A5032401979- Lung Cancer Treatments and Mutations
- PI3K/AKT/mTOR signaling in cancer
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- Ovarian cancer diagnosis and treatment
- Computational Drug Discovery Methods
- Melanoma and MAPK Pathways
- Protein Degradation and Inhibitors
- Heat shock proteins research
- Advanced Breast Cancer Therapies
- PARP inhibition in cancer therapy
- Cancer Treatment and Pharmacology
- Pancreatic and Hepatic Oncology Research
- Cancer Research and Treatments
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Statistical Methods in Clinical Trials
- Cancer Mechanisms and Therapy
- Molecular Biology Techniques and Applications
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- HER2/EGFR in Cancer Research
- Epigenetics and DNA Methylation
- Cancer Immunotherapy and Biomarkers
- Renal cell carcinoma treatment
Institute of Cancer Research
2016-2025
Royal Marsden NHS Foundation Trust
2016-2025
Institute of Cancer Research
2011-2025
Royal Marsden Hospital
2014-2024
Cancer Research UK
2008-2023
Princess Margaret Cancer Centre
2018
Memorial Sloan Kettering Cancer Center
2013-2018
Centro de Investigación Biomédica en Red de Cáncer
2018
INCLIVA Health Research Institute
2018
Hospital Clínico Universitario de Valencia
2018
To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) to recommend a dose for phase II trials.This was I examining once-weekly dosing schedule 17-AAG. Thirty patients with advanced malignancies were treated.The highest level reached 450 mg/m(2)/week. The dose-limiting toxicities (DLTs) encountered grade 3 diarrhea in three (one at 320 mg/m(2)/week two mg/m(2)/week) 4 hepatotoxicity (AST/ALT) one patient Two nine DLTs level....
Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity AKT inhibition AKT-mutant cancers. Patients Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary points progression-free survival (PFS) response according Response Evaluation Criteria Solid Tumors (RECIST)....
PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined DNA-damaging drugs such carboplatin. PATIENTS AND METHODS This phase I trial assessed the inhibitor M6620 (VX-970) (once or twice weekly) carboplatin (carboplatin on day 1 days 2 9 21-day cycles). Primary objectives were safety, tolerability, maximum tolerated dose; secondary included...
Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part a first-in-human trial AZD3965, first-in-class MCT1 inhibitor, in advanced cancer.
Abstract Purpose: In part A, the aim was to define maximum tolerated dose (MTD) of hydrogen sulfate (Hyd-Sulfate) oral capsule formulation mitogen-activated protein kinase inhibitor AZD6244 (ARRY-142886). B, compare pharmacokinetic profile new Hyd-Sulfate with initial free-base suspension and further characterize pharmacodynamic efficacy formulation. Experimental Design: 30 patients received escalating doses twice daily. 29 were randomized a single or suspension, followed by washout, then...
A phase I study to define toxicity and recommend a II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation pharmacokinetic profile, tumor response, definition biologically effective (BED).Patients with advanced solid cancers were treated weekly, intravenous (i.v.) 17-DMAG. An accelerated titration escalation design was used. The maximum tolerated (MTD) highest at which ≤ 1/6 patients experienced...
Abstract Purpose: We evaluated whether next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA) could be used for patient selection and as a tumor clone response biomarker in patients with advanced cancers participating early-phase clinical trials targeted drugs. Experimental Design: Plasma samples from known mutations who completed at least two courses investigational therapy were collected monthly, until disease progression. NGS was performed sequentially on the Ion Torrent...
A phase I study was conducted with the primary objective of determining maximum tolerated dose (MTD) AUY922 in patients advanced solid tumors. Secondary objectives included characterization safety, pharmacokinetic, and pharmacodynamic profiles.Patients tumors received 1-hour i.v. infusions once a week 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities (DLT) first treatment cycle used to guide dose-escalation decisions, established MTD...
Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) advanced cancer patients is largely derived from tumor, has prognostic utility, can be utilized multiplex mutation sequencing when repeat biopsy not feasible. the Sequenom MassArray System OncoCarta panel somatic profiling. Matched...
Abstract Purpose: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of first-in-class dual MEK/RAF inhibitor, RO5126766. Experimental Design: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation completed 2 intermittent schedules [7 on treatment followed by 7 off (7on/7off); 4 3 (4on/3off)]. Results: Fifty-two...
KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and AKT inhibitors (such as MK-2206), combination of which overcome both monotherapies.
This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of first-in-class dual mammalian target rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055. Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation AZD8055 starting at 10 mg twice-daily oral dosing (BID). Forty-nine patients received Dose-limiting toxicities reported 40 (n=1), 90 (n=1) 120 (n=3) BID; all grade 3 rises in transaminases, reversible...
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...
Abstract Purpose: HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim this clinical trial was to evaluate the feasibility using 89Zr-trastuzumab PET (for HER2-positive cancer) or 89Zr-bevacizumab [for estrogen receptor (ER)–positive cancer] determine vivo degradation caused by novel inhibitor NVP-AUY922. Experimental Design: Of note, 70 mg/m2 NVP-AUY922 administered intravenously a weekly schedule patients with...