A5025045855- Adenosine and Purinergic Signaling
- PI3K/AKT/mTOR signaling in cancer
- Pharmacological Receptor Mechanisms and Effects
- Lung Cancer Treatments and Mutations
- Chronic Lymphocytic Leukemia Research
- Cancer, Stress, Anesthesia, and Immune Response
- PARP inhibition in cancer therapy
- Protein Degradation and Inhibitors
- Cancer Immunotherapy and Biomarkers
- Advanced Breast Cancer Therapies
- Receptor Mechanisms and Signaling
- Peptidase Inhibition and Analysis
- Prostate Cancer Treatment and Research
- Antibiotics Pharmacokinetics and Efficacy
- CAR-T cell therapy research
- Computational Drug Discovery Methods
- Antifungal resistance and susceptibility
- Pharmacogenetics and Drug Metabolism
- Pharmaceutical studies and practices
- Health Systems, Economic Evaluations, Quality of Life
- Cancer, Lipids, and Metabolism
- Cancer Genomics and Diagnostics
- Brain Metastases and Treatment
- Diabetes Treatment and Management
- Urologic and reproductive health conditions
AstraZeneca (United States)
2017-2024
University of Pennsylvania
2024
Quantitative BioSciences
2023
University of Cincinnati
2014-2017
University of Florida
2016
Columbus Oncology and Hematology Associates
2016
University of Cincinnati Medical Center
2012-2015
Children's Hospital of Philadelphia
2010-2012
The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in preclinical model. To establish clinical feasibility, phase Ib dose-escalation trial investigating safety pharmacokinetics this patients with advanced tumors was performed. orally administered daily escalating doses 200, 400, 800 mg along at 2.5 28-day cycles. Nineteen were enrolled. Adverse events tumor responses evaluated using CTCAE v4.0 RECIST 1.1,...
Abstract Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab patients advanced solid tumors. Patients and Methods: In phase Ia (dose escalation), had relapsed/refractory tumors; Ib expansion), checkpoint inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) colorectal carcinoma, non–small cell lung prior anti–PD-1/PD-L1 exposure, other tumors (checkpoint-naïve exposure). received AZD4635 (75–200 mg once daily...
Abstract Background: AZD5305 is a potent, highly selective PARP1 inhibitor and trapper with superior preclinical tolerability, target engagement efficacy vs 1st generation dual PARP1/2 inhibitors (PARPi). This the first report of ongoing Phase 1/2a PETRA (NCT04644068) trial. Methods: Pts advanced breast, ovarian, prostate or pancreatic cancer bearing germline somatic BRCA1/2, PALB2 RAD51C/D mutations received QD PO until disease progression. ECOG PS 0-2 Hb ≥9.0 g/dL were required. Prior...
Invasive candidiasis is a leading cause of morbidity and mortality in critically ill infants. Prompt administration fluconazole achievement the therapeutic target (area under curve 0 to 24 hours >400 mg*h/L) improve outcomes candidemic patients. A loading dose advised for older patients but has not been evaluated We sought determine pharmacokinetics safety infants at risk invasive fungal infection.We enrolled 10 hospitalized <60 days old with suspected systemic infection this open-label...
Abstract Purpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), assess preliminary efficacy in combination with abiraterone acetate or vistusertib. Patients Methods: This I open-label study included patients advanced solid tumors, particularly prostate cancer, triple-negative breast squamous non–small cell lung cancer. The comprised four arms: (i) AZD8186 monotherapy finding; (ii) expansion; (iii)...
Abstract AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib patients relapsed/refractory solid tumors lymphoma. Adults relapsed intolerant of, refractory to, prior therapies received escalating doses oral once daily twice continuously (21-day cycles), daily/twice intermittently plus 300 mg daily, until disease progression...
Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics; thus, standard fluconazole dosing children on may result suboptimal exposure. This study determined the pharmacokinetics ECMO.Infants <120 days age received either intravenous prophylaxis (25 mg/kg once week) or treatment (12 daily) while ECMO. Paired plasma samples were collected preoxygenator and...
Acalabrutinib, a selective, covalent Bruton tyrosine kinase inhibitor, is CYP3A substrate and weak CYP3A/CYP2C8 inhibitor. A physiologically-based pharmacokinetic (PBPK) model was developed for acalabrutinib its active metabolite ACP-5862 to predict potential drug-drug interactions (DDIs). The indicated would not perpetrate CYP2C8 or DDI with the sensitive CYP substrates rosiglitazone midazolam, respectively. reasonably predicted clinically observed perpetrators itraconazole (4.80-fold vs....
Objectives: Saruparib (AZD5305) was developed through rational design to be highly selective for poly(ADP-ribose) polymerase-1 (PARP1), with increased potency & improved physicochemical properties versus approved PARP inhibitors. Multiple dose expansion cohorts were evaluated at 20, 60, 90 mg QD characterize the exposure-safety -efficacy relationships aid in optimization (Project Optimus). Here we present model informed drug development (MIDD) using comprehensive quantitative exposure...
Abstract Extracellular adenosine signals through the Adenosine 2a Receptor (A2aR) leading to immunosuppression, in part though decreased antigen presentation and effector T cells. AZD4635 inhibits A2aR signaling leads improved immune activation anti-tumor activity preclinical models. This multicenter Phase I clinical trial (NCT02740985) assessed safety, PK, pharmacodynamic, preliminary of as monotherapy (125mg BID, 75mg QD, 100mg QD) combination (75 or with durvalumab @ 1.5g IV q4 wk...
3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription additional mechanisms. AZD5153 novel, reversible inhibitor with bivalent mechanism of action enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), pharmacodynamics (PD). We report here preliminary, unvalidated data from monotherapy pts RR solid...
123 Background: The combination of PARP inhibitors (PARPi) with novel hormonal agents (NHAs) has recently demonstrated significant improvement in progression-free survival patients (pts) metastatic castration-resistant prostate cancer (mCRPC) compared NHAs alone. AZD5305, a PARP1-selective inhibitor, the potential for an improved safety profile and limited drug-drug interactions (DDIs) first-generation PARPi. PETRANHA, open-label nonrandomized study, is evaluating DDIs AZD5305 physician’s...
2570 Background: Loss of PTEN function leads to increased PI3Kβ signalling. AZD8186 (AZD) exhibits significant anti-tumour activity in PTEN-deficient preclinical models, particularly when combined with anti-androgens or the dual mTORC1/2 inhibitor vistusertib (AZD2014). Here we report on dose-finding part this Phase 1 study. Methods: AZD single agent was administered twice daily (BD) 3 different schedules (5 days on/ 2 off, 5 off and continuous). Escalating doses were evaluated cohorts 3-6...
Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes pharmacokinetics betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during randomized, placebo-controlled, single blind, dose escalation to determine safety, tolerability once daily mg, 100 mg 200 ADHD. Plasma levels...
To compare outcomes of men undergoing prostate artery embolization (PAE) for return lower urinary tract symptoms (LUTS) following failure UroLift with a contemporaneous control group benign prostatic hyperplasia and LUTS PAE as an index procedure. Over four-year period, prospectively maintained database identified 17 PAEs performed in mean 48.4 months (range 33-93) UroLift. These cases were compared to 49 volumes < 100 g who underwent PAE; threshold was utilized these would otherwise have...
Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] CYP1A2 inhibitors) to support continued clinical development AZD4635.Study (comparative PK study; nonsmokers) consists Part A B. Participants (fasted) in were administered 50 mg either as nanosuspension or capsule. In B, these participants a 50-mg capsule following high-fat meal with PPI...
e13518 Background: The mammalian target of rapamycin (mTOR) is a critical signaling pathway in many tumors including cancers the breast and colon, glioblastoma multiforme, hepatocellular carcinoma (HCC). Preclinical studies demonstrated combination BEZ235, competitive dual phosphatidylinositide 3-kinase (PI3K)/mTOR inhibitor, mTOR everolimus led to greater regression carcinogen-induced HCC than treatment with higher doses either drug alone. Based on this, we initiated study BEZ235 combined...
TPS296 Background: AZD5305 is a potent and selective oral PARP inhibitor (PARPi) that specifically targets traps PARP1, in contrast to approved PARPis which target both PARP1 PARP2. Preclinical data suggest inhibition confers antiproliferative effects, while PARP2 major driver of hematological toxicity. Thus, may have an improved therapeutic index with less The Phase 3 PROpel study showed first-line olaparib plus abiraterone (abi) significantly radiographic progression-free survival (rPFS)...
TPS3116 Background: Downregulation of a number signaling pathways, including the mammalian target rapamycin (mTOR) pathway, has been demonstrated to be efficacious in large range solid tumors such as breast, colon, endometrial, glial and hepatocellular carcinoma (HCC). However, we find that rapamycins lead suppression negative feedback loop from S6 Kinase 1 (S6K1) Protein B (PKB), leading hyperactivation PKB. In pre-clinical studies using mouse model carcinogen-induced HCC, have combining...
Abstract AZD4635 is an orally administered, selective adenosine 2A receptor (A2AR) antagonist, being evaluated in patients with advanced solid tumors. In the phase 1 trial, safety and pharmacokinetics (PK) of nanosuspension (NS) was assessed as monotherapy or combination durvalumab. HV study, a single dose to assess relative bioavailability, effect high fat meal proton pump inhibitor (PPI) on new capsule formulation (CF). Here we present PK results from both trials provide dosing...
<p>Supplementary Tables and Figures</p>
<div>Abstract<p>AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase 1 study investigated AZD5153 alone or with olaparib patients relapsed/refractory solid tumors lymphoma. Adults relapsed intolerant of, refractory to, prior therapies received escalating doses oral once-daily (QD) twice-daily (BID) continuously (21-day cycles), QD/BID intermittently plus 300 mg...
<p>Supplementary Tables and Figures</p>