A5071204980- Estrogen and related hormone effects
- Advanced Breast Cancer Therapies
- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- PARP inhibition in cancer therapy
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Breast Cancer Treatment Studies
- Lung Cancer Treatments and Mutations
- Cancer Treatment and Pharmacology
- BRCA gene mutations in cancer
- Statistical Methods in Clinical Trials
- Lung Cancer Research Studies
- Renal cell carcinoma treatment
- Biochemical and Molecular Research
- Radiopharmaceutical Chemistry and Applications
- Cancer Cells and Metastasis
- Cancer therapeutics and mechanisms
- Synthesis and Catalytic Reactions
- Gene expression and cancer classification
- Chronic Lymphocytic Leukemia Research
- Chemical Reactions and Isotopes
- Histone Deacetylase Inhibitors Research
- CRISPR and Genetic Engineering
AstraZeneca (United Kingdom)
2015-2024
Heidelberg University
2017
Melbourn Science Park
2017
University Hospital of Zurich
2017
German Cancer Research Center
2017
Memorial Sloan Kettering Cancer Center
2017
Cornell University
2017
AstraZeneca (Brazil)
2010-2014
Health Sciences Centre
2012
Sunnybrook Health Science Centre
2012
Purpose We compared fulvestrant 500 mg regimen with the approved dose of 250 per month for treatment postmenopausal women estrogen receptor–positive advanced breast cancer who experienced progression after prior endocrine therapy. Patients and Methods Comparison Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. were randomly assigned to (500 intramuscularly [IM] on day 0, then IM days 14 28 every thereafter) days....
To compare the clinical activity of pure antiestrogen fulvestrant at 500 mg/mo (double approved dose) with aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor-positive breast cancer in postmenopausal women.FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study high-dose (HD) regimen (500 plus mg on day 14 month 1) versus (1 mg/d). The primary efficacy end point was benefit rate...
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 To compare the effect of therapy with anastrozole versus a combination fulvestrant and in women first relapse endocrine-responsive breast cancer. Patients Methods Postmenopausal women, or premenopausal receiving gonadotropin-releasing hormone agonist, estrogen receptor– and/or progesterone receptor–positive disease at after primary treatment localized were open-label randomly assigned to loading dose (LD) regimen followed by monthly injection plus 1 mg daily alone. The end point was...
Abstract Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) the Phase 1 SERENA-1 study1,2 with dose-dependent safety profile. The 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) post-menopausal women HER2˗ BC disease recurrence or progression after ≤1 endocrine therapy (ET) advanced setting. Methods evaluated...
Background SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2− advanced breast cancer. Parts A B aim to determine the safety tolerability monotherapy define doses for clinical evaluation. Patients Methods Women aged 18 years or older metastatic recurrent cancer, refractory (or intolerant) therapy were assigned 25 mg up 450 once daily (QD; escalation) 75, 150, 300 QD (expansion). Safety tolerability, anti-tumor...
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 Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 BRCA2 (BRCA1/2)–deficient BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP 64 patients advanced solid Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage...
Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent selective antagonist degrader ERα. This first-in-human phase I study determined the safety tolerability ascending doses in women with (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, made preliminary assessment antitumor activity.Patients Methods: Forty-five patients received [20 mg once daily (QD) to 600 twice (BID)] dose-escalation,...
Abstract Purpose: The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant expansion cohorts patients AKT1E17K-mutant ER+ MBC. Patients Methods: mutation, detected by local (next-generation sequencing) central (plasma-based BEAMing) testing,...
Abstract Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for receptor–positive (ER+) breast cancer, as they achieve greater inhibition ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated preclinical pharmacology efficacy next-generation oral SERD camizestrant (AZD9833) assessed ER–co-targeting strategies by combining with CDK4/6 inhibitors (CDK4/6i) PI3K/AKT/mTOR-targeted in models...
Objective: This trial compared the efficacy/safety of two IV doses AZD9773, a polyclonal antibody to tumor necrosis factor-α, in adult patients with severe sepsis/septic shock. Design: Multicenter, randomized, double-blind, placebo-controlled phase IIb trial. Setting: ICUs seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain). Patients: Patients 18 years old or older sepsis and/or septic were required have 1) objective clinical evidence infection; 2) at...
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,...
High-throughput analyses have revealed the presence of activating mutations in AKT1 gene a subpopulation meningiomas. We report female patient with multiple intracranial tumor manifestations and histologically verified meningotheliomatous meningioma lung. The was continuously growing at sites despite six surgical resections, radiotherapy, two lines systemic therapy. Following detection an AKT1E17K mutation three independent samples by sequencing, treatment AZD5363, selective AKT inhibitor,...
1032 Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+, HER2− advanced breast cancer (ABC). Parts A/B (escalation/expansion) assessed monotherapy and have been presented previously. C/D examine combination palbociclib; here we present mature data from 75 mg being the dose currently under investigation 3 studies SERENA-4 (NCT04711252) SERENA-6 (NCT04964934). Methods: The primary objective was to determine safety tolerability once...
Abstract AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those the breast and urinary bladder. Although this mutation has been shown to transform rodent cells culture, it was found be less oncogenic than PIK3CA epithelial cells. Moreover, therapeutic potential AKT inhibitors human tumors with an endogenous is not known. Expression exogenous copies MCF10A increased phosphorylation its substrates, induced colony formation soft agar, lesions mammary fat pad...
Abstract Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations the ligand-binding domain of gene (ESR1LBDm). ESR1 mutational mediated may be overcome by selective degraders (SERD). During first-in-human study oral SERD AZD9496, early changes circulating tumor cells (CTCs) DNA (ctDNA) were explored as potential noninvasive tools, alongside paired biopsies,...
Investigate the safety and tolerability of AZD5363 define a recommended dose for evaluation in Japanese patients with advanced solid malignancies. was administered orally as single dose, then escalated to twice daily (bid) separate continuous (every day) intermittent (4 days on, 3 off [4/3] or 2 5 [2/5]) dosing schedules reach doses defined by dose-limiting toxicity (DLT). Doses continuous, 4/3, 2/5 were 80–400, 360–480, 640 mg, respectively, informed results from an equivalent study...
1066 Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer disease recurrence or progression after ≤1 endocrine therapy the setting Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant clinically meaningful benefit vs F progression-free survival (PFS) overall...
Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation not achieved at fulvestrant's feasible dose. This presurgical study (NCT03236974) compared pharmacodynamic effects of fulvestrant AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, treatment-naïve HER2- primary cancer awaiting...
1024 Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown antitumor efficacy in a range of preclinical models breast cancer. Methods: SERENA-1 (NCT03616587) ongoing Phase 1, open-label study pre- post-menopausal women, after ≥1 endocrine therapy ≤2 prior chemotherapies for ER+ HER2- advanced cancer (ABC). The primary objective to determine the safety tolerability once daily (QD), with dose-limiting toxicities (DLTs) 28d defining...