Safety, Tolerability and Pharmacokinetics of Oral Tablet of Irinotecan in Adult Patients With Solid Tumors
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2255276 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:In order to study the gene expression profiles of monocyte and macrophages, we collected three type of cells and performed pair-wised comparison. It includes human peripheral blood monocyte (MONO), human peripheral blood monocyte derived macrophages treated with M-CSF (MACRO)and primary alveolar macrophages (BAL). All the experiments are performed comparing two of the three cell types from the same person (total 4 persons). Totally we got three set of microarray data, MONO/MACRO, MONO/BAL and MACRO/BAL with 4 biological replicates. Keywords: cell_type_comparison_design
2007-01-10 | GSE5207 | GEO
Project description:In order to study the gene expression profiles of monocyte and macrophages, we collected three type of cells and performed pair-wised comparison. It includes human peripheral blood monocyte (MONO), human peripheral blood monocyte derived macrophages treated with M-CSF (MACRO)and primary alveolar macrophages (BAL). All the experiments are performed comparing two of the three cell types from the same person (total 4 persons). Totally we got three set of microarray data, MONO/MACRO, MONO/BAL and MACRO/BAL with 4 biological replicates.
2006-12-01 | E-MEXP-524 | biostudies-arrayexpress
Project description:Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumor efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p=0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven percent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted.
2024-08-26 | GSE275628 | GEO
Project description:Advanced colorectal cancer (CRC) is an unresolved clinical problem. Epigenetic drugs belonging to the group of histone deacetylase inhibitors (HDACi) may combat CRC in rationally designed treatment schedules. Unfortunately, there is sparse evidence on molecular mechanisms and markers that determine cellular sensitivity to HDACi. Irinotecan is widely used to treat CRC and causes replication stress (RS) and DNA damage as topoisomerase-I inhibitor. We applied irinotecan and the class I HDACi entinostat (MS-275) to isogenic p53-positive and -negative CRC cells. Combinations of irinotecan and MS-275 evoke mitochondrial damage, caspase-mediated apoptosis, and RS-associated DNA damage synergistically and p53-dependently. Targeted mass spectrometry and immunoblot show that irinotecan induces phosphorylation, acetylation, and accumulation of p53 and its target genes. Addition of MS-275 augments the irinotecan-induced acetylation of C-terminal lysine residues of p53 but decreases its phosphorylation and p53 target gene induction. Furthermore, MS-275 increases the amount of acetylated p53 at mitochondria and dysregulates the expression of pro- and anti-apoptotic BCL2 proteins in irinotecan-treated cells. Regarding DNA repair, we see that MS-275 represses the homologous recombination (HR) filament protein RAD51, which limits DNA damage and pro-apoptotic effects of irinotecan. These data suggest that key class I HDAC-dependent functions of p53 in cells with RS are linked to mitochondrial damage and a breakdown of HR. Most importantly, combinations of irinotecan plus MS-275 also kill short-term primary CRC cell cultures and organoids from CRC patients but spare organoids of adjacent matched normal tissue. Thus, irinotecan/HDACi treatment is a promising new approach for the therapy of p53-proficient tumors with clinically tractable inhibitors.
2022-02-15 | PXD019999 | Pride
Project description:Refined quantitative core-clock model based on the model by Relógio et al. 2011. The translation-transcription network is extended by a set of irinotecan-relevant genes, which allows to connect the core clock to the irinotecan pharmacokinetics and -dynamics model by Ballesta et al. 2011. The original model by Ballesta et al. 2011 is extended by an explicit simulation of the number of living and dead cells.
2021-09-15 | MODEL2109140001 | BioModels
Project description:Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single-center (Quotient Sciences, UK), open-label, 2-period crossover trial, 26 healthy men received single doses of 10 mg oral semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96-2.37; P = .072). Area under the semaglutide concentration-time curve from 0 to 24 hours (AUC0-24h,semaglutide ) and maximum semaglutide concentration (Cmax,semaglutide ) were ∼70% higher with 50 versus 240 mL water (P = .056 and P = .048, respectively). Median time to maximum semaglutide concentration (tmax,semaglutide ) was 1.5 hours independent of water volume with dosing. Higher AUC0-24h,semaglutide and Cmax,semaglutide and longer tmax,semaglutide were significantly correlated with longer time to CTE and later gastric emptying of tablet and water (all P < .05). The safety profile was as expected for the GLP-1 receptor agonist drug class. In conclusion, the oral semaglutide tablet erodes in the stomach irrespective of water volume with dosing. Slower tablet erosion in the stomach results in higher semaglutide plasma exposure.
| S-EPMC8251533 | biostudies-literature
Project description:BACKGROUND:There is evidence to suggest that rates of hearing loss are increasing more rapidly than the capacity of traditional audiometry resources for screening. A novel innovation in tablet, self-administered portable audiometry has been proposed as a solution to this discordance. The primary objective of this study was to validate a tablet audiometer with adult patients in a clinical setting. Secondarily, word recognition with a tablet audiometer was compared against conventional audiometry. METHODS:Three distinct prospective adult cohorts underwent testing. In group 1 and group 2 testing with the automated tablet audiometer was compared to standard sound booth audiometry. In Group 1, participants' pure tone thresholds were measured with an automated tablet audiometer in a quiet clinic exam room. In Group 2, participants completed monosyllabic word recognition testing using the NU-6 word lists. In Group 3, internal reliability was tested by having participants perform two automated tablet audiometric evaluation in sequence. RESULTS:Group 1 included 40 patients mean age was 54.7?±?18.4?years old and 60% female; Group 2 included 44 participants mean age was 55.2?±?14.8?years old and 68.2% female; Group 3 included 40 participants with mean age of 39.4 + 15.9?years old and 60.5% female. In Group 1, compared to standard audiometry, 95.7% (95% CI: 92.6-98.9%) of thresholds were within 10?dB. In Group 2, comparing word recognition results, 96.2% (95% CI: 89.5-98.7%) were clinically equivalent and within a critical difference range. In Group 3, One-way Intraclass Correlation for agreement for the both left- and right-ear pure tone average was 0.98. The mean difference between repeat assessments was 0 (SD?=?2.1) in the left ear, and 0.1 (SD?=?1.1) in the right ear. CONCLUSION:Puretone audiometry and word recognition testing appears valid when performed by non-healthcare experts using a tablet audiometer outside a sound booth in a quiet environment. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02761798. Registered April, 2016 < https://clinicaltrials.gov/ct2/show/NCT02761798>.
| S-EPMC6839098 | biostudies-literature
Project description:A phase II study of guadecitabien combined with irinotecan vs regorafenib or TAS-102 in previously treated metastatic colorectal cancer patients
2023-03-31 | GSE226221 | GEO
Project description:To compare the pharmacokinetic (PK) properties of the pediatric dispersible tablet formulation of macitentan and the adult film-coated tablet formulation of macitentan in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover, Phase 1 study was conducted in 12 healthy adults. Subjects were randomized to one of the two possible treatment sequences A/B or B/A on Day 1 under fasted conditions. Treatment A was a single 10 mg dose of macitentan (film-coated adult formulation) and Treatment B was a single 10 mg dose of macitentan, consisting of two 5 mg dispersible tablets (pediatric formulation). PK sampling over 216 hours was conducted, and PK parameters were derived using non-compartmental methods. For macitentan, geometric means ratio of peak plasma concentrations (Cmax ), plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC0- t ), and plasma concentration-time curve from zero to infinity (AUC0-? ) were 1.140, 0.974, and 0.974, respectively. The corresponding 90% confidence intervals fell entirely within the referenced range of 0.8000 to 1.2500, which is used for evaluation of bioequivalence. These results indicate no significant differences between the pediatric dispersible tablet and the adult film-coated tablet. Both formulations were well tolerated. The pediatric dispersible tablet is biocomparable to the adult film-coated tablet formulation.
| S-EPMC7164404 | biostudies-literature
Project description:Metastatic colorectal cancer (mCRC) is associated with multiple somatic copy number alterations (SCNAs). We analyzed SCNAs to estimate overall survival (OS) and progression free suvival (PFS) for mCRC patients treated with bevacizumab in combination with oxaliplatin or irinotecan.
2018-11-21 | GSE110785 | GEO