consisted a female group), 31 (44.9%) in Part A and 29 (72.5%) in Part B experienced treatment‐emergent adverse events (TEAEs) in a dose‐related manner. Common drug‐related TEAEs in Part A and B were dizziness (8.7% and 15.0%), headache (5.8% and 12.5%) and blurred vision (8.7% and 20%). One male (20 mg) and one female (10 mg) from Part B discontinued the study due to a confusional state, and nausea and vomiting. Irrespective of sex, DA‐8010 was steadily absorbed following single and multiple doses in the fasted state with increased systemic exposure in a dose‐proportional manner with maximum plasma concentration occurring at a median tmax between 4.0 and 6.0 h. A high‐fat meal increased systemic exposure. DA‐8010 was safe, well tolerated, and well absorbed at lower doses and moderately tolerated at higher doses without any notable effects of food and sex. [ABSTRACT FROM AUTHOR]

Ethosuximide, the first-line therapy for childhood absence epilepsy, is currently formulated as a syrup (Zarontin®, Pfizer) with a bitter taste and high sugar content, poorly adapted to children, and a ketogenic diet. The collaborative European FP7 project KIEKIDS aimed at developing an innovative sugar-free, tasteless formulation convenient for pediatric use. This dual Phase-I study evaluated two granule formulations based on lipid multiparticulate (LMP) technology. Two panels of 6 healthy adult volunteers underwent a randomized, placebo-controlled, partly blinded, 3-way cross-over trial, comparing ethosuximide granules A or B with placebo granules and syrup at single 10 mg/kg doses. Corresponding plasma pharmacokinetic profiles of ethosuximide were compared, along with palatability, safety, and tolerability. The LMP granule A proved suboptimal due to bitterness and adherence to beaker walls, while the optimized granule B revealed excellent palatability, similar to placebo granules, and low adherence to glass. The relative bioavailability of granules A versus syrup, based on dose-normalized Cmax and AUC0-∞ was 93.7% [90% CI: 76.3-115.1] and 96.1% [91.0-101.5], respectively. For granules B it was 87.6% [81.6-94.0] and 92.5% [88.5-96.6], respectively, with slightly delayed tmax of 0.75h [0.5-4.05] compared to syrup 0.5 h [0.3-0.8]. Tolerability visual analog scales revealed a trend for statistically non-significant improvement versus syrup at peak (30min) for transient dizziness (both granules), fatigue (granules A), and anxiety (granules B). The innovative ethosuximide granule formulation B achieves a suitable profile for pediatric use, being sugar-free, tasteless, bioequivalent, and well-tolerated while enabling precise adjustment to body weight. [ABSTRACT FROM AUTHOR]

Purpose: The prognosis of diffuse‐type gastric cancer (DGC) is poorer than that of intestinal type, but S‐1 is a potential treatment option in DGC. This study explored the maximal tolerated dose (MTD) and the recommended dose for phase II study (RP2D) of nab‐paclitaxel combined with S‐1 (AS regimen) as adjuvant chemotherapy in stage III DGC. Methods: Patients with stage III DGC were recruited into this phase I dose‐escalation study between July 2019 and June 2020 in Zhongshan Hospital. Nab‐paclitaxel and S‐1 (80–120 mg/day, d1‐14, q3w) were administrated for 6 cycles, and then 8 cycles of S‐1 monotherapy were applied. The patients received nab‐paclitaxel at 180, 220, or 260 mg/m2 according to the 3 + 3 design based on dose‐limiting toxicity (DLT). The primary endpoint was RP2D. Secondary endpoints were the 1‐year disease‐free survival (DFS) rate and adverse events (AEs). Results: One case experienced DLT in 180‐mg/m2 dose group, subsequently three additional subjects were enrolled. DLT was not observed in the 220‐ and 260‐mg/m2 dose groups (both n = 3). Therefore, the MTD has not reached, and the RP2D of nab‐paclitaxel would be 260 mg/m2. Five participants showed progressive disease, with three and two participants in the 180‐ and 220‐mg/m2 dose groups, respectively. The 6‐, 12‐, and 18‐month DFS rates were 100%, 63.6%, and 50.9%, respectively. The most frequently observed AEs were neutropenia (83.3%) and leukopenia (66.7%). Conclusion: The RP2D of nab‐paclitaxel as adjuvant chemotherapy in DGC was 260 mg/m2. The AS regimen had a tolerable AE profile in stage III DGC. [ABSTRACT FROM AUTHOR]

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients. • Recent experience with targeted anticancer drugs and immunotherapies suggest the traditional approach of using the maximal tolerated dose (MTD) is not ideal. • Project Optimus recommends optimizing the dosage of oncology drugs to ensure they are both effective and tolerable. • MDICT developed practical recommendations for the design and conduct of phase I oncology trials. [ABSTRACT FROM AUTHOR]

Aims: During phase I study conduct, blinded data are reviewed to predict the safety of increasing the dose level. The aim of the present study was to describe the probability that effects are observed in blinded evaluations of data in a simulated phase I study design. Methods: An application was created to simulate blinded pharmacological response curves over time for 6 common safety/efficacy measurements in phase I studies for 1 or 2 cohorts (6 active, 2 placebo per cohort). Effect sizes between 0 and 3 between‐measurement standard deviations (SDs) were simulated. Each set of simulated graphs contained the individual response and mean ± SD over time. Reviewers (n = 34) reviewed a median of 100 simulated datasets and indicated whether an effect was present. Results: Increasing effect sizes resulted in a higher chance of the effect being identified by the blinded reviewer. On average, 6% of effect sizes of 0.5 between‐measurement SD were correctly identified, increasing to 72% in 3.0 between‐measurement SD effect sizes. In contrast, on average 92–95% of simulations with no effect were correctly identified, with little effect of between‐measurement variability in single cohort simulations. Adding a dataset of a second cohort at half the simulated dose did not appear to improve the interpretation. Conclusion: Our analysis showed that effect sizes <2× the between‐measurement SD of the investigated outcome frequently go unnoticed by blinded reviewers, indicating that the weight given to these blinded analyses in current phase I practice is inappropriate and should be re‐evaluated. [ABSTRACT FROM AUTHOR]

Background: Cluster of differentiation (CD) 73-targeted immunotherapy and CD73 inhibition may reduce adenosine production, which can augment the host and/or immunotherapy response to tumours. We aimed to assess the safety and tolerability, pharmacokinetics, and antitumour activity of oleclumab, an anti-CD73 monoclonal antibody, in adult Japanese patients with advanced solid malignancies resistant to standard therapy. Methods: In this phase I, single-centre, open-label study, patients received oleclumab 1500 mg (Cohort 1) or 3000 mg (Cohort 2) intravenously every 2 weeks. Results: In total, six patients were enrolled in the study (three in each cohort), and all six patients received the study treatment. The median patient age was 56.0 years and 4/6 were males. All patients (100%) reported adverse events (AEs) during the study; five (83.3%) patients reported AEs related to the study treatment. One (16.7%) patient reported a Grade 3 AE (neutrophil count decreased) that was not related to the study treatment. No AEs with an outcome of death were reported, and no patients reported AEs or serious AEs leading to oleclumab discontinuation/dose interruption. No dose-limiting toxicities were reported, and no patient discontinued due to an AE related to the study treatment. Oleclumab exposure increased dose proportionally. No patient achieved disease control at 8 weeks, and all six patients developed progressive disease. Conclusions: Oleclumab was well tolerated in adult Japanese patients with advanced solid malignancies and no unexpected safety concerns were raised; oleclumab exposure increased with dose. Future studies on combination therapy with other agents are warranted. [ABSTRACT FROM AUTHOR]

The Mann–Whitney (MW) test is one of the most important nonparametric tests used in the comparison of the location parameters of two populations. Unlike the t-test, the MW test can be used when the assumption of normality fails to hold. In this paper, the MW U statistic is used to construct two efficient distribution-free monitoring schemes, namely the mixed generally weighted moving average-cumulative sum (GWMA-CUSUM) MW U scheme (denoted as U-MGC) as well as its reversed version, i.e. the CUSUM-GWMA MW U scheme (denoted as U-MCG). The performances of the proposed schemes are investigated using the average run-length (ARL) and average extra quadratic loss (AEQL) values through extensive simulations. The newly proposed charts are found to be superior in small shifts detection than their competing (existing and others that are briefly introduced here) distribution-free Shewhart, EWMA, CUSUM, mixed EWMA-CUSUM, mixed CUSUM-EWMA and GWMA MW U charts in many situations. A real-life example is used to demonstrate the design and implementation of the new schemes. [ABSTRACT FROM AUTHOR]

Background: Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone.Methods: Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of 'dose-limiting toxicity' (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing.Discussion: Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen's use in alcoholism and guidelines for the management of opiate dependence.Trial Registration: Clinicaltrials.gov NCT05161351. Registered on 16 December 2021. [ABSTRACT FROM AUTHOR]

Simple Summary: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have provided clinical benefits for a subset of patients with advanced breast cancer; however, treatment resistance generally emerges over time in patients with breast cancer, and the efficacy of existing CDK4/6 inhibitors in patients with other cancers is modest. The aim of this study was to explore the safety and preliminary antitumor efficacy of a novel, orally available CDK4/6 inhibitor, FCN-437c, in patients with advanced solid tumors. The results demonstrated promising signs of durable tumor response and disease control in this patient population. The safety profile was consistent with that of approved CDK4/6 inhibitors, with no concerning signals in terms of pulmonary, cardiac, or thrombotic risk. The efficacy and safety of FCN-437c merit further study, and this novel agent holds promise as a new alternative treatment for patients with few options. A phase I study evaluated the safety, tolerability, and maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of FCN-437c, a novel, orally available cyclin-dependent kinase inhibitor (CDK4/6i), in participants with advanced/metastatic solid tumors (aSTs). FCN-437c was escalated from 50 mg (once daily [QD] on days 1–21 of 28-day cycles) to the MTD/RP2D. In the dose-expansion phase, patients with CDK4/6i-treated breast cancer, or KRAS-mutant (KRASmut) non-small-cell lung cancer (NSCLC) received the MTD. Twenty-two patients were enrolled. The most common tumors in the dose-escalation phase (n = 15) were breast, colorectal, and lung (each n = 4 [27.3%]). The dose-expansion phase included five (71.4%) patients with breast cancer and two (28.6%) with KRASmut NSCLC. Twenty (90.9%) participants experienced FCN-437c–related adverse events. Dose-limiting toxicities occurred in two (33.3%) participants (200-mg dose, dose-escalation phase): grade 3 neutropenia and grade 4 neutrophil count decreased. Due to toxicities reported at 150 mg QD, the MTD was de-escalated to 100 mg QD. One (4.5%) participant (KRASmut NSCLC, 100-mg dose) achieved a partial response lasting 724+ days, and five (22.7%) had stable disease lasting 56+ days. In conclusion, FCN-437c was well tolerated with encouraging signs of antitumor activity and disease control. Further exploration of FCN-437c in aSTs is warranted. [ABSTRACT FROM AUTHOR]

Introduction: LCL161 is a novel oral pan‐inhibitor of apoptosis protein (IAP) antagonist. LCL161 enhances paclitaxel activity in cell lines and xenograft models. A phase I study of LCL161 combined with paclitaxel for the treatment of Japanese patients with advanced solid tumors was conducted. Methods: Each patient received oral LCL161 in a single weekly dose on days 1, 8, and 15 of a 21‐day treatment cycle. In the second cycle, patients received a combination treatment with weekly paclitaxel (80 mg/m2) whenever possible. A Bayesian logistic regression model by escalation with the overdose control principle was used. Results: Nine patients were treated with LCL161 at a dose of 600 mg (five patients) or 1200 mg (four patients). Seven patients were treated with LCL161 plus paclitaxel, and two patients received only LCL161 monotherapy. Because this study was terminated early due to a change in the LCL161 development strategy, the maximum tolerated dose (MTD) was not determined. One patient treated with LCL161 monotherapy at a dose of 1200 mg experienced dose limitind toxicity (grade 3 maculopapular rash). Another patient died on day 86 of bacterial pneumonia, which was suspected to be related to the study treatment. The most common serious adverse events were infections and infestations (n = 3). Conclusion: The present study suggests that the risk of infection may increase when LCL161 is combined with paclitaxel, but other conclusions about the MTD, pharmacokinetic profile, and preliminary activity of the combination of LCL161 plus paclitaxel were not drawn. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is an incurable disease, demanding new therapeutic approaches. Our preclinical studies proved that the antidiabetic drug metformin could induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation, suggesting the potential of metformin for treating glioblastoma. Taking into consideration that the anti-cancer effects of metformin are known to be dose-dependent, we conducted a dose-escalation phase I study to evaluate the safety and determine the recommended phase II dose of metformin in combination with maintenance temozolomide in patients with newly diagnosed glioblastoma. We show that the 2250 mg/day metformin appeared to be well tolerated with acceptable toxicity. Therefore, we proceed to a phase II study with 2250 mg/day metformin to evaluate its clinical benefits. Cancer stem/initiating cells are resistant to existing radiotherapy or chemotherapy; thus, our strategy targeting glioma-initiating cells using metformin is a novel therapeutic strategy which could possibly improve the outcome of glioblastoma. Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF. [ABSTRACT FROM AUTHOR]

Purpose: Aurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion.Methods: Key inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles.Results: In total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration.Conclusions: This trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent. [ABSTRACT FROM AUTHOR]

• Dietary protein affects mercury accumulation in tissues. • Dietary chicken intake increases the hepatic expression of Phase I and Phase II enzymes. • Enzymes of the methionine and glycine betaine cycles were up-regulated by dietary chicken. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

• Two target validation approaches are emerging as useful in phase I (P1): P1-PIV and P1-FCTE. • P1-PIV uses primary endpoints in pivotal clinical studies (PIV). • P1-FCTE uses functional changes necessary for therapeutic effects (FCTE). • Their benefits and challenges are compared with those of the conventional P1 approach. This review discusses the growing importance of target validation within phase I (P1) trials as a new trend in drug development, especially in establishing proof of concept (POC) for first-in-class drugs. The paper describes two approaches: the P1-PIV approach, which directly evaluates the primary endpoint for a pivotal clinical study to confirm therapeutic effects during P1, and the newly introduced P1-FCTE, which assesses functional changes necessary for therapeutic effect as a novel target validation milestone in P1. By providing practical examples of first-in-class drugs, we compare the benefits, costs, hurdles and applicable therapeutic areas of these approaches. Finally, we discuss the potential of these novel approaches to facilitate POC success, shorten development timelines and ultimately increase drug discovery success rates. [ABSTRACT FROM AUTHOR]

HY0721 is a novel inhibitor of sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. The study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. The administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. This study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. ChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020. [Display omitted] [ABSTRACT FROM AUTHOR]

When monitoring a multiple stream process (MSP) where multiple processes which are assumed to be identical are being simultaneously monitored, but the assumption of normality cannot be reasonably be verified, the NEMT-CUSUM control chart has been proposed as a possible non parametric alternative. However, in the beginning stages of a monitoring program, it would be useful to the chart operator to know how effective the NEMT-CUSUM will be at detecting shifts away from target given. One way of assessing effectiveness is via statistical power, which is the probability of detecting a shift in some subset of streams at a particular point in time. The purpose of this study is to derive the alternative distribution of the NEMT-CUSUM plotting statistic such that statistical power can be estimated. Examples, practical implications, and future directions are given. [ABSTRACT FROM AUTHOR]

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS‐based tri‐therapy regimen in advanced non‐small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD‐L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design). Results: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. The most common ≥Grade 3 adverse events were neutropenia, hypertension, and fatigue. The recommended Phase II dose (RP2D) was DL1: avelumab 10 mg/kg IV q2weeks, axitinib 3 mg po bid, and palbociclib 75 mg po daily (7 days off/21 days on). Four patients (27%) achieved a partial response (PR) (progression‐free survival [PFS]: 14, 24, 25 and 144+ weeks), including two after progression on pembrolizumab. Four patients attained stable disease (SD) that lasted ≥24 weeks: 24, 27, 29, and 64 weeks. At DL1 (RP2D), four of six patients (66%) achieved stable disease (SD) ≥6 months/PR (2 each). Responders included patients with no detectable PD‐L1 expression and low tumor mutational burden. Conclusions: Overall, eight of 15 patients (53%) achieved clinical benefit (SD ≥ 24 weeks/PR) on the avelumab, axitinib, and palbociclib combination. This triplet showed antitumor activity in NSCLC, including in tumors post‐pembrolizumab progression, and was active at the RP2D, which was well tolerated. NCT03386929 clinicaltrial.gov [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). Methods: In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. Results: A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55–40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. Conclusion: Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. Trial registration: ClinicalTrials.gov, NCT02856425. Registered August 4, 2016 — Prospectively registered. [ABSTRACT FROM AUTHOR]

Summary: This single‐arm, multicentre, phase I study is the first study of zanubrutinib, a potent, specific, irreversible Bruton tyrosine kinase (BTK) inhibitor, in Chinese patients with relapsed/refractory B‐cell malignancies. The objectives were to evaluate safety and preliminary anti‐tumour activity. Forty‐four patients received zanubrutinib 320 mg once daily (QD) (n = 10) or 160 mg twice daily (BID) (n = 34) until disease progression or unacceptable toxicity. 29.5% of patients received zanubrutinib for at least two years. The most common adverse event (AE) and the most common grade 3 or higher AE was neutrophil count decreased (54.5% and 25.0% respectively). Two patients (4.5%) discontinued treatment due to AEs and one treatment‐emergent AE led to death. All haemorrhagic events were grade 1–2 (except for one non‐serious grade 3 purpura). No second primary malignancies, tumour lysis syndrome, or atrial fibrillation/flutter occurred. The overall response rate was 52.3% (complete response rate, 18.2%). Patients with all cancer subtypes benefited from treatment. BTK C481S/R or L528W mutations were found in zanubrutinib‐progressive patients. The safety/efficacy profiles of patients treated with 320 mg QD and 160 mg BID were comparable and similar daily area under the curve (AUC) was achieved. Overall, zanubrutinib was well tolerated and either of these two regimens is clinically practical. Registered at ClinicalTrials.gov (NCT03189524, on 16 June 2017, https://clinicaltrials.gov/ct2/show/NCT03189524). [ABSTRACT FROM AUTHOR]