title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
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Declarations | PMC10284730 | |||
Conflict of interest | TD, Johnson & Johnson and | ONCOLOGY | MG has served in an advisory capacity for Amgen, Eli Lilly and Company, Merck Pharmaceuticals, Roche, Italfarmaco and Servier Pharmaceuticals. HH reports medical writing support for the submitted work and payment for expert testimony from Taiho Oncology, Inc. TD reports institutional research funding from AbbVie, BMS, ... | PMC10284730 |
References | PMC10284730 | |||
2. Materials and Methods | PMC10384543 | |||
2.1. Study Design | This prospective, double-blind, randomized, actively controlled study was conducted at Seoul National University Bundang Hospital in South Korea from July 2020 to September 2021. This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital. Informed consent was obtained from a... | PMC10384543 | ||
2.2. Particpants | bleeding, ischemic heart disease, chronic liver disease, hyperkalemia, ulcer stenosis, hypersensitivity, esophageal gastric varices | PERIPHERAL ARTERIAL DISEASE, BLEEDING, RENAL IMPAIRMENT, LUMBAR SPINAL STENOSIS, ISCHEMIC HEART DISEASE, GASTROINTESTINAL BLEEDING, CHRONIC LIVER DISEASE, ESOPHAGEAL STENOSIS, CONGESTIVE HEART FAILURE, COAGULATION DISORDER, MALIGNANT TUMOR, HEART, BARRETT ESOPHAGUS, HYPERSENSITIVITY, CEREBROVASCULAR DISEASE, PEPTIC ULC... | The inclusion criteria were as follows: patients aged ≤80 years who voluntarily agreed to participate and who were taking nonselective NSAIDs continuously due to lumbar spinal stenosis. The exclusion criteria were as follows: (1) patients with a previous diagnosis of esophageal stenosis, ulcer stenosis, esophageal gast... | PMC10384543 |
2.3. Efficacy and Safety Evaluation | Dyspepsia, dyspepsia | SECONDARY | The primary efficacy endpoint was the mean change in the Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) scores from baseline to treatment week 8. The SF-LDQ is a shortened version of the Leeds dyspepsia questionnaire, a tool used to assess the severity and impact of dyspepsia on an individual’s daily life [The secon... | PMC10384543 |
2.4. Sample Size Calculation | The sample size required to evaluate the superiority of combination therapy over celecoxib monotherapy was calculated via the equation below, using the following conditions: ZA sample size of 63 patients per group was determined using the above formula. Subsequently, considering a dropout rate of 10%, a final sample si... | PMC10384543 | ||
2.5. Statistical Analysis | Data from this study were analyzed in safety, full analysis (FA), and per protocol (PP) sets. The safety set included all patients who received at least one drug during the study. The FA set included all patients for whom primary efficacy endpoints were obtained at least once before the end of the study. The PP set com... | PMC10384543 | ||
3. Results | PMC10384543 | |||
3.1. Demographic Characteristics | A total of 140 patients was enrolled in this study (The patients’ demographic characteristics are shown in | PMC10384543 | ||
3.2. Primary Efficacy Results | The primary efficacy results are presented in | PMC10384543 | ||
3.3. Secondary Efficacy Results | SECONDARY | The secondary efficacy results are shown in | PMC10384543 | |
3.4. Safety Results | ADVERSE EVENT | Adverse events (AEs) were reported in seven (10.9%) and six (9.4%) patients in the combination therapy and celecoxib groups, respectively, with no significant difference in their incidence ( | PMC10384543 | |
4. Discussion | NSAID-induced dyspepsia, osteoarthritis | OSTEOARTHRITIS, DUODENAL ULCERS | This randomized double-blind clinical trial was the first to compare the efficacy of a combination therapy of aceclofenac plus ilaprazole with celecoxib monotherapy for NSAID-induced dyspepsia. This study showed no significant intergroup difference in treatment efficacy or safety. Although there were no statistically s... | PMC10384543 |
Author Contributions | Conceptualization, H.-J.K.; methodology, H.-J.K.; formal analysis; S.L. and J.G.K.; resources, S.L. and H.-J.K.; data curation, H.-J.K.; writing—original draft preparation, S.L.; writing—review and editing, H.-J.K. All authors have read and agreed to the published version of the manuscript. | PMC10384543 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Seoul National University Bundang Hospital (code number B-1907-553-003 on 17 December 2019). | PMC10384543 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10384543 | ||
Data Availability Statement | Data can be obtained from the corresponding author upon reasonable request. | PMC10384543 | ||
Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study. | PMC10384543 | ||
Key Points | PMC10724761 | |||
Question | Does the effectiveness of mass administration of azithromycin to children aged 1 to 59 months vary by distance to the nearest primary health center? | PMC10724761 | ||
Findings | SECONDARY | In this secondary analysis of a cluster randomized trial of 594 communities in Niger, the effectiveness of azithromycin mass administration to reduce child mortality varied significantly by distance to the nearest primary health center, with reductions of 0% at 0 km from the health center, 4% at 1 km, 16% at 5 km, and ... | PMC10724761 | |
Meaning | SECONDARY | Children in communities farthest from primary health facilities likely benefit the most from mass azithromycin administration to reduce mortality.This secondary analysis of a cluster randomized trial examines the association among distance to primary health centers, child mortality, and the effectiveness of azithromyci... | PMC10724761 | |
Importance | The MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial demonstrated that mass azithromycin administration reduced mortality by 18% among children aged 1 to 59 months in Niger. The identification of high-risk subgroups to target with this intervention could reduce the risk of antimicro... | PMC10724761 | ||
Objective | To evaluate whether distance to the nearest primary health center modifies the effect of azithromycin administration to children aged 1 to 59 months on child mortality. | PMC10724761 | ||
Design, Setting, and Participants | SECONDARY | The MORDOR cluster randomized trial was conducted from December 1, 2014, to July 31, 2017; this post hoc secondary analysis was conducted in 2023 among 594 clusters (communities or | PMC10724761 | |
Interventions | Biannual (twice-yearly) administration of a single dose of oral azithromycin or matching placebo over 2 years. | PMC10724761 | ||
Main Outcomes and Measures | REGRESSION | A population-based census was used to monitor mortality and person-time at risk (trial primary outcome). Community distance to a primary health center was calculated as kilometers between the center of each community and the nearest health center. Negative binomial regression was used to evaluate the interaction betwee... | PMC10724761 | |
Results | deaths | Between December 1, 2014, and July 31, 2017, a total of 594 communities were enrolled, with 76 092 children (mean [SD] age, 31 [2] months; 39 022 [51.3%] male) included at baseline, for a mean (SD) of 128 (91) children per community. Median (IQR) distance to the nearest primary health center was 5.0 (3.2-7.1) km. Over ... | PMC10724761 | |
Conclusions and Relevance | SECONDARY | In this secondary analysis of a cluster randomized trial of mass azithromycin administration for child mortality, children younger than 5 years who lived farthest from health facilities appeared to benefit the most from azithromycin administration. These findings may help guide the allocation of resources to ensure tha... | PMC10724761 | |
Trial Registration | ClinicalTrials.gov Identifier: | PMC10724761 | ||
Introduction | WEST | Mortality in children younger than 5 years remains among the highest in the world in West and Central Africa.Prior work suggests that mortality in those younger than 5 years is associated with distance to health care facilities. Pooled analyses have demonstrated that mortality in infants and children in low- and middle... | PMC10724761 | |
Methods | SECONDARY | This post hoc secondary analysis of the MORDOR trial aimed to examine the association between distance to a primary health center and mortality and to determine the presence of a differential effect of azithromycin MDA on child mortality by distance to a primary health center. This analysis used data from the MORDOR Ni... | PMC10724761 | |
MORDOR Trial: Design, Participants, Interventions, and Data Collection | The original MORDOR trial was conducted from December 1, 2014, to July 31, 2017, in Niger, Malawi, and Tanzania. | PMC10724761 | ||
Additional Data Sources | Locations of roads and rivers were obtained from OpenStreetMap (OpenStreetMap Foundation). Primary health center locations were available from Carte Sanitaire du Niger (Ministère de la Santé Publique de la Population et des Affaires Sociales, Niamey, Niger). This analysis included location data on Centre de Santé Integ... | PMC10724761 | ||
Statistical Analysis | deaths | REGRESSION, SECONDARY | This secondary analysis was conducted in 2023. The sample size for this analysis was fixed by enrollment in the MORDOR Niger trial, which was powered to detect a community-level effect of azithromycin MDA on mortality among children aged 1 to 59 months over 2 years. Details of sample size calculations have been reporte... | PMC10724761 |
Results | Between December 1, 2014, and July 31, 2017, a total of 594 communities were enrolled, with 76 092 children (mean [SD] age, 31 [2] months; 39 022 [51.3%] male and 37 070 [48.7%] female) included at baseline for a mean (SD) of 128 (91) children per community ( | PMC10724761 | ||
Participant Flow Diagram | PMC10724761 | |||
Baseline Characteristics of Communities Included in the MORDOR Niger Trial by Treatment Arm | MACROLIDES | Abbreviation: MORDOR, Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance. | PMC10724761 | |
Map of Communities Included in the MORDOR Niger Trial From 2014 to 2017 | deaths | MACROLIDES | MORDOR indicates Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance.The analysis included 3615 deaths and 145 693 person-years at risk ( | PMC10724761 |
Evaluation of Heterogeneity of Effect of Azithromycin vs Placebo Distribution on Child Mortality by Distance | REGRESSION | To aid interpretation of the interaction, outcomes were estimated at specific distances from health centers that were chosen to align with thresholds at which the Niger health system distributes different community services.Adjusted incidence rate ratios were estimated using negative binomial regression and adjusted fo... | PMC10724761 | |
Association Between Distance to a Primary Health Center and Mortality Incidence Rate | REGRESSION | Values from a negative binomial regression model estimating the mortality incidence rate by treatment arm and distance to a primary health center, controlling for community mean age at baseline. Shaded areas indicate 95% CIs.Similarly, the incidence rate difference in mortality increased as distance increased (eTable 2... | PMC10724761 | |
Discussion | malaria, diarrheal disease | RESPIRATORY INFECTIONS, SECONDARY, DIARRHEAL DISEASE, MALARIA | In this secondary analysis of the MORDOR Niger cluster randomized trial, we evaluated associations among distance to a primary health center, child mortality, and the effectiveness of azithromycin MDA to reduce child mortality. Mortality among children aged 1 to 59 months increased sharply with distance from a primary ... | PMC10724761 |
Strengths and Limitations | EVENT | Strengths of this study include the cluster randomized trial design, which involved a randomized and masked intervention, standardized and rigorous data collection procedures, and a low likelihood of misclassification of exposure, outcome, or other variables. In addition, the large sample size enabled examination of ef... | PMC10724761 | |
Conclusions | SECONDARY | In this secondary analysis of a cluster randomized trial, we found that the effectiveness of azithromycin MDA to reduce child mortality increased significantly as distance to the nearest primary health center increased. These findings suggest that resources should be allocated to ensure that those with the least access... | PMC10724761 | |
Background | high-grade gastroenteropancreatic | NEUROENDOCRINE NEOPLASM | The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. | PMC10703888 |
Methods | Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m | PMC10703888 | ||
Results | NEC | DISEASE | For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC ... | PMC10703888 |
Conclusion | Toxicity, GEP-NET | Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. | PMC10703888 | |
Clinical trial registration | ClinicalTrials.gov (NTC02248012). | PMC10703888 | ||
Subject terms | PMC10703888 | |||
Background | tumours of the digestive system, NEC, neoplasms, GEP-NET G3, tumours of the digestive system [ | NEOPLASMS, NEUROENDOCRINE CARCINOMA, GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASM, NEUROENDOCRINE TUMOURS | Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are a heterogeneous group of neoplasms differing in biological behaviour, treatment benefit, and survival. The 2019 WHO classification of tumours of the digestive system separates high-grade (HG) GEP-NEN with a Ki-67 index above 20% into two distinct entities; w... | PMC10703888 |
Methods | PMC10703888 | |||
Study design and patients | advanced/metastatic disease, tumour | DISEASE, TUMOUR | This study was a non-randomised, single-arm, first-line prospective multi-centre phase II trial. Patients were included with histologically confirmed and advanced high-grade neuroendocrine neoplasms of gastroenteropancreatic or of unknown origin with a predominance of gastrointestinal metastasis. The study had the foll... | PMC10703888 |
Treatment and evaluation | toxicity, toxicities | Everolimus 10 mg daily continuously was combined with temozolomide 150 mg/mFor haematological toxicities, both drugs were held at the occurrence of Grade ≥3 toxicity and re-administered at the subordinate dose level (everolimus 5 mg daily continuously and temozolomide 100 mg/mCT evaluation was performed at baseline (be... | PMC10703888 | |
Re-evaluation of pathology | NEC | PATHOLOGY, NEUROENDOCRINE CARCINOMA | At the time of protocol development (2014) and study enrolment (2014-2017), all GEP-NEN with a Ki-67 > 20% were classified as neuroendocrine carcinoma, NEC G3. The 2019 WHO pathology grading system divides HG GEP-NEN into the well-differentiated NET G3 and the poorly differentiated NEC [ | PMC10703888 |
Outcomes | toxicity | DISEASE | An interim analysis was planned to evaluate the toxicity and benefit of treatment for the first 20 consecutive patients. If >50% of the patients experienced dose-limiting toxicity, a trial amendment with revised study drug dosing would be performed. The study would be terminated for lack of efficacy if <60% had at best... | PMC10703888 |
Quality of life | diarrhoea, nausea/vomiting, fatigue, pain, constipation, insomnia, dyspnoea, Cancer | APPETITE LOSS, CANCER | Quality of life during the trial was evaluated using the European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30). The QoL questionnaire was to be completed at baseline, 6 weeks after the start of treatment, and then every 8 weeks during the entire treatment course. The 30-item quest... | PMC10703888 |
Statistics | NEC, tumour | REGRESSION, TUMOUR | Patient and tumour characteristics were analysed using descriptive statistics. Continuous variables (DOR, PFS and OS) were analysed using the Kaplan–Meier method, log-rank test, and Breslow-test. Median follow-up time was analysed with the use of the reverse Kaplan–Meier method. Univariate analyses were performed using... | PMC10703888 |
Results | toxicity, non-NEN disease | ADVERSE EVENT | The assessment of adverse event rates for the first 20 patients showed that 75% needed dose reduction and 65% needed dose delay, but only three patients discontinued treatment due to toxicity. The interim analysis demonstrated a DCR of 90% at 6 weeks. Therefore, the study proceeded without adjustments to the study medi... | PMC10703888 |
Response and survival in 37 HG GEP-NEN patients receiving first-line treatment with everolimus/temozolomide. | Waterfall-plot ( | PMC10703888 | ||
[18F]FDG-PET/CT evaluation | METABOLIC DISEASE | Response evaluation with [18F]FDG-PET/CT after 6 weeks of treatment was available for 29 patients. Fifteen patients (52%) had a partial metabolic response, nine (31%) had stable metabolic disease, four (14%) had progressive metabolic disease, and one (3%) had a mixed metabolic response. Fourteen/29 patients (48%) had a... | PMC10703888 | |
Safety | toxicity | During study treatment, 43% experienced Grade 3 and 38% Grade 4 toxicity (Fig. | PMC10703888 | |
Toxicity reported under first-line treatment with everolimus/temozolomide. | ADVERSE EVENT | The stacked bar chart showing the safety profile according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | PMC10703888 | |
Quality of life | MINOR | Quality of life was generally preserved during study treatment, with minor changes in the QoL mean score between baseline, 4 months (mean difference 8) and 6 months (mean difference 4) (Fig. | PMC10703888 | |
Quality of life (QoL) under first-line treatment with everolimus/temozolomide. | Cancer | CANCER | Forest-plot describing changes in the QoL according to the European Organization for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30). | PMC10703888 |
Second-line treatment | PD | Twenty-eight patients received second-line treatment (76%), mainly PRRT (32%), carboplatin-etoposide (32%) or capecitabine/temozolomide (CAPTEM) (7%). RR was 15%, DCR 48%, and 22% experienced immediate PD. PFS and OS from the start of second-line treatment was 3.7 months (95% CI: 2.8–4.6 months) and 11.8 months (95% CI... | PMC10703888 | |
Subgroup analysis after pathological re-evaluation: NET G3 and NEC | NEC, tumour, NEC-like | TUMOUR, MINEN | All 37 patients were re-evaluated according to the 2019 WHO classification, identifying 26 NET G3, nine NEC, one mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) and one case with ambiguous morphology. Pathological re-evaluation confirmed a Ki-67 ≤ 55% in 30 patients, while seven patients had Ki-67 > 55%, among... | PMC10703888 |
Second-line treatment | NEC | Second-line treatment was received by 21 patients with NET G3 (nine received PRRT) and six patients with NEC. After start of second-line treatment, NET G3 had a PFS of 5.4 months (95% CI: 0–11.6 months) compared to 2.1 months (95% CI: 0–4.6 months) for NEC ( | PMC10703888 | |
Discussion | pneumonitis, NEC, cancers, cardiovascular disease, neutropenia, toxicity, GEP-NET | PNEUMONITIS, CANCERS, NEUTROPENIA, CARDIOVASCULAR DISEASE, DISEASE | To the best of our knowledge, this is the first prospective clinical trial examining everolimus and temozolomide as first-line treatment in metastatic HG GEP-NEN. The study’s primary endpoint was met (DCR at 6 months of 65%), PFS was 10.2 months and OS was 26.4 months. Grade 3–4 toxicity was commonly observed. Dose red... | PMC10703888 |
Strengths and limitations | NEC, GEP-NET | NEOPLASMS | The prospective design of the study and re-evaluation of HE and immunohistochemically stained slides (including Ki-67) by experienced NEN pathologists according to the 2019 WHO classification are major strengths of this study. The main limitations are the trial’s single-arm design, which makes it difficult to compare t... | PMC10703888 |
Conclusion | toxicity, GEP-NET | In summary, everolimus and temozolomide may be a treatment option for selected patients with metastatic GEP-NET G3 resulting in a high DCR at 6 months of 77%, PFS 12.6 months, and OS 31.4 months. The benefit for the few GEP-NEC patients was limited. Careful monitoring of toxicity is essential when using this combinatio... | PMC10703888 | |
Supplementary information | The online version contains supplementary material available at 10.1038/s41416-023-02462-0. | PMC10703888 | ||
Acknowledgements | ENETS, Neuroendocrine Tumour | The Nordic Neuroendocrine Tumour Group initiated this study. The authors would like to thank Randi Eikeland for data management. The study was presented as an oral presentation at the ENETS conference in March 2022. | PMC10703888 | |
Author contributions | PATHOLOGY | The study protocol was designed by HS, SWL and AS. Principal investigators for the study were HS, SWL, AS, LWV, ML, GOH and JBS. SM did the statistical analyses with help from the study statistician JA. Figures were created by JA. TMH helped with the interpretation of the nuclear imaging analyses. The pathology re-eval... | PMC10703888 | |
Funding | The study received a research grant from Novartis. | PMC10703888 | ||
Data availability | The data generated and analysed in this study are available from the corresponding author upon reasonable request. | PMC10703888 | ||
Competing interests | ONCOLOGY | HS: Consultant/advisory board: Hutchison, Bayer, ITM, AAA. Lecture Honoraria; Novartis, Ipsen, Bayer, SAM Nordic, Pierre Fabre. ML: Unrestricted research grant from Scandion Oncology A/S. | PMC10703888 | |
Ethics approval and consent to participate | ICH | The protocol was approved by the National Competent Authorities in the participating countries (Sweden, Norway and Denmark) and registered in ClinicalTrials.gov (NTC02248012). The study was conducted in accordance with the Declaration of Helsinki and ICH guidelines for Good Clinical Practice. Written informed consent w... | PMC10703888 | |
Consent for publication | Not relevant. | PMC10703888 | ||
References | PMC10703888 | |||
Purpose | gastrointestinal malignancies | Guanylyl cyclase C (GCC) is highly expressed in several gastrointestinal malignancies and preclinical studies suggest that it is a promising target for antibody-based therapeutics. This phase I trial assessed the safety and tolerability of TAK-164, an investigational, anti-GCC antibody–drug conjugate (NCT03449030). | PMC10068631 | |
Methods | gastrointestinal cancers | GASTROINTESTINAL CANCERS | Thirty-one patients with GCC-positive, advanced gastrointestinal cancers received intravenous TAK-164 on day 1 of 21-day cycles. Dose escalation proceeded based on cycle 1 safety data via a Bayesian model. | PMC10068631 |
Results | nausea, DLTs, fatigue, toxicities, hepatic failure, anemia, pyrexia | ADVERSE EVENTS, ANEMIA, HEPATIC FAILURE, COLORECTAL CARCINOMA | Median age was 58 years (range 32–72), 25 patients (80.6%) had colorectal carcinoma, and median number of prior therapies was four. No dose-limiting toxicities (DLTs) were reported during cycle 1 DLT evaluation period. After cycle 2 dosing, 3 patients reported dose-limiting treatment-emergent adverse events (TEAEs): gr... | PMC10068631 |
Conclusions | TAK-164 | HEPATIC TOXICITY | TAK-164 appeared to have a manageable safety profile at 0.064 mg/kg. Hepatic toxicity was identified as a potential risk. The RP2D of 0.064 mg/kg was considered insufficient to derive clinical benefit; there are no plans for further clinical development. | PMC10068631 |
Clinical Trial Registration | NCT03449030. | PMC10068631 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00280-023-04507-w. | PMC10068631 | ||
Keywords | PMC10068631 | |||
Introduction | TAK-164 | TAK-164 is a novel second-generation anti-guanylyl cyclase C (GCC) antibody–drug conjugate (ADC), consisting of a human immunoglobulin (IgG)1 monoclonal antibody (mAb) specifically targeting GCC, linked to a novel class of DNA alkylating agents termed mono-indolinobenzodiazepine pseudodimers (IGNs), by a peptide linker... | PMC10068631 | |
Materials and methods | PMC10068631 | |||
Patients | Eligible patients were aged ≥ 18 years, with histologically or cytologically confirmed GCC-positive ( | PMC10068631 | ||
Study design | tumor, DLTs, neutropenia, toxicity, toxicities | DISEASE PROGRESSION, TUMOR, NEUTROPENIA | This was an open-label, multicenter, first in-human, phase I dose-escalation study of TAK-164. Patients received TAK-164 as a single intravenous infusion with a duration of up to 2 h, on day 1 of each 21-day cycle or every 3 weeks, until disease progression, unacceptable toxicity, or withdrawal from the study. Doses of... | PMC10068631 |
Assessments | Tumors, tumor, Cancer | ADVERSE EVENT, TUMOR, ADVERSE EVENTS, TUMORS, CANCER | Treatment-emergent adverse events (TEAEs) were assessed after administration of the first dose of TAK-164 and through 30 days after the last dose of TAK-164, were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5 and were tabulated according to the Me... | PMC10068631 |
Sample size and statistical analyses | toxicity | DISEASE | Approximately, 25 patients were planned to be enrolled. The mTPI dosing schema was planned to maximize patients treated at or near the MTD. Any excessive toxicity, defined as the probability of the DLT level exceeding 25% being greater than 95%, would prevent the escalation to next or higher dose levels and would lead ... | PMC10068631 |
Results | PMC10068631 | |||
Response assessment | colon cancer | COLON CANCER | Overall, 25 patients had received at least one dose of TAK-164 and had at least one post-baseline response assessment and so were evaluable for response. One patient with colon cancer and high baseline apical GCC | PMC10068631 |
PK analysis | TAK-164 concentration–time profiles were consistent with an intravenous infusion, with peak concentrations generally occurring at (or near) the time of end of the infusion (Fig. Plasma concentration–time profiles of TAK-164 at 0.004–0.32 mg/kg Q3W on Cycle 1 day 1 (TAK-164 plasma clearance | PMC10068631 | ||
Target engagement assessment | colon cancer | DNA DAMAGE, COLON CANCER | Paired biopsies from 2 patients were available to assess target engagement before and after treatment with TAK-164. Since the payload of TAK-164 is an alkylating agent, we utilized the DNA damage marker, γH2AX, as a surrogate marker of target engagement. Analysis of γH2AX staining from a patient with colon cancer recei... | PMC10068631 |
Discussion | GI toxicities, colorectal, gastric, and esophageal carcinomas, GI cancers, toxicity, nausea and vomiting, Serious hepatic toxicities, all-grade | MALIGNANCIES, DNA DAMAGE, SOLID TUMOR | ADCs are becoming increasingly prominent for the treatment of hematologic and solid tumor malignancies, with eleven ADCs approved globally, six of which, including the human epidermal growth factor receptor 2-directed ADC Enhertu, were approved since 2019 [Overall, TAK-164 had a manageable safety profile with no hepati... | PMC10068631 |
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