A5085453177- PI3K/AKT/mTOR signaling in cancer
- Advanced Breast Cancer Therapies
- Lung Cancer Research Studies
- Lung Cancer Treatments and Mutations
- Peptidase Inhibition and Analysis
- PARP inhibition in cancer therapy
- Neuroendocrine Tumor Research Advances
- Protein Degradation and Inhibitors
- Atrial Fibrillation Management and Outcomes
- Fibroblast Growth Factor Research
- Cancer Genomics and Diagnostics
- Venous Thromboembolism Diagnosis and Management
- Pharmacogenetics and Drug Metabolism
- Chemokine receptors and signaling
- Eosinophilic Disorders and Syndromes
- Chronic Obstructive Pulmonary Disease (COPD) Research
- HER2/EGFR in Cancer Research
- Asthma and respiratory diseases
- Blood Coagulation and Thrombosis Mechanisms
- Renal cell carcinoma treatment
- Multiple Myeloma Research and Treatments
- Plant-based Medicinal Research
- Tuberous Sclerosis Complex Research
- Medical Imaging and Pathology Studies
- Lymphoma Diagnosis and Treatment
AstraZeneca (Sweden)
2005-2025
Hudson Institute
2023
John Wiley & Sons (United States)
2023
Liechtenstein Institute
2023
AstraZeneca (United Kingdom)
2001-2019
University of Liverpool
2019
Poole Hospital NHS Foundation Trust
2019
University of Nottingham
2019
Royal Bournemouth Hospital
2019
Royal Derby Hospital
2019
Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis these patients is poor and treatment options are limited. Amplified FGFR1 one most common oncogenic events in SQCLCs, occurring approximately 20% cases. AZD4547 a potent selective FGFR1-3 inhibitor with antitumor activity FGFR1-amplified SQCLC lines patient-derived xenografts.Experimental Design: On basis data, we performed phase I study previously treated stage IV SQCLCs (NCT00979134). amplification...
Abstract Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate safety, tolerability, and pharmacokinetics define recommended dosing schedule, evaluate preliminary clinical activity. Experimental Design: Patients aged ≥18 years World Health Organization (WHO) performance status 0 1. Dose escalation conducted...
BackgroundBEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor AKT isoforms 1–3, in combination with first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer, and a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+).Patients methodsBEECH consisted open-label, phase Ib safety run-in (part A) 38 patients randomised,...
Abstract Purpose This study aimed to evaluate capivasertib exposure–response relationships for clinical safety events support dosage selection. Methods Data from 277 patients with solid tumors participating in three phase 1 studies were analyzed. Capivasertib 80–800 mg was administered as monotherapy orally twice daily (BID) on continuous or intermittent (4 days on, 3 off [4/3] 2 5 [2/5]) schedules. Relationships between exposure related metrics (dose, weekly dose, AUC, AUC PWD , C max and...
Capivasertib is a potent, selective inhibitor of all 3 Akt isoforms (Akt1/2/3), and it currently being tested in Phase III trials for the treatment prostate breast cancer. To investigate effect cytochrome P450 3A4 (CYP3A4) on pharmacokinetics capivasertib, I drug-drug interaction study capivasertib itraconazole was conducted 11 healthy volunteers (median age, 54 years). The 8-day had stages: Participants received single dose 80 mg Stage 1, 4 doses 200 over days 2, final coadministered with...
Abstract Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) determine if this drug can reach its therapeutic target in sufficient concentration significantly modulate key biomarkers of AKT pathway and tumor proliferation. Patients Methods: was a two-stage, double-blind, randomized, placebo-controlled, “window-of-opportunity” patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed 480 mg b.i.d....
An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose capivasertib (400 mg; tablets) followed by [
This two-part, adaptive study assessed the effect of food and an acid-reducing agent (rabeprazole) on pharmacokinetics (PK) safety capivasertib, a potent AKT inhibitor, in clinical development for cancer treatment.In Part 1, healthy participants (n = 24) were randomized to receive single-dose capivasertib after overnight fasting, high-fat, high-calorie meal with rabeprazole postovernight fasting one six treatment sequences. Based 1 results, new group (Part 2) low-fat, low-calorie modified...
Abstract Purpose Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials advanced breast and prostate cancer. This study the drug–drug interaction risk capivasertib with cytochrome P450 3A substrate midazolam previously treated adults solid tumors. Methods Patients received oral 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 off) starting day 2 cycle 1 (29 days) each 28-day thereafter. In...
Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives this analysis were to develop population pharmacokinetic model for capivasertib and quantitatively assess impact intrinsic extrinsic factors on pharmacokinetics capivasertib.
AZD5363 is a potent pan-AKT inhibitor originally formulated as capsule; tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) effect food B) on PK/safety tablet. Adults with advanced solid tumours received 480 mg bid in partially fasted state by (Week 1) capsule 2) '4-days-on/3-days-off' schedule A). parameters were evaluated using pre-defined 90% CIs AUCτ Cmax ratios 0.75–1.33 to assess comparability. In...
The aim of this study was to summarise the pharmacokinetic findings from eight phase I studies in healthy volunteers given oral AZD5069, a selective small-molecule CXCR2 antagonist. 240 across received single (0.1–200 mg) or multiple once- twice-daily (10–120 AZD5069 as solution, suspension, capsules tablets. Pharmacokinetics were evaluated using non-compartmental analysis methods. rapidly absorbed (time maximum concentration ~ 2 h) under fasting conditions. A high-fat, high-calorie meal...
The novel oral anticoagulant AZD0837 is currently in clinical development for the prevention of stroke and systemic embolic events patients with atrial fibrillation. bioconverted to AR-H067637, a selective reversible direct thrombin inhibitor. This first-time-in-man study (study code D1250C00001) investigated safety, tolerability, pharmacokinetics (PK) pharmacodynamics (PD) AZD0837.Healthy Caucasian male volunteers (n = 44, age 20 - 39 y) were enrolled into this single escalating doses given...
Objective Our objective was to characterize the pharmacokinetics of melagatran, active form oral direct thrombin inhibitor ximelagatran, and relationship between melagatran exposure clinical outcome in patients with acute deep vein thrombosis. Methods A population pharmacokinetic analysis performed on samples from thrombosis participating a randomized dose-finding study (THRombin Inhibitor Venous thromboEmbolism [THRIVE I]). Patients received fixed doses ximelagatran (24, 36, 48, or 60 mg...
Abstract Background: Preclinical synergy between PARP and PI3K pathway inhibition in BRCA m sporadic cancers provided rationale for this trial. Methods: Ola 300mg BID was combined with 2 schedules of AZD BID: 4 days on 3 off (4/7) 5 (2/7) using a novel intrapatient dose escalation design (Michalarea et al, AACR 2015). Cohort expansion pts gBRCA tumors relevant somatic mutations or BRCAness phenotype, assessed regimens: (1) + 400mg 4/7 (2) 640mg 2/7 AZD. Targeted next generation sequencing...
Aims The purpose of this study was to characterize the relationship between degree anticoagulation, assessed by APTT, and plasma concentration inogatran in healthy subjects patients with coronary artery disease. Methods Data from five phase I studies 78 males two II multicentre 948 both sexes unstable angina pectoris or non‐Q‐wave myocardial infarction were evaluated. A total 3296 pairs concentration‐APTT samples obtained before, during, after intravenous infusions inogatran. Mixed effects...
Pharmacokinetics-matched digital electrocardiogram data (n = 503 measurements from 180 patients) collected in a first-in-human, multi-part, dose-escalation (from 80 to 800 mg) and dose expansion (at 480 phase 1 study patients with advanced solid malignancies, were used assess potential risk of QT prolongation associated the AKT inhibitor capivasertib. The relationship between plasma drug concentrations baseline-adjusted Fridericia-corrected (ΔQTcF) values was estimated using prespecified...
The objectives were to estimate and compare, in silico vivo, the effects of a strong moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations performed with computer software Simcyp, predicted outcome was compared results observed healthy male subjects. geometric mean plasma exposure + ketoconazole showed 7.1-fold higher AUC 4.4-fold Cmax alone. Coadministration verapamil gave 1.9-fold 1.7-fold 7.7-fold 4.8 -fold 2.2-fold 2.0-fold maximum QTcF increase from baseline 407,...
85 Background: Androgen receptor (AR) targeting therapies prolong survival of patients with metastatic castration-resistant prostate cancer (mCRPC); however, in many cases, resistance develops, resulting disease progression. Activation the PI3K/AKT/mTOR signaling pathway is common mCRPC and contributes to resistance, mostly due loss PTEN, which occurs 40–60% patients. Preclinical studies have demonstrated reciprocal regulation between AR pathways significant anti-tumor activity when both are...