61 results on '"Patrick Urban"'
Search Results
2. An Architecture for Solving the Eigenvalue Problem on Embedded FPGAs.
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Alwyn Burger, Patrick Urban, Jayson Boubin, and Gregor Schiele
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- 2020
- Full Text
- View/download PDF
3. Multi-device UI Development for Task-Continuous Cross-Channel Web Applications.
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Enes Yigitbas, Thomas Kern, Patrick Urban, and Stefan Sauer 0001
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- 2016
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- View/download PDF
4. Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study
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Ben Solomon, D-W. Kim, Enriqueta Felip, D.S-W. Tan, Lilli Petruzzelli, Sebastian Szpakowski, Michael Thomas, Laura Q.M. Chow, Johan Vansteenkiste, Alice T. Shaw, Serafino Pantano, Patrick Urban, Ranee Mehra, D.R. Camidge, and Sunil Sharma
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Pulmonary and Respiratory Medicine ,Oncology ,Alectinib ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,non-small cell lung cancer (NSCLC) ,hemic and lymphatic diseases ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Biopsy ,medicine ,Anaplastic lymphoma kinase ,Humans ,Anaplastic Lymphoma Kinase ,Sulfones ,Lung cancer ,Protein Kinase Inhibitors ,Ceritinib ,Crizotinib ,medicine.diagnostic_test ,business.industry ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,ALK inhibitor ,Pyrimidines ,business ,medicine.drug - Abstract
Objectives To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non–small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥300 mg in the ASCEND-1 study. Methods ASCEND-1 was an open-label, multicentre, phase 1, dose–escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naive or ALKi-pretreated patients with locally advanced or metastatic ALK+ NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK+ NSCLC patients were treated with ceritinib at doses ≥300 mg. Results NGS data were generated for 85 pts (ALKi-pretreated [n=54]; ALKi-naive [n=31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naive patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification. Conclusions This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients. Trial registration: ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516
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- 2021
5. Photolipid Bilayer Permeability is Controlled by Transient Pore Formation
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Stefanie D. Pritzl, David B. Konrad, Theobald Lohmüller, Dirk Trauner, Patrick Urban, James A. Frank, and Alexander Prasselsperger
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Liposome ,Membrane permeability ,Bilayer ,Vesicle ,02 engineering and technology ,Surfaces and Interfaces ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,Membrane ,chemistry ,Phosphatidylcholine ,Electrochemistry ,Biophysics ,General Materials Science ,0210 nano-technology ,Lipid bilayer ,Isomerization ,Spectroscopy - Abstract
Controlling the release or uptake of (bio-) molecules and drugs from liposomes is critically important for a range of applications in bioengineering, synthetic biology, and drug delivery. In this paper, we report how the reversible photoswitching of synthetic lipid bilayer membranes made from azobenzene-containing phosphatidylcholine (azo-PC) molecules (photolipids) leads to increased membrane permeability. We show that cell-sized, giant unilamellar vesicles (GUVs) prepared from photolipids display leakage of fluorescent dyes after irradiation with UV-A and visible light. Langmuir-Blodgett and patch-clamp measurements show that the permeability is the result of transient pore formation. By comparing the trans-to-cis and cis-to-trans isomerization process, we find that this pore formation is the result of area fluctuations and a change of the area cross-section between both photolipid isomers.
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- 2020
6. A Lipid Photoswitch Controls Fluidity in Supported Bilayer Membranes
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Stefanie D. Pritzl, David B. Konrad, Patrick Urban, Theobald Lohmueller, Martina F. Ober, Christina F. Dirscherl, Carla Pernpeintner, Dirk Trauner, James A. Frank, and Bert Nickel
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Materials science ,Photoswitch ,Photoisomerization ,Diffusion ,Bilayer ,Fluorescence recovery after photobleaching ,02 engineering and technology ,Surfaces and Interfaces ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,Fick's laws of diffusion ,0104 chemical sciences ,Membrane ,Chemical physics ,Electrochemistry ,General Materials Science ,0210 nano-technology ,Lipid bilayer ,Spectroscopy - Abstract
Supported lipid bilayer (SLB) membranes are key elements to mimic membrane interfaces on a planar surface. Here, we demonstrate that azobenzene photolipids (azo-PC) form fluid, homogeneous SLBs. Diffusion properties of azo-PC within SLBs were probed by fluorescence microscopy and fluorescence recovery after photobleaching. At ambient conditions, we find that the trans-to-cis isomerization causes an increase of the diffusion constant by a factor of two. Simultaneous excitation with two wavelengths and variable intensities furthermore allows to adjust the diffusion constant D continuously. X-ray reflectometry and small-angle scattering measurements reveal that membrane photoisomerization results in a bilayer thickness reduction of ∼0.4 nm (or 10%). While thermally induced back-switching is not observed, we find that the trans bilayer fluidity is increasing with higher temperatures. This change in diffusion constant is accompanied by a red-shift in the absorption spectra. Based on these results, we suggest that the reduced diffusivity of trans-azo-PC is controlled by intermolecular interactions that also give rise to H-aggregate formation in bilayer membranes.
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- 2020
7. Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy
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Patrick Urban, Barbara Pistilli, Emmanuelle di Tomaso, D. Farci, Cristian Massacesi, Ander Urruticoechea, Cristina Saura, Anthony Kong, H. S. Han, Steve Chan, Guy Jerusalem, S. L. Mouhaer, Thomas Bachelot, Douglas Robinson, and T. Pluard
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Adult ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Receptor, ErbB-2 ,Morpholines ,Buparlisib ,Aminopyridines ,Phases of clinical research ,Breast Neoplasms ,Article ,Capecitabine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Trastuzumab ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,skin and connective tissue diseases ,Response Evaluation Criteria in Solid Tumors ,Aged ,Brain Neoplasms ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,030104 developmental biology ,Tolerability ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,business ,medicine.drug - Abstract
PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION: Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.
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- 2017
8. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial
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Carlos L. Arteaga, Mark Clemons, Soulef Hachemi, Barbara Pistilli, Javier Cortes, José Baselga, Zefei Jiang, Norikazu Masuda, Agnieszka Jagiełło-Gruszfeld, Bharani Dharan, Seock–Ah –A Im, Masato Takahashi, Patrick Urban, Peter Vuylsteke, Ling Ming Tseng, Hiroji Iwata, Mario Campone, Walter Jonat, Yoshinori Ito, Sara A. Hurvitz, Ahmad Awada, Michele De Laurentiis, Cristian Massacesi, Stephen Chia, Emmanuelle di Tomaso, Baselga, José, Im, Seock-ah, Iwata, Hiroji, Cortés, Javier, De Laurentiis, Michele, Jiang, Zefei, Arteaga, Carlos L, Jonat, Walter, Clemons, Mark, Ito, Yoshinori, Awada, Ahmad, Chia, Stephen, Jagiełło-gruszfeld, Agnieszka, Pistilli, Barbara, Tseng, Ling-ming, Hurvitz, Sara, Masuda, Norikazu, Takahashi, Masato, Vuylsteke, Peter, Hachemi, Soulef, Dharan, Bharani, Di Tomaso, Emmanuelle, Urban, Patrick, Massacesi, Cristian, and Campone, Mario
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0301 basic medicine ,Morpholine ,Aging ,Receptor, ErbB-2 ,DNA Mutational Analysis ,Buparlisib ,Aminopyridines ,Phases of clinical research ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,ErbB-2 ,0302 clinical medicine ,Receptors ,Antineoplastic Combined Chemotherapy Protocols ,Neoplasm Metastasis ,Fulvestrant ,Progesterone ,Class I Phosphatidylinositol 3-Kinase ,Cancer ,education.field_of_study ,Tumor ,Estradiol ,Alanine Transaminase ,DNA, Neoplasm ,Middle Aged ,Neoplasm Metastasi ,Postmenopause ,Survival Rate ,Receptors, Estrogen ,Oncology ,Response Evaluation Criteria in Solid Tumors ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Retreatment ,Female ,Drug Eruptions ,Receptors, Progesterone ,Breast Neoplasm ,Human ,Receptor ,Signal Transduction ,medicine.drug ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,Morpholines ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Population ,Response Evaluation Criteria in Solid Tumor ,Breast Neoplasms ,Placebo ,Article ,Disease-Free Survival ,DNA Mutational Analysi ,03 medical and health sciences ,Breast cancer ,Double-Blind Method ,Clinical Research ,Internal medicine ,Breast Cancer ,Biomarkers, Tumor ,medicine ,Humans ,Oncology & Carcinogenesis ,Aspartate Aminotransferases ,education ,Survival rate ,Aged ,Gynecology ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Evaluation of treatments and therapeutic interventions ,Aspartate Aminotransferase ,DNA ,Exanthema ,medicine.disease ,Estrogen ,Aminopyridine ,030104 developmental biology ,chemistry ,Drug Eruption ,Hyperglycemia ,Neoplasm ,Phosphatidylinositol 3-Kinase ,business ,Biomarkers - Abstract
BackgroundPhosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.MethodsThe BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.FindingsBetween Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [
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- 2017
9. Light-Controlled Membrane Mechanics and Shape Transitions of Photoswitchable Lipid Vesicles
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Carla Pernpeintner, James A. Frank, Christian R. Roeske, Stefanie D. Pritzl, Dirk Trauner, Theobald Lohmüller, and Patrick Urban
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Photoisomerization ,Ultraviolet Rays ,Lipid Bilayers ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Isomerism ,Phosphatidylcholine ,Electrochemistry ,General Materials Science ,Unilamellar Liposomes ,Spectroscopy ,Chemistry ,Vesicle ,Bilayer ,Surfaces and Interfaces ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,Molecular machine ,0104 chemical sciences ,Crystallography ,Membrane ,Membrane mechanics ,Phosphatidylcholines ,Biophysics ,Lipid vesicle ,0210 nano-technology ,Azo Compounds - Abstract
Giant unilamellar vesicles (GUVs) represent a versatile model system to emulate the fundamental properties and functions associated with the plasma membrane of living cells. Deformability and shape transitions of lipid vesicles are closely linked to the mechanical properties of the bilayer membrane itself and are typically difficult to control under physiological conditions. Here, we developed a protocol to form cell-sized vesicles from an azobenzene-containing phosphatidylcholine (azo-PC), which undergoes photoisomerization on irradiation with UV-A and visible light. Photoswitching within the photolipid vesicles enabled rapid and precise control of the mechanical properties of the membrane. By varying the intensity and dynamics of the optical stimulus, controlled vesicle shape changes such as budding transitions, invagination, pearling, or the formation of membrane tubes were achieved. With this system, we could mimic the morphology changes normally seen in cells, in the absence of any molecular machines associated with the cytoskeleton. Furthermore, we devised a mechanism to utilize photoswitchable lipid membranes for storing mechanical energy and then releasing it on command as locally usable work.
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- 2017
10. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2– advanced breast cancer (BELLE-4)
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Patrick Urban, M. Campone, Petr Krivorotko, Cristian Massacesi, Roberto Hegg, Arlene Chan, JT Beck, M. Ramos Vazquez, L.Y. Dirix, Alexey Manikhas, E. Di Tomaso, Suzette Delaloge, Miguel Martin, Mikhail Shtivelband, N. Batista López, M. Ruiz Borrego, Joyce O'Shaughnessy, Qamar J. Khan, and S. Goteti
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0301 basic medicine ,Oncology ,Receptor, ErbB-2 ,medicine.medical_treatment ,Buparlisib ,Aminopyridines ,Kaplan-Meier Estimate ,chemistry.chemical_compound ,0302 clinical medicine ,buparlisib (BKM120) ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Phosphoinositide-3 Kinase Inhibitors ,advanced breast cancer ,Aged, 80 and over ,education.field_of_study ,Hematology ,Middle Aged ,Metastatic breast cancer ,Treatment Outcome ,Paclitaxel ,030220 oncology & carcinogenesis ,Female ,Adult ,medicine.medical_specialty ,Morpholines ,Population ,Breast Neoplasms ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,breast cancer ,Breast cancer ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,education ,Aged ,Proportional Hazards Models ,Chemotherapy ,business.industry ,HER2− ,Interim analysis ,medicine.disease ,Surgery ,PI3K pathway ,030104 developmental biology ,chemistry ,business - Abstract
Background Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.
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- 2017
11. Light-Controlled Lipid Interaction and Membrane Organization in Photolipid Bilayer Vesicles
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David B. Konrad, Carla Pernpeintner, Patrick Urban, Stefanie D. Pritzl, Dirk Trauner, James A. Frank, Christian R. Roeske, and Theobald Lohmüller
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0301 basic medicine ,Photoisomerization ,Ultraviolet Rays ,Lipid Bilayers ,Phospholipid ,02 engineering and technology ,03 medical and health sciences ,chemistry.chemical_compound ,Membrane Microdomains ,Isomerism ,Electrochemistry ,Molecule ,General Materials Science ,Lipid bilayer ,Spectroscopy ,Unilamellar Liposomes ,Chemistry ,Bilayer ,Vesicle ,Surfaces and Interfaces ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,030104 developmental biology ,Membrane ,Azobenzene ,Microscopy, Fluorescence ,Biophysics ,Phosphatidylcholines ,lipids (amino acids, peptides, and proteins) ,0210 nano-technology ,Azo Compounds - Abstract
Controlling lateral interactions between lipid molecules in a bilayer membrane to guide membrane organization and domain formation is a key factor for studying and emulating membrane functionality in synthetic biological systems. Here, we demonstrate an approach to reversibly control lipid organization, domain formation, and membrane stiffness of phospholipid bilayer membranes using the photoswitchable phospholipid azo-PC. azo-PC contains an azobenzene group in the sn2 acyl chain that undergoes reversible photoisomerization on illumination with UV-A and visible light. We demonstrate that the concentration of the photolipid molecules and also the assembly and disassembly of photolipids into lipid domains can be monitored by UV-vis spectroscopy because of a blue shift induced by photolipid aggregation.
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- 2018
12. Application of time-dependent modeling for the exposure-efficacy analysis of ceritinib in untreated ALK-rearranged advanced NSCLC patients
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Ying Hong, Wen Gu, Yu-Yun Ho, Yvonne Y. Lau, Xinrui Zhang, and Patrick Urban
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,Antineoplastic Agents ,Toxicology ,Logistic regression ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Medicine ,Anaplastic lymphoma kinase ,Humans ,Pharmacology (medical) ,Anaplastic Lymphoma Kinase ,Sulfones ,Aged ,Pharmacology ,Aged, 80 and over ,Gene Rearrangement ,Ceritinib ,business.industry ,Proportional hazards model ,Brain Neoplasms ,Hazard ratio ,Odds ratio ,Middle Aged ,Prognosis ,Clinical trial ,Survival Rate ,030104 developmental biology ,Pyrimidines ,030220 oncology & carcinogenesis ,Female ,Geometric mean ,business ,medicine.drug ,Follow-Up Studies - Abstract
Ceritinib 750 mg/day was approved for the treatment of patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) based on ASCEND-4 study. The objective of this article is to introduce the use of time-dependent modeling approach in the updated exposure–efficacy analysis of ceritinib for the first-line indication. Exposure–efficacy analyses, including data from 156 patients, were first conducted using time-independent logistic regression model for response of complete or partial response and Cox regression model for progression-free survival (PFS). The exposure measure used was average Ctrough, which is defined as the geometric mean of all evaluable Ctrough for each patient. To further investigate the impact of exposure measure on exposure–efficacy analyses, a time-dependent modeling approach was used, where exposure at different time intervals was associated with the corresponding response endpoints in a longitudinal manner. With exposure measure being average Ctrough, it was observed that higher exposure was associated with reduced efficacy in terms of response (odds ratio = 0.77) and PFS [hazard ratio (HR) = 1.12]. These time-independent models do not account for the impact of time-varying concentration due to dose modifications. Subsequently, a new time-dependent modeling approach was used, where exposure and efficacy were associated longitudinally in the analyses. The results showed that the odds ratio of response became 1.07, and the HR of PFS became 1.04, indicating no apparent reverse relationship between exposure and efficacy across the exposure range studied. The drug effect on efficacy in clinical trials could be better characterized using time-dependent exposure–response models.
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- 2018
13. Multicenter phase 2 study of patupilone for recurrent or progressive brain metastases from non-small cell lung cancer
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Patrick Y. Wen, Lisa M. DeAngelis, Antonio Omuro, Alona Muzikansky, H. Ian Robins, Karen Kelly, Shirish M. Gadgeel, Steven S. Rosenfeld, James R. Rigas, Ming Zheng, Ramaswamy Govindan, Patrick Urban, Lauren E. Abrey, David M. Peereboom, and Lakshmi Nayak
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Cancer Research ,Chemotherapy ,medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Population ,Phases of clinical research ,medicine.disease ,Gastroenterology ,Surgery ,Oncology ,Internal medicine ,Patupilone ,medicine ,Clinical endpoint ,Prospective cohort study ,education ,business ,Lung cancer ,Survival analysis - Abstract
Author(s): Nayak, Lakshmi; DeAngelis, Lisa M; Robins, H Ian; Govindan, Ramaswamy; Gadgeel, Shirish; Kelly, Karen; Rigas, James R; Peereboom, David M; Rosenfeld, Steven S; Muzikansky, Alona; Zheng, Ming; Urban, Patrick; Abrey, Lauren E; Omuro, Antonio; Wen, Patrick Y | Abstract: BackgroundTreatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases.MethodsAdult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity.ResultsFifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively.ConclusionsThis is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients.
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- 2015
14. Overcoming Phosphatidylinositol 3-Kinase (PI3K) Activation in Breast Cancer: Emerging PI3K Inhibitors
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Christina Coughlin, Nathalie Fretault, Samit Hirawat, Bharani Bharani-Dharan, Emmanuelle di Tomaso, Patrick Urban, Cristian Massacesi, Ranjana Tavorath, C. Germa, and Cornelia Quadt
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Cancer Research ,Kinase ,business.industry ,medicine.disease ,Pathology and Forensic Medicine ,chemistry.chemical_compound ,Breast cancer ,Oncology ,chemistry ,Cancer research ,medicine ,Phosphatidylinositol ,business ,PI3K/AKT/mTOR pathway - Published
- 2015
15. Effect of nitrogen atom positioning on the trade-off between emissive and photocatalytic properties of carbon dots
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Regina Wyrwich, Jacek K. Stolarczyk, Florian Ehrat, Santanu Bhattacharyya, Patrick Urban, Markus Döblinger, Roland Teves, Alexander S. Urban, and Jochen Feldmann
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Photoluminescence ,Materials science ,Luminescence ,Nitrogen ,Science ,General Physics and Astronomy ,chemistry.chemical_element ,Nanotechnology ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,Catalysis ,Citric Acid ,Article ,Nanomaterials ,Quantum Dots ,lcsh:Science ,Microwaves ,Hydrogen production ,Multidisciplinary ,General Chemistry ,021001 nanoscience & nanotechnology ,Photochemical Processes ,Carbon ,0104 chemical sciences ,Chemical engineering ,chemistry ,Photocatalysis ,Light emission ,lcsh:Q ,0210 nano-technology - Abstract
Carbon dots (CDs) are a versatile nanomaterial with attractive photoluminescent and photocatalytic properties. Here we show that these two functionalities can be easily tuned through a simple synthetic means, using a microwave irradiation, with citric acid and varying concentrations of nitrogen-containing branched polyethyleneimine (BPEI) as precursors. The amount of BPEI determines the degree of nitrogen incorporation and the different inclusion modes within the CDs. At intermediate levels of BPEI, domains grow containing mainly graphitic nitrogen, producing a high photoluminescence yield. For very high (and very low) BPEI content, the nitrogen atoms are located primarily at the edge sites of the aromatic domains. Accordingly, they attract photogenerated electrons, enabling efficient charge separation and enhanced photocatalytic hydrogen generation from water. The ensuing ability to switch between emissive and photocatalytic behavior of CDs is expected to bring substantial improvements on their efficiency for on-demand light emission or energy conversion applications., Carbon dots are an emergent class of nanomaterials that hold promise for innovations in imaging, sensing, and catalytic technologies. Here, Stolarczyk and colleagues control the nitrogen-atom content and location within carbon dots, reporting the resulting impact on emissivity and photocatalytic behaviour.
- Published
- 2017
16. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial
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Lucio Crinò, Patrick Urban, S. Deudon, Makoto Nishio, Tae Min Kim, Alice T. Shaw, Giorgio V. Scagliotti, Oliver Gautschi, Tony Mok, Cheng Zheng, Silvia Novello, Geoffrey Liu, Serafino Pantano, Enriqueta Felip, Kalyanee Viraswami-Appanna, Cesare Gridelli, Alessandra Bearz, David R. Spigel, Katsuyuki Kiura, and Cristian Massacesi
- Subjects
Male ,0301 basic medicine ,Lung Neoplasms ,Pyridines ,Platinum Compounds ,Docetaxel ,Gastroenterology ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Sulfones ,Gene Rearrangement ,Alanine Transaminase ,gamma-Glutamyltransferase ,Middle Aged ,Editorial ,Oncology ,030220 oncology & carcinogenesis ,Retreatment ,Disease Progression ,Female ,Taxoids ,medicine.drug ,Adult ,medicine.medical_specialty ,medicine.drug_class ,Antineoplastic Agents ,Pemetrexed ,Disease-Free Survival ,03 medical and health sciences ,Crizotinib ,Internal medicine ,medicine ,Humans ,Aspartate Aminotransferases ,Lung cancer ,Response Evaluation Criteria in Solid Tumors ,Neoplasm Staging ,Ceritinib ,Performance status ,business.industry ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,Lorlatinib ,Surgery ,ALK inhibitor ,Pyrimidines ,030104 developmental biology ,Pyrazoles ,business - Abstract
Summary Background Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK -rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK -rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK -rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0–2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1–2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. Findings Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5–21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1–6·9] for ceritinib vs 1·6 months [1·4–2·8] for chemotherapy; hazard ratio 0·49 [0·36–0·67]; p vs 12 [11%] in the chemotherapy group). The most frequent grade 3–4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. Interpretation These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. Funding Novartis Pharmaceuticals Corporation.
- Published
- 2017
17. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer : A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE)
- Author
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Dimitrios Zardavas, Valentina Nekljudova, Sherene Loi, Gunter von Minckwitz, Andrea Gombos, Soo-Chin Lee, Martine Piccart, Lorena de la Peña, Michael P. Lux, Begoña Bermejo, Stefan Michiels, Sabine Turri, Patrick Urban, Sibylle Loibl, Carsten Denkert, Sherko Kümmel, Michael Untch, José Baselga, Guenther G. Steger, and Mahdi Rezai
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,Time Factors ,Receptor, ErbB-2 ,Biopsy ,medicine.medical_treatment ,Buparlisib ,Medizin ,Aminopyridines ,chemistry.chemical_compound ,0302 clinical medicine ,Trastuzumab ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,skin and connective tissue diseases ,Neoadjuvant therapy ,medicine.diagnostic_test ,Middle Aged ,Neoadjuvant Therapy ,Europe ,Treatment Outcome ,Paclitaxel ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Early Termination of Clinical Trials ,Cohort ,Female ,Chemical and Drug Induced Liver Injury ,medicine.drug ,Adult ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,Morpholines ,Breast Neoplasms ,Placebo ,Article ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Breast cancer ,Double-Blind Method ,Internal medicine ,Biomarkers, Tumor ,Humans ,Protein Kinase Inhibitors ,Aged ,business.industry ,Australia ,medicine.disease ,Ki-67 Antigen ,030104 developmental biology ,chemistry ,Mutation ,business - Abstract
Aim The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. Methods NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15. Results Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA . Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup ( P interaction = 0.03). Conclusions Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors. Trial registration identifier NCT01816594 .
- Published
- 2017
18. 444PD Patient-reported outcomes (PROs) in ASCEND-5: A randomized, phase 3 study of ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase rearranged (ALK+) NSCLC previously treated with CT and crizotinib (CRZ)
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Cheng Zheng, C. Gridelli, E. Felip, Tony Mok, Makoto Nishio, S. Deudon, G. Liu, David R. Spigel, Tae Min Kim, L. Crinò, K. Kiura, Oliver Gautschi, G.V. Scagliotti, Alessandra Bearz, Silvia Novello, Patrick Urban, and Alice T. Shaw
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Chemotherapy ,Ceritinib ,Crizotinib ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Hematology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Anaplastic lymphoma kinase ,In patient ,Previously treated ,business ,medicine.drug - Published
- 2016
19. Abstract OT2-6-07: Buparlisib (BKM120), an oral pan-PI3K inhibitor, in combination with paclitaxel in patients with HER2-negative, locally advanced or metastatic breast cancer, with or without PI3K pathway activation: A phase II, randomized, double-blind, placebo-controlled study – BELLE-4
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Luc Dirix, E DiTomaso, Mikhail Shtivelband, Soo-Chin Lee, Patrick Urban, S Le Mouhaër, Suzette Delaloge, S Nanni, Joyce A. O'Shaughnessy, Arlene Chan, M. Martin, and N Batista
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Hazard ratio ,Buparlisib ,Placebo-controlled study ,Cancer ,Pharmacology ,medicine.disease ,Metastatic breast cancer ,chemistry.chemical_compound ,Breast cancer ,chemistry ,Internal medicine ,medicine ,Clinical endpoint ,education ,business - Abstract
Background: Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is the most frequently activated signaling pathway in breast cancer. Activation of this pathway has been implicated in tumor growth, progression, and resistance to anticancer therapies. Buparlisib (BKM120) is an oral pan-PI3K inhibitor that targets all four isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in combination with weekly paclitaxel in patients with advanced solid tumors. The maximum tolerated dose of this combination was declared as 100 mg/day and 80 mg/m2/week for buparlisib and paclitaxel, respectively (Dirix et al. ESMO 2012). Trial design: BELLE-4 (NCT01572727) is a randomized, double-blind, placebo-controlled, Phase II trial of buparlisib or placebo plus weekly paclitaxel in adult women with chemotherapy-naïve, HER2-negative, locally advanced or metastatic breast cancer. Key inclusion criteria are: known PI3K pathway activation status (activated vs non-activated; centrally determined); ECOG performance status ≤1; and adequate bone marrow and organ function. Key exclusion criteria are: no prior treatment with a PI3K or Akt inhibitor; no prior systemic chemotherapy for advanced breast cancer (prior endocrine and adjuvant chemotherapy allowed); and no symptomatic CNS metastases. Patients are randomized 1:1 to receive oral buparlisib (100 mg once daily) or matching placebo, and IV paclitaxel (80 mg/m2 once weekly) in a 28-day treatment cycle until disease progression, unacceptable toxicity, death or discontinuation from study treatment for any other reason. Stratification at randomization is based upon PI3K pathway activation and hormone receptor status. Tumor assessments are performed locally every 8 weeks from randomization until radiologic progression (RECIST 1.1). Endpoints: The primary endpoint is progression-free survival* (PFS; per local investigator) in the full and PI3K pathway-activated populations. Secondary endpoints include overall survival (OS), overall response rate (ORR)*, duration of response (DOR)*, clinical benefit rate (CBR)*, time to response*, buparlisib pharmacokinetics, and safety† (*RECIST 1.1, †CTCAE v4.03). Statistical methods: PFS analysis will be performed in PI3K pathway-activated sub-population, PI3K non-activated sub-population, and the full population, using Bayesian methodology. A stratified Cox proportional hazard model will estimate the hazard ratio of PFS. The Kaplan–Meier method will estimate PFS, OS and DOR (if relevant) for both full and PI3K pathway-activated populations. ORR and CBR will be summarized with exact 95% confidence intervals. Target accrual: Approximately 200 patients will be randomized onto BELLE-4 at around 80 centers across 18 countries. Recruitment is ongoing across America, Europe, and Asia. Contact: For further information about the study, contact your local Novartis representative. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-07.
- Published
- 2013
20. Abstract OT2-6-08: Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE
- Author
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G. von Minckwitz, L de la Pena, Patrick Urban, S. Di Cosimo, M.J. Piccart, S. Loibl, Patrick Flamen, Stefan Michiels, J. Baselga, S Nanni, Valentina Nekljudova, Sherene Loi, and Kamal S Saini
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Buparlisib ,Cancer ,medicine.disease ,Loading dose ,Surgery ,chemistry.chemical_compound ,Breast cancer ,chemistry ,Paclitaxel ,Trastuzumab ,Internal medicine ,medicine ,Breast-conserving surgery ,Clinical endpoint ,business ,medicine.drug - Abstract
Background: The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is important for the oncogenic function of HER2. Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in patients (pts) with advanced BC as a single agent, and in combination with paclitaxel (Dirix et al. ESMO 2012) or trastuzumab (Pistilli et al. ESMO 2012). Study design: NeoPHOEBE (NCT01816594) is a Phase II, randomized, double-blind, parallel-cohort study of neoadjuvant buparlisib or matched placebo plus trastuzumab and weekly paclitaxel. Upfront stratification of pts into 2 independent cohorts according to PIK3CA mutation status will determine whether pts with PIK3CA-mutant tumors may benefit more from this treatment combination. Adult women with newly diagnosed, HER2-positive, primary non-inflammatory BC who have not previously received systemic therapy for invasive disease are eligible. Other eligibility criteria: tumor size >2 cm; unilateral disease; available tumor tissue for central review of estrogen receptor (ER) and HER2 status, and PIK3CA genotype; known PIK3CA mutation status; and ECOG PS ≤1. Pts in each cohort (PIK3CA mutant or wild-type [wt]) are randomized (1:1) to receive continuous daily buparlisib (100 mg) or placebo and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg) for 6 weeks, followed by continuous daily buparlisib (80 mg) or placebo with weekly trastuzumab (2 mg/kg) and weekly paclitaxel (80 mg/m2) for 12 weeks. Study treatment is followed by surgery within 4 weeks of last paclitaxel dose. Stratification at randomization is based on PIK3CA (mutant vs wt) and ER (positive vs negative) status. Endpoints: All endpoints will be measured in both PIK3CA-mutant and wt cohorts. The primary endpoint is rate of pathologic complete response (pCR; ypT0) at time of surgery. The key secondary endpoint is objective response rate (ORR) at the end of week 6. Other secondary endpoints include pCR by other definitions, ORR prior to surgery, pCR and objective response by ER status, percent of pts with node-negative disease at surgery, rate of breast conserving surgery, and safety. Exploratory objectives include change in standardized uptake value (SUV) at Day 15 by FDG-PET; and ORR and pCR by PTEN expression, Ki67 level, apoptosis rates, percentage of tumor infiltrating lymphocytes (TIL), and by phenotype of 50% TIL at baseline. Statistical methods: The sample size is based on a minimax 2-stage randomized Phase II design with a prospective control. This design allows for early stopping if the desired efficacy is not observed after stage 1. Both cohorts are powered (80%) to detect a clinically meaningful increase in pCR of 18% at a one-sided significance level (α = 0.15). Target accrual: Planned enrollment for NeoPHOEBE is up to 220 pts at 65 sites in 12 countries across South America, Europe, and Asia-Pacific. Contact: For further study information, contact BIG@bordet.be. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-08.
- Published
- 2013
21. Abstract P2-16-22: A dose-finding phase lb study of BEZ235 in combination with paclitaxel in patients with HER2-negative, locally advanced or metastatic breast cancer
- Author
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M. Campone, M Gil-Martin, D Csonka, Patrick Urban, JT Beck, E. di Tomaso, K Roiffe, A Gaur, P. Fumoleau, Ander Urruticoechea, Nicolas Isambert, and G Vincent
- Subjects
Cancer Research ,medicine.medical_specialty ,Nausea ,business.industry ,Cmax ,Cancer ,Neutropenia ,medicine.disease ,Metastatic breast cancer ,Gastroenterology ,Surgery ,chemistry.chemical_compound ,Breast cancer ,Oncology ,Paclitaxel ,chemistry ,Internal medicine ,medicine ,Vomiting ,medicine.symptom ,business - Abstract
Background: The PI3K/Akt/mTOR pathway is the most frequently activated signaling pathway in breast cancer (BC). Activation of this pathway promotes tumor growth and progression, and resistance to anticancer therapies, including paclitaxel (PTX). BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. BEZ235 has shown antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. In a Ph I study, single-agent BEZ235 given twice daily (BID) showed preliminary signs of clinical activity. Methods: This was a multicenter, open-label Ph Ib/II study of daily, oral BEZ235 given BID in combination with weekly (QW) intravenous PTX in women with HER2-, metastatic or locally advanced BC (NCT01495247). For the Ph Ib part, the primary objective was to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with PTX based on dose-limiting toxicities (DLTs) using a 5-parameter adaptive Bayesian logistic regression model with overdose control. MTD was defined as the highest dose not causing medically unacceptable DLTs in >35% of pts during Cycle 1 (28 days). Secondary objectives included safety, preliminary activity, and PK. Safety was monitored by physical exams, vital signs, laboratory tests, weight, and cardiac health. AEs were assessed continuously by CTCAE v4.03. Tumor evaluations were performed at screening and every 8 wks after starting treatment, and assessed locally by RECIST v1.1. Results: As of April 12, 2013, 18 pts (mean age: 50 yr; 67% ≥4 prior lines of antineoplastic therapy) had been enrolled into Ph Ib. 13 pts received BEZ235 200 mg BID + PTX 80 mg/m2 QW. The dose level was then reduced to BEZ235 100 mg BID + PTX 80 mg/m2 QW (n = 5). Of 17 evaluable pts (12 at the 200-mg BID dose; 5 at the 100-mg BID dose), 6 (35%) developed ≥1 DLTs (5 [42%] at the 200-mg BID dose; 1 [20%] at the 100-mg BID dose): neutropenia (n = 3 [1 at the 100-mg BID dose]), stomatitis (n = 3), nausea (n = 2), and vomiting (n = 1). Of 18 pts, 12 have discontinued (6 due to disease progression; 4 AEs; 1 physician decision; 1 pt/guardian decision). Median duration of exposure to BEZ235 and PTX was 76 days each. The most common suspected study drug-related AEs included asthenia (78%), nausea (72%), neutropenia (72%), diarrhea (67%), stomatitis (61%), and decreased appetite (56%). Among 13 pts receiving BEZ235 200 mg BID, 2 (15%) achieved a PR, 4 (31%) had SD, and 4 (31%) had PD; all 5 pts receiving BEZ235 100 mg BID had SD. PK results showed large interpatient variability at both dose levels. Analysis of pAKT and p4EBP1 was performed on peripheral blood mononuclear cells collected from pts before treatment and 4 h following treatment (Cmax). PK/PD analysis did not provide evidence of a strong and consistent correlation between BEZ235 plasma concentrations and pAKT inhibition. Conclusions: The MTD/RP2D of BEZ235 in combination with PTX in pts with locally advanced or metastatic HER2- BC was not reached. Based on the observed overall safety profile, efficacy, variable PK, and PD data from the Ph Ib part of this study, further enrollment has stopped. The Ph II part of the study will not be conducted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-22.
- Published
- 2013
22. P1.01-012 Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis
- Author
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D.S.W. Tan, Alice T. Shaw, D.R. Camidge, Laura Q.M. Chow, Ranee Mehra, Martin Schuler, Patrick Urban, Ben Solomon, D. Kim, Enriqueta Felip, C. Ortmann, I. Malet, and G. J. Riely
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,Crizotinib ,Ceritinib ,business.industry ,medicine ,Cancer research ,Anaplastic lymphoma kinase ,Subgroup analysis ,business ,medicine.drug - Published
- 2017
23. Abstract P6-11-08: A multicenter, open-label Ph IB/II study of BEZ235, an oral dual PI3K/mTOR inhibitor, in combination with paclitaxel in patients with HER2-negative, locally advanced or metastatic breast cancer
- Author
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Mikhail Shtivelband, JT Beck, Pantelia Roussou, Carlos Becerra, Vincent Duval, Pierre Fumoleau, E. di Tomaso, Patrick Urban, Ander Urruticoechea, M. Campone, M Gil-Martin, and Nicolas Isambert
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Pharmacology ,Neutropenia ,medicine.disease ,Metastatic breast cancer ,chemistry.chemical_compound ,Breast cancer ,Pharmacokinetics ,Paclitaxel ,chemistry ,Internal medicine ,medicine ,Adverse effect ,business ,Stomatitis - Abstract
Background: The PI3K/AKT/mTOR pathway is frequently altered in breast cancer (BC). Alterations in PIK3CA or inactivation of PTEN are observed in 10–40% and in up to 50% of breast tumors, respectively. The PI3K/AKT/mTOR pathway can be further activated through various receptor classes or cross-talk with other pathways, making it a rational target for therapeutic intervention in BC. BEZ235 is an oral dual inhibitor of mTOR and PI3K. It has demonstrated anti-proliferative activity, substantial growth inhibition, and induction of apoptosis in preclinical studies. In a Ph I study, single-agent BEZ235 (600 mg BID) was shown to have less toxicity than the equivalent once-daily dosing, and have preliminary evidence of activity in advanced solid tumors (Arkenau, et al. ASCO 2012:#3097). Methods: This is a multicenter, open-label Ph IB/II study of continuous, oral BEZ235 twice daily (BID) in combination with paclitaxel (80 mg/m2; IV weekly [QW]) in women with HER2-negative (HER2–), metastatic or inoperable locally advanced BC (NCT01495247). For the Ph IB part, women with HER2–, metastatic or inoperable locally advanced BC, who are suitable for treatment with paclitaxel, are eligible for enrollment. The primary objective is to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with paclitaxel based on dose-limiting toxicities (DLTs) using an adaptive 5-parameter Bayesian logistic regression model with overdose control. The MTD is defined as the highest drug dosage not causing medically unacceptable DLTs in more than 35% of the treated patients during Cycle 1 (1 cycle = 28 days). Secondary objectives include safety (CTCAE), preliminary activity (RECIST), and pharmacokinetics (PK). Estimated enrollment is 15–30 patients into the Ph IB part. Results: As of June 2012, 13 pts have been enrolled into the Ph IB part of the trial. The first cohort (n = 7 pts) received BEZ235 200 mg BID + 80 mg/m2 QW paclitaxel. Of these 7 pts, 3 are ongoing, with 2 pts having received treatment for more than 12 weeks so far, and 4 pts have discontinued (2 due to an adverse event [AE]; 1 due to an AE/pt's decision; and 1 due to disease progression). Of the 6 evaluable pts in the first cohort, 2 experienced DLTs: Grade 3 stomatitis (1 pt) and Grade 2/3 neutropenia (1 pt). Most common AEs included stomatitis and GI toxicity (e.g. diarrhea, nausea/vomiting). To date, reported Grade 3 AEs related to study drug were stomatitis (2 pts), neutropenia (1 pt), and skin rash (1 pt). Among the 3 pts with at least one tumor evaluation, 1 pt with a triple-negative metastatic BC, who had previously been treated with paclitaxel, experienced a RECIST partial response which was confirmed on second tumor evaluation. PK analysis is ongoing. Conclusions: Additional patients have been enrolled at BEZ235 200 mg BID/paclitaxel 80 mg/m2 QW to provide further information on the safety and activity profile of this combination. Updated safety and efficacy results will be presented. Upon determination of the MTD/RP2D, the randomized Ph II part will begin to compare weekly paclitaxel given with or without BEZ235 BID as the first-line treatment of HER2– metastatic BC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-08.
- Published
- 2012
24. Götter - Gene - Genesis : Die Biologie der Religionsentstehung
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Ina Wunn, Patrick Urban, Constantin Klein, Ina Wunn, Patrick Urban, and Constantin Klein
- Subjects
- Religion and science
- Abstract
Ist Gott in den Genen zu finden? Ist Religion göttlichen Ursprungs – oder doch ein natürliches, also biologisches Phänomen? Und wenn Religion in unserer Biologie angelegt ist, wie und warum ist sie entstanden? Wie sehen ihre Anfänge aus, die ja sehr einfach gewesen sein müssen – Religion im Einzellerstadium sozusagen! Wie entwickelte sie sich dann weiter, und lassen sich in dieser Entwicklung, wie bei der biologischen Evolution, Gesetzmäßigkeiten feststellen? Anders ausgedrückt: Gibt es eine Biologie der Religionen beziehungsweise eine Biologie der Religionsentstehung? Dieses Buch unternimmt erstmalig den Versuch einer umfassenden Antwort auf diese Fragen. Die Autoren – Experten aus Biologie, Paläontologie, Psychologie, Religionswissenschaft und Theologie – entwerfen auf der Basis fächerübergreifender wissenschaftlicher Befunde ein Modell der Religionsentstehung, das das Aufkommen religiöser Verhaltensweisen schlüssig aus dem natürlichen Verhaltensrepertoire des Menschen erklärt. So wird die menschheitsgeschichtliche Entwicklung von Religiosität plausibel und nachvollziehbar. Wer wissen will, wie Religion entstanden ist, wird in diesem breiten und sachkundigen Überblick die Antwort finden. _____ Die Götter fielen nicht vom Himmel – die biologischen Grundlagen der Religionsentstehung Religion ist ein universal verbreitetes Phänomen, und überall auf der Welt prägen religiöse Überzeugungen politisches und gesellschaftliches Handeln. Viele Menschen wollen verstehen, warum Religion trotz aller rationalen Kritik fortbesteht, und fragen deshalb auch nach ihren Anfängen und ihrer Entwicklung in der Menschheitsgeschichte. Götter – Gene – Genesis ist der ehrgeizige Versuch dreier interdisziplinär arbeitender Autoren, den Ursprung von Religion schlüssig und nachvollziehbar zu erklären. Ihr Buch verfolgt insofern einen originellen Ansatz, als es den aktuellen kognitionswissenschaftlichen und evolutionär-psychologischen Entwürfen zur Erklärung der Religionsentstehung eine ganz bewusst verhaltensorientierte Perspektive entgegensetzt: Religiöses Verhalten wird konsequent verhaltenswissenschaftlich – ethologisch, biologisch, psychologisch – erklärt. Entscheidende Faktoren für die frühe Entwicklung von Religiosität sind Territorialverhalten und Gefahrenabwehr, innerartliche Aggression und Ritualisierung, Angstbewältigung und Konfliktlösung sowie die kulturelle Evolution als Fortsetzung der biologischen Evolution. Mit der konsequenten Herausarbeitung der biologischen Grundlagen bietet das Buch einen Überblick zur Religionsentstehung, der sehr viel „bodenständiger“ und oft auch im Wortsinne „anschaulicher“ ist als manch andere, spekulative Entstehungsszenarien. Die Lektüre des Buches vermittelt dem Leser fundierte Kenntnisse über die Erscheinungsformen und Geschichte religiösen Verhaltens – und liefert so einen wichtigen Beitrag für die heute oft so emotional geführte Debatte zu Glaubensfragen.
- Published
- 2015
25. Reversible control of current across lipid membranes by local heating
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Silke R. Kirchner, Christian Mühlbauer, Theobald Lohmüller, Patrick Urban, and Jochen Feldmann
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0301 basic medicine ,Hot Temperature ,Materials science ,Lipid Bilayers ,02 engineering and technology ,Article ,Cell Line ,03 medical and health sciences ,Electric Impedance ,Membrane fluidity ,Humans ,Semipermeable membrane ,Low-Level Light Therapy ,Surface plasmon resonance ,Lipid bilayer ,Ion channel ,Membranes ,Multidisciplinary ,Bilayer ,Biological membrane ,021001 nanoscience & nanotechnology ,030104 developmental biology ,Membrane ,Biochemistry ,Biophysics ,Nanoparticles ,Gold ,0210 nano-technology - Abstract
Lipid membranes are almost impermeable for charged molecules and ions that can pass the membrane barrier only with the help of specialized transport proteins. Here, we report how temperature manipulation at the nanoscale can be employed to reversibly control the electrical resistance and the amount of current that flows through a bilayer membrane with pA resolution. For this experiment, heating is achieved by irradiating gold nanoparticles that are attached to the bilayer membrane with laser light at their plasmon resonance frequency. We found that controlling the temperature on the nanoscale renders it possible to reproducibly regulate the current across a phospholipid membrane and the membrane of living cells in absence of any ion channels.
- Published
- 2016
26. Multi-device UI Development for Task-Continuous Cross-Channel Web Applications
- Author
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Thomas Kern, Enes Yigitbas, Stefan Sauer, and Patrick Urban
- Subjects
Web development ,business.industry ,Computer science ,Distributed computing ,05 social sciences ,Solution architecture ,020207 software engineering ,02 engineering and technology ,Task (project management) ,Model-based design ,0202 electrical engineering, electronic engineering, information engineering ,Retail banking ,Web application ,0501 psychology and cognitive sciences ,Data synchronization ,User interface ,business ,050107 human factors - Abstract
The growing number of various types of web-enabled smart devices presents a special challenge for retail banks. In the world of Omni-Channel-Banking, customers demand a flexible and easy usage for carrying out their banking activities. Establishing such an Omni-Channel-Banking experience is a challenging task that requires support for the development of heterogeneous user interfaces (UIs) allowing flexible access to different channels (e.g. PC, Smartphone, ATM) and a seamless hand-over between these channels to allow task-continuity for the customer. Therefore, we present a model-based solution architecture for the development of multi-device UIs. Our solution architecture minimizes recurrent UI development efforts for different channels and enables data synchronization between them. To show the feasibility of our approach, we present an industrial case study, where we implement a cross-channel banking web-application that enables a modern customer experience.
- Published
- 2016
27. Metabolism of patupilone in patients with advanced solid tumor malignancies
- Author
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Piet Swart, Frédéric Lozac'h, Felix Waldmeier, Kevin R. Kelly, Yanfeng Wang, Patrick Urban, Suraj Anand, Eugene Tan, Chris H. Takimoto, Alain C. Mita, Markus Zollinger, and Monica M. Mita
- Subjects
Male ,Pharmacology ,Volume of distribution ,Chemistry ,Antineoplastic Agents ,Urine ,Middle Aged ,medicine.disease ,Tubulin Modulators ,Feces ,Oncology ,Pharmacokinetics ,Epothilones ,Neoplasms ,Renal physiology ,Patupilone ,medicine ,Humans ,Distribution (pharmacology) ,Female ,Pharmacology (medical) ,Progressive disease ,ADME - Abstract
A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m(2) (1.1 MBq) of (14) C-radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (Vss: 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2-3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion.
- Published
- 2012
28. P3.02a-015 Ceritinib as First-Line Therapy in Patients with ALK-Rearranged Non-Small Cell Lung Cancer: ASCEND-1 Subgroup Analysis
- Author
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Patrick Urban, Alice T. Shaw, Sunil Sharma, Santosh Sutradhar, Siyu Li, Daniel Shao-Weng Tan, Laura Qm Chow, Enriqueta Felip, and I. Malet
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Ceritinib ,business.industry ,Subgroup analysis ,medicine.disease ,First line therapy ,Internal medicine ,Medicine ,In patient ,Non small cell ,business ,Lung cancer ,medicine.drug - Published
- 2017
29. Pharmacokinetics and antitumor activity of patupilone combined with midazolam or omeprazole in patients with advanced cancer
- Author
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Apostolia Maria Tsimberidou, Patrick Urban, Eugene Y. Tan, Razelle Kurzrock, Tony R. Reid, Cynthia Uehara, Howard A. Burris, Suraj Anand, and Nancy L. Lewis
- Subjects
Male ,Cancer Research ,Midazolam ,CYP2C19 ,Pharmacology ,Toxicology ,Pharmacokinetics ,Neoplasms ,Patupilone ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Drug Interactions ,Pharmacology (medical) ,Omeprazole ,CYP3A4 ,business.industry ,Middle Aged ,Drug interaction ,Cytochrome P-450 CYP2C19 ,Oncology ,Epothilones ,Area Under Curve ,Toxicity ,Cytochrome P-450 CYP3A Inhibitors ,Female ,Aryl Hydrocarbon Hydroxylases ,business ,medicine.drug - Abstract
Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways. This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m2 IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase). Forty-six patients were treated. The areas under the concentration–time curves (AUC)s of midazolam with or without patupilone co-administration were similar. The C max of midazolam when co-administered with patupilone was highly variable and was lower compared with midazolam alone; however, the oral clearance and terminal half-lives were similar. Both the C max and AUC of omeprazole when co-administered with patupilone were highly variable and lower than with omeprazole alone. However, the oral clearance and terminal half-lives were similar. The latter data suggest that patupilone decreased the absorption of omeprazole (by ~20%). The overall safety profile was consistent with that of previous single-agent patupilone studies; 2 partial responses (ovarian and pancreatic cancer) and 1 complete response (serous ovarian adenocarcinoma) were observed. Patupilone was not a potent CYP3A4 or CYP2C19 inhibitor. No dose adjustment is required when omeprazole or midazolam is used in patients treated with patupilone. Patupilone exhibited promising antitumor activity in heavily pretreated patients with ovarian and pancreatic cancer.
- Published
- 2011
30. Effects of Patupilone on the Pharmacokinetics and Pharmacodynamics of Warfarin in Patients with Advanced Malignancies: A Phase I Clinical Trial
- Author
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Yanfeng Wang, Alain C. Mita, Chris H.M. Takimoto, Eugene Tan, Apostolia Maria Tsimberidou, Razelle Kurzrock, Patrick Urban, David Vining, Monica M. Mita, Stacy L. Moulder, and Cynthia Uehara
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Phases of clinical research ,Antineoplastic Agents ,Pharmacology ,Gastroenterology ,Young Adult ,Pharmacokinetics ,Neoplasms ,Internal medicine ,Patupilone ,medicine ,Humans ,Drug Interactions ,Adverse effect ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Warfarin ,Area under the curve ,Middle Aged ,Oncology ,Epothilones ,Response Evaluation Criteria in Solid Tumors ,Pharmacodynamics ,Female ,business ,medicine.drug - Abstract
Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug–drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m2 i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for Cmax and area under the curve0–168 of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer. Mol Cancer Ther; 10(1); 207–17. ©2011 AACR.
- Published
- 2011
31. Götter - Gene - Genesis
- Author
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Patrick Urban, Constantin Klein, and Ina Wunn
- Subjects
Psychology - Published
- 2015
32. A guided simulated annealing search for solving the pick-up and delivery problem with time windows and capacity constraints
- Author
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Karsten-Patrick Urban
- Subjects
Mathematical optimization ,Job shop scheduling ,Total cost ,Computer science ,Strategy and Management ,Metaheuristics ,Management Science and Operations Research ,Simulated annealing ,Management Information Systems ,Scheduling (computing) ,Management of Technology and Innovation ,Management studies ,Guided Local Search ,Pick-up and delivery problem ,Guided neighbourhood search ,Business and International Management ,Applying non-linear cost functions in combinatorial optimisation ,Metaheuristic ,Hill climbing ,Implementation - Abstract
Routing and scheduling requests with pick-ups and deliveries is still one of the greatest operative challenges in inter-company logistics. Pick-up and delivery activities have to be bundled into efficient routes and their sequence has to be optimised within the routes without violating time and capacity constraints. The objective is to find a schedule of routes with minimal total costs. These costs result from the arising travelling costs, costs due to waiting and service times, and due to dispatching vehicles. This paper presents a guided local search method based on simulated annealing for solving this kind of routing and scheduling problem. Additionally, a new more realistic objective function that covers the total decision-relevant costs is introduced. The computational results show that the algorithm presented clearly outperforms standard implementations of simulated annealing and hill climber search. Routing and scheduling requests with pick-ups and deliveries is still one of the greatest operative challenges in inter-company logistics. Pick-up and delivery activities have to be bundled into efficient routes and their sequence has to be optimised within the routes without violating time and capacity constraints. The objective is to find a schedule of routes with minimal total costs. These costs result from the arising travelling costs, costs due to waiting and service times, and due to dispatching vehicles. This paper presents a guided local search method based on simulated annealing for solving this kind of routing and scheduling problem. Additionally, a new more realistic objective function that covers the total decision-relevant costs is introduced ...
- Published
- 2006
33. Increased Expression of Urokinase-Type Plasminogen Activator mRNA Determines Adverse Prognosis in ErbB2-Positive Primary Breast Cancer
- Author
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Christopher C. Benz, Hans-Jörg Senn, Edward Wight, Patrick Urban, Mauro Delorenzi, Serenella Eppenberger-Castori, Vincent Vuaroqueaux, Pratyaksha Wirapati, Martin Labuhn, and Urs Eppenberger
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Receptor, ErbB-2 ,Breast Neoplasms ,Polymerase Chain Reaction ,Breast cancer ,Predictive Value of Tests ,Internal medicine ,Biomarkers, Tumor ,Odds Ratio ,medicine ,Humans ,RNA, Messenger ,skin and connective tissue diseases ,Oligonucleotide Array Sequence Analysis ,Proportional Hazards Models ,Urokinase ,Regulation of gene expression ,Analysis of Variance ,Proportional hazards model ,business.industry ,Microarray analysis techniques ,Odds ratio ,Middle Aged ,Prognosis ,medicine.disease ,Urokinase-Type Plasminogen Activator ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Predictive value of tests ,Female ,business ,Plasminogen activator ,medicine.drug - Abstract
Purpose To evaluate and validate mRNA expression markers capable of identifying patients with ErbB2-positive breast cancer associated with distant metastasis and reduced survival. Patients and Methods Expression of 60 genes involved in breast cancer biology was assessed by quantitative real-time PCR (qrt-PCR) in 317 primary breast cancer patients and correlated with clinical outcome data. Results were validated subsequently using two previously published and publicly available microarray data sets with different patient populations comprising 295 and 286 breast cancer samples, respectively. Results Of the 60 genes measured by qrt-PCR, urokinase-type plasminogen activator (uPA or PLAU) mRNA expression was the most significant marker associated with distant metastasis-free survival (MFS) by univariate Cox analysis in patients with ErbB2-positive tumors and an independent factor in multivariate analysis. Subsequent validation in two microarray data sets confirmed the prognostic value of uPA in ErbB2-positive tumors by both univariate and multivariate analysis. uPA mRNA expression was not significantly associated with MFS in ErbB2-negative tumors. Kaplan-Meier analysis showed in all three study populations that patients with ErbB2-positive/uPA–positive tumors exhibited significantly reduced MFS (hazard ratios [HR], 4.3; 95% CI, 1.6 to 11.8; HR, 2.7; 95% CI, 1.2 to 6.2; and, HR, 2.8; 95% CI, 1.1 to 7.1; all P < .02) as compared with the group with ErbB2-positive/uPA–negative tumors who exhibited similar outcome to those with ErbB2-negative tumors, irrespective of uPA status. Conclusion After evaluation of 898 breast cancer patients, uPA mRNA expression emerged as a powerful prognostic indicator in ErbB2-positive tumors. These results were consistent among three independent study populations assayed by different techniques, including qrt-PCR and two microarray platforms.
- Published
- 2006
34. Bedrohte Lebenswelten und Sicherung des Territoriums: Schädeldeponierungen und erste feste Siedlungen
- Author
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Constantin Klein, Ina Wunn, and Patrick Urban
- Abstract
Um 10.000 vor unserer Zeit anderte sich die Lebensweise unserer Vorfahren grundlegend: Sie wurden sesshaft. Das bedeutet jedoch nicht, dass sie auf erprobte Schutzmechanismen verzichteten. Immer noch verwiesen Schadel auf den legitimen, weil von den Vorfahren ererbten Landbesitz, und immer noch schutzten apotropaische Figuren und Bilder vor Eindringlingen oder dem Bosen uberhaupt. Aber die Rolle der Toten anderte sich. Sie wurden jetzt zunehmend unter den Fusboden der Hauser begraben und blieben so Teil der Familie.
- Published
- 2014
35. Aedifico ergo sum – Ich baue, also bin ich
- Author
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Ina Wunn, Patrick Urban, and Constantin Klein
- Abstract
Wahrend die Bewohner des neolithischen Gobekli Tepe in Ostanatolien ihre massiven Hauser (ja, es sind Hauser!) mit den bekannten apotropaischen Bildern, darunter eindrucksvollen wehrhaften Tieren, schmuckten, konzentrierten sich die Bauern in Cayonu auf den anderen Teil des ererbten Verhaltensrepertoires: den Umgang mit dem Tod. Bestattet wurde nun in einem eigens zu diesem Zweck errichteten Gebaude – Ursprung und Grundlage des spateren Tempels in Mesopotamien.
- Published
- 2014
36. Not lehrt beten – der Mensch im Altpaläolithikum und die Bedeutung der Angst
- Author
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Constantin Klein, Patrick Urban, and Ina Wunn
- Abstract
Religion gehort zum Menschsein, ist also ein naturliches Phanomen und muss irgendwann einmal im Laufe der Menschheitsgeschichte entstanden sein – und zwar entsprechend dem Einzellerprinzip aus einfachsten Ursprungen, die selbst moglicherweise noch gar keine Religion im eigentlichen Sinne gewesen sein mussen. Bereits Darwin hatte da klare Vorstellungen: Es geht um Emotionen, und hier vor allem um die Angst, es geht um Drohen und Beschwichtigen!
- Published
- 2014
37. Doppelaxt und Stier – ein Götterpantheon entsteht
- Author
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Constantin Klein, Ina Wunn, and Patrick Urban
- Abstract
Das Gabentauschverhaltnis, in Malta bis zum Extrem getrieben, begann auch in den ubrigen Gesellschaften an der Schwelle zur Bronzezeit das Verhaltnis der Menschen zu den ubermachtigen Wesen zu bestimmen: Aus den im Ritual vergegenwartigten ubermachtigen Ahnen wurden im Laufe der Zeit die im Kultus verehrten Gottheiten, denen man Opfer darbrachte.
- Published
- 2014
38. A forest of symbols: der Homo sapiens während des Jungpaläolithikums
- Author
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Patrick Urban, Ina Wunn, and Constantin Klein
- Subjects
Homo sapiens ,media_common.quotation_subject ,Art ,Humanities ,media_common - Abstract
Der Kulturnachfolger des Neandertalers, der Homo sapiens, begnugte sich nun nicht mehr mit Bestattungen, um sein Territorium zu markieren, sondern griff auf das ganze Arsenal von Abwehrzeichen und Gesten zuruck, um sich vor Konkurrenten zu schutzen. In diesem Zusammenhang erwiesen sich vor allem kleine schamweisende Frauenfigurinen als wirkungsvoll, die mit ihrer Kombination aus Droh- und Beschwichtigungsgesten zunachst Eindringlinge, dann aber auch das Bose an sich fernhielten.
- Published
- 2014
39. Çatal Hüyük, das Ritual und der Tod
- Author
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Constantin Klein, Ina Wunn, and Patrick Urban
- Abstract
Auch wenn man auf kollektive Grabstatten verzichtete und weiterhin individuell im Haus bestattete, gewann der Tod und mit ihm der Verstorbene an Bedeutung. Im Rahmen von komplexen Ritualen wurde der Tote in die jenseitige Welt geleitet, von der aus er das Schicksal der Lebenden weiterhin beeinflusste. Ein Teil seiner Personlichkeit fand ihren Platz in einer Ahnenfigur – und das sind genau die Figurchen mit den apotropaischen Signalen, die bereits aus dem Palaolithikum bekannt sind.
- Published
- 2014
40. Einleitung
- Author
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Ina Wunn, Patrick Urban, and Constantin Klein
- Published
- 2014
41. Von Göttern und Helden
- Author
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Patrick Urban, Constantin Klein, and Ina Wunn
- Abstract
Mit dem ausgehenden Neolithikum haben sich weibliche ubermachtige Gestalten etablieren konnen. Inzwischen aber hat sich auch das Umfeld geandert. Die Vorrate an leicht bebaubarem Land gingen zur Neige, und die Konkurrenz wurde deutlicher spurbar. Dies alles schlug sich in kriegerischen Auseinandersetzungen nieder, die wiederum den mannlichen Helden hervorbrachten. Von der Verehrung des toten Helden als ubermachtigem Bewohner der Unterwelt zur chthonischen Gottheit ist der Weg nicht weit!
- Published
- 2014
42. My cave is my castle – Neandertaler, Territorialität und Tod
- Author
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Ina Wunn, Patrick Urban, and Constantin Klein
- Abstract
Fur die Entwicklung der Religion spielt auch der Besitz von Territorien eine wichtige Rolle. Die Neandertaler haben eine ganz eigene Methode entwickelt, legitimen Territorialbesitz anzuzeigen: durch deutlich sichtbare Bestattungen und das Deponieren von Schadeln! Dass gerade die bearbeiteten Schadel zum schlechten Ruf des Neandertalers beigetragen haben und er bis heute des Kannibalismus verdachtigt wird, ist Teil der Geschichte.
- Published
- 2014
43. Gabentausch und Totenreich: Malta
- Author
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Constantin Klein, Ina Wunn, and Patrick Urban
- Abstract
Welche Macht die unterirdischen Toten erlangen konnen, zeigt das Beispiel des neolithischen Malta. Hier wurden den Toten nicht nur machtige unterirdische Grabstatten, sondern gleichzeitig uberirdische Tempel errichtet, um auf dem Wege des Gabentausches die Toten zu verpflichten, fur die Fruchtbarkeit von Vieh und Feldern zu sorgen.
- Published
- 2014
44. Ex Oriente Lux oder: Die neolithische Weltsicht wird populär
- Author
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Patrick Urban, Constantin Klein, and Ina Wunn
- Abstract
Vom fruchtbaren Halbmond ausgehend, trat neben der neolithischen Wirtschaftsweise auch die neolithische Weltsicht ihren Siegeszug an und breitete sich aus. Das Ritual um die Toten, die apotropaischen Frauenfiguren und Vorstellungen von einer Existenz in einer jenseitigen, unteren Welt fanden im Mythos ihre Entsprechung. Gleichzeitig lasst sich eine Entwicklung der ursprunglich apotropaischen Frauenfigurchen in Richtung Urmutter, also ubermachtige Gestalt, nachweisen.
- Published
- 2014
45. Der Gott Israels
- Author
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Patrick Urban, Ina Wunn, and Constantin Klein
- Abstract
Wahrend die fur eine konkrete Stadt verantwortlichen Gotter einen Namen und ein Gesicht hatten, blieb der Stadtgott des eisenzeitlichen Juda unsichtbar; ja mehr noch, denn wahrend im Zuge von Reichsbildungen die einzelnen Stadtgotter zu einem polytheistischen Pantheon zusammengefasst wurden, konzentrierte Juda den Kult auf ein einziges Kultzentrum und seinen Gott, der im Tempel zu Jerusalem wohnte – JHWH (Jahwe), der von hier aus in knapp 3000 Jahren seinen Siegeszug antrat.
- Published
- 2014
46. Religionsethologie – die biologischen Wurzeln religiösen Verhaltens
- Author
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Constantin Klein, Ina Wunn, and Patrick Urban
- Subjects
Religionsethologie ,media_common.quotation_subject ,ethology ,religion ,Religious studies ,Kulturethologie ,Dewey Decimal Classification::200 | Religion, Religionsphilosophie ,ddc:200 ,Art ,Theology ,media_common - Abstract
Der Artikel skizziert die Grundlagen einer neuen Subdisziplin innerhalb der Religionswissenschaft, der Religionsethologie. Religionsethologie lässt sich letztlich auf Charles Darwin selbst zurückführen, der bereits in seinem Buch The expression of the emotions in man and animals (1872) belegen konnte, dass jede Form von Verhalten (also auch religiöses Verhalten) für das Überleben der Art genau so wichtig ist wie die Adaptation des Phänotypus. In den Geisteswissenschaften wurde der Darwinsche Ansatz sofort aufgegriffen und von bedeutenden Forschern wie Karl Meuli (1891–1968), Aby Warburg (1866–1929) und in jüngerer Zeit von Roy Rappaport (1926–1997), Marvin Harris (1927–2001) und anderen aufgegriffen und fruchtbar gemacht, indem sie einerseits religiöse Universalien herausarbeiten, andererseits aber auch die Grundzüge einer religiösen Evolution darstellen konnten. Religion ist demnach tief in der Biologie des Menschen verwurzelt und kann demzufolge auch unter biologischen Gesichtspunkten erforscht werden., This article describes a new sub-discipline: Ethology of Religion, which goes back to Charles Darwin himself who revealed in his book The expression of the emotions in man and animals (1872) that any form of behavior is just as important for the survival of the species as the adaptation of morphological structures in the course of their phylogenetic histories. In the humanities this approach was adapted by skilled scholars such as Karl Meuli (1891–1968), Aby Warburg (1866–1929), and currently by Roy Rappaport (1926–1997), Marvin Harris (1927–2001) and others. They were able to outline both human universals and the historical development (evolution) of religious behavior. According to the protagonists of this ethological approach and according to recent biology religion is deeply rooted in the biological human heritage. Inherited behavioral patterns did not only form the main patterns of ritual and iconography, but are most probably at least partly responsible for the origin of religion itself.
- Published
- 2014
47. NEURO/MEDICAL ONCOLOGY
- Author
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Irene Helenowski, Naoya Hashimoto, Jan J. Heimans, Toshiki Yoshimine, Johan A F Koekkoek, Evelyne Emery, José L. Asencio, Andrea Chamczuck, Carly Bridge, Gilbert Faure, Barbara-Ann Millar, Arthur Rosiello, Michela Casanova, John Freymann, Giulio Bertani, Jun-ich Adachi, Christian LaFougere, Julianne Bloom, Paul Vincent Opinaldo, Tobey J. McDonald, Alexander Khandji, Maciej M. Mrugala, Agnieszka Kowalska, Clifford G. Robinson, Josef Pichler, Jayesh Mehta, Lisa M. DeAngelis, Katie Slusarz, Rachel Grossman, Juan Armando Mejía, Sadhana Kannan, In Ah Kim, Pierre Soubeyran, Nabil Ahmed, Matthew J. Matasar, David A. Reardon, Marie-Laure Tanguy, Andrea Pace, Vani Santosh, Tackeun Kim, Adrienne C. Lahti, John E. Donahue, Pavlina Poloskova, Marc H. A. Jansen, Nilanjana Banerji, Margaret Schwartz, Matthias Kirsch, Robert Jeraj, Guus A.M.S. van Dongen, Samuel Singer, Tom J. Snijders, Santosh Kesari, Riccardo Soffetti, Takashi Sasayama, Diana Ly, Kaoru Kurisu, Carsten Friedrich, Shinji Kawabata, Cedric Revil, Michael A. Jacobs, Ryuichi Hirayama, Wan-Soo Yoon, Kathleen Lupica, Christopher Reilly, Takuichiro Hideo, Miguel Gil, Josep Garcia, Ming Zheng, Edward K. Avila, Mairéad G McNamara, Hartmut Uschmann, Jeffrey S. Weinberg, Craig H. Moskowitz, Jörg Hense, Manmeet Ahluwalia, Georg Bjarnason, David Corwin, Shakti Ramkissoon, Jad Alshami, Eric C. Leuthardt, Paul Dilfer, Margaret Patton, Lindsey Heathcock, Cees van Montfort, Rakesh Kumar Gupta, Akihiko Yoshida, Carmine Maria Carapella, Guy K. Mckhann, Marian Hajduch, Meinhard Nevinny-Stickel, Patricia Bruns, Ashish Suri, Hernán Carranza, David A. Gutman, Carlos Yepes, Patrick Y. Wen, T. Cloughesy, Anna Kaltenboeck, Carlos Bartels, Paul D. Brown, Lisa Fichtel, Lorenzo Giammattei, Steven Hamilton, Nobuyuki Takayama, Nan Lin, Jan Drappatz, Roland Eils, Akihiro Tsuboi, Patrick Urban, Minesh P. Mehta, Remy Gressin, Zarnie Lwin, Clarence Eng, Ian F. Dunn, Sin-Soo Jeun, Alva B. Weir, Elisa Trevisan, silviya Meletath, Fumiyuki Yamasaki, Scott N. Hwang, Navya Nambudiri, Timothy F. Cloughesy, Paolo Rampini, Kathryn J. Ruddy, Justin Kirby, Marc C. Huisman, Normand Laperriere, Abajo Guijarro, Alberto González-Aguilar, David M. Peereboom, Antoine F. Carpentier, Steven M. Greenberg, Chikashi Ishioka, Sarah C. Gaffey, Sneha Arya, Guy M. McKhann, Richard Curry, Takashi Watanabe, Keishi Makino, Radek Trojanec, Hideo Takeshima, Joseph F. Megyesi, Jasmina I. Ivanova, Victor Rodriguez Berrocal, Marcel Kool, Eric Burton, Sandra K. Johnston, Hideyuki Arita, Konstantina Karabatsou, Robert C. Rostomily, Sean Grimm, Ralph G. Dacey, Karl Olson, Sonia Gómez, Harry C. Schouten, Christof M. Kramm, Fred H. Hochberg, Darren Hargrave, Kazuhiko Sugiyama, Wilhelm Boogerd, Stefano Tiziani, Christine McCluskey, Albert H. Kim, Tejpal Gupta, Ida Martinelli, Friedrich-Wilhelm Kreth, Lennea Coombs, Keith L. Ligon, J. Manuel Sarmiento, David R. Macdonald, Holly Dickinson, Cristian Massacesi, Basile Wittwer, Jung-Il Lee, Volker Hovestadt, Mark Smolkin, Sampath Somanna, Ingo K. Mellinghoff, Nancy Ann Oberheim Bush, Sanjeev Francis, Roland Goldbrunner, Jai Ho Choi, John Sampson, Roy Allan Dominique Torcuator, Kathleen R. Lamborn, Simon V. Liubinas, Daniel J. Sargent, Christina K. Cramer, Francine Armentano, Heather Leeper, Stefan Rutkowski, Prakash Shetty, Arivazhagan Arimappamagan, Alicia Ortega, Enrique Jiménez, Kazuhiro Tanaka, Kolette D. Fly, Seunggu Han, Nicolas U. Gerber, David Schiff, Antonella Castellano, Isabel Arrillaga-Romany, Robert J. Wechsler-Reya, Sophie Taillibert, Macarena de la Fuente, Wolfgang Wick, Monica Bennett, Francesco Cognetti, John de Groot, Michael Gonzales, Leon D. Ortiz, Yoshiaki Shiokawa, George Sachs, Ivo Tremont, Charles A. Conrad, Michael D. Taylor, Igor J. Barani, Shannon Langmead, Lisa Sturla, Doosik Kong, Rebecca D. Folkerth, Garrett Riggs, Yoon-La Choi, Carole Soussain, Calvin Soh, Peter Canoll, Mariza Daras, Melissa Hoag, James Rigas, Dana Cernea, Liu Diane, Kenji Wakiya, Sandra Silberman, Ivan A. Reveles, Jeffrey S. Wefel, Wenting Wu, Marie Blonski, MA Majaid, Vanessa A. Nestor, Maurits W.C.B. Sanders, Cynthia Harrison, Ruxandra Costa, Andrea Hawkins-Daarud, Mark R. Gilbert, Ruth Katz, Masayuki Kanamori, Tomek Janicki, Aaron C. Spalding, Dong-Sup Chung, Lauren Foresman, Fateme Salehi, Allan H. Friedman, Eric P. Winer, Robert Kwiecien, Joachim Kuehl, Motoo Nagane, Stanislaw Burzynski, Tomokazu Aoki, Gregory N. Fuller, Nina Paleologos, Darell D. Bigner, Max Wintermark, Adam E. Flanders, Eiichi Ishikawa, Subramanian Hariharan, Doreen Pachow, Glen Stevens, Ulrich Schüller, Jennifer Lycette, Jennifer Garst, Jeffery T. Williams, Gordana Vlahovic, Tjeerd J. Postma, Tribhwan Vats, Isabel Arrilaga, Krista Follmer, Henry S. Friedman, Kenneth Schwartz, James Perry, Jonas M. Sheehan, Christian Grommes, Annette M. Molinaro, Seung-Ho Yang, Peter Lichter, Naoki Kagawa, Trish Whitcomb, Monica Loghin, Amanda L. Bergner, Miroslav Vaverka, Jayashree Kalpathy-Cramer, Chitra Sarkar, Thomas Davidson, Nithya Ramnath, Leland Rogers, Roberta Rudà, Steven A. Toms, Martin Gore, Khê Hoang-Xuan, Emmanuel Gyan, Hani Malone, Jun-ichi Adachi, Jennifer Rifenburg, Stefan M. Pfister, Luis Carlos Mayor, Vanja Vaccaro, Hannah E. Goldstein, Karen Fink, Eva Dombi, Timothy Cloughsey, Sabina Eigenbrod, Jiri Ehrmann, Li Li, Pamela R. Jackson, Makoto Ohno, Craig Nolan, Gerald P. Linette, Tatjana Seute, Eric Bouffet, Patricia M. M. B. Soetekouw, David J. Pisapia, Marc Remke, Susan Snodgras, David Tran, Keiichi Kobayashi, Warren P. Mason, Setsu Sakamoto, Chiara Bosa, Gabriele Schackert, Alfred Yung, David Cachia, Toshihiko Kuroiwa, María Ángeles Vaz Salgado, F. Lonnqvist, Francesca Piludu, Alvina Acquaye, Keisuke Ueki, Jung Ho Han, Kathy Newell, Mythili Shastry, Yoon Jae Cho, Marco Riva, Laura M. Fayad, Kristin Diefes, André O. von Bueren, Ina Ly, Beatrix Lutiger, Hiroyoshi Suzuki, Jeanette K. Doorduijn, Eiji Kohmura, Olivier Chinot, Ichiyo Shibahara, Nathalie Jansen, Marta Del Álamo de Pedro, Scott L. Pomeroy, Andreas Zwergal, Terri S. Armstrong, Elmar Kirches, Daniel P. Cahill, Howard A. Fine, Cezary Szczylik, Stéphane Oudard, Gregg C. Shepard, Mark G. Kris, Andrea Milbourne, Dominique Jennings, Marco Locatelli, Dereck Amakye, Takumi Kudo, Simon Bailey, Alessandra Fabi, Taketoshi Maehara, Soumen Khatua, Caroline Houllier, Klaus J. Müller, Jaishri O. Blakeley, Karen Kelly, Jonathon Yun, Thomas Gergel, Diane Liu, Eric T. Wong, Alin Borha, Brian J. Williams, Rakesh Jalali, Birgit Geoerger, Naosuke Nonoguchi, Julie Walker, Jasmin Jo, Manmohan Singh, Mary Noel, Denise Lally-Goss, Tracy T. Batchelor, Andrea Falini, Maximilian Niyazi, Jeffrey Raizer, Martin J. van den Bent, Aleksandra Gruslova, Phioanh L. Nghiemphu, Kristin R. Swanson, Maaike J. Vos, Jethro Hu, Rebeca Alcalce Pampliega, Craig S. Sauter, Leena Ketonen, Michael A. Vogelbaum, Donald Picker, Robert Hawkins, Chris Halpin, Otto S. Hoekstra, Elizabeth Vera-Bolanos, Ahmad Awada, Sawan Kumar, Alexandra Benouaich-Amiel, Joseph Pernicone, Noriyuki Kawabata, Andrew H. Kaye, David Brachman, Kurt A. Jaeckle, Cameron J. Nowell, Maria Carlo, Tom Mikkelsen, Jorg Dietrich, Tomonari Suzuki, Kohei Fukuoka, Philippe Aftimos, Christine Schmid-Tannwald, Vera Wenter, Valeria Conte, Scott Turner, Brian J A Gill, John D. Cullen, Jiayi Huang, Saurabh Dahiya, Vincent Delwail, Lien Bekaert, Priya Kumthekar, Roberta Seidman, Scott R. Plotkin, Priya Deshpande, Christopher Zalewski, Vaibhav Patel, Peter Kurniali, Martha Nowosielski, Zvi Ram, Susan M. Chang, Dannis G. van Vuurden, Stuart A. Grossman, Vaishali Suri, Rajan Jain, Christine Carico, Ying Yuan, Yoji Yamashita, Bojana Milojkovic-Kerklaan, Yannick Kerloeguen, Michael B. Sisti, Rameen Beroukhim, Andrea Artoni, Frances McSherry, John J. Evans, Mark E. Shaffrey, Lauren E. Abrey, Akshal S. Patel, Laura Bernal-Vaca, Rolf-Dieter Kortmann, Robert Grubb, Mimi Lee, Jörg-Christian Tonn, Shinobu Yamada, Andrés Quintero, Kazuhiko Mishima, Ania Marszalek, Stephen Gancher, Amal Melhem-Bertrandt, Takamitsu Fujimaki, Monika Warmuth-Metz, George Avgeropoulos, Rifaquat Rahman, Franck Bourdeaut, Frank Feleppa, Jennifer Clarke, Meredith A. Reid, Maria Werner-Wasik, Andrew D. Norden, Kenneth D. Swanson, Jeffrey N. Bruce, Chae-Yong Kim, Steven S. Rosenfeld, Haiyan Jiang, Oliver Schnell, Toshihiro Kumabe, Michael J. Sullivan, W. Gladdines, Glenn J. Lesser, Chang-Ho Yun, Epari Sridhar, Sophie Lebouvier-Sadot, Andrea Baldwin, Chirag G. Patil, Thomas Smith, Shin-Ichi Miyatake, Renato LaRocca, Kent C. Shih, Russell C. Rockne, Katsu Mizukawa, Antonio Omuro, Ryuta Saito, Mohamed H. Hamza, Eunju Hurh, Silke Soucek, Michel Lacroix, Brian J. Scott, Thomas Kaley, Tetsuya Yamamoto, Gregory J. Zipfel, Andrew Lin, Elena Pentsova, Carlos Emilio Restrepo, Utkarsh Bhagat, Masao Matsutani, Andrew B. Lassman, Stephanie L. Pugh, Yasuji Miyakita, Manabu Kinoshita, Christian Hagel, D. Brandsma, Jorge M. Otero, Marco Timmer, Ke Zhang, S. Altintas, Thierry Lamy, Hirofumi Hirano, Mehar Chand Sharma, Wafik S. El-Deiry, Peter A. Sims, Evanthia Galanis, Yong-Kil Hong, Terence J. O'Brien, Haruo Sugiyama, Dieta Brandsma, Loretta Barron, Joshua J. Jacobs, Roger Henriksson, Albert Lai, David White, Xiao-Tang Kong, John D. Hainsworth, Petronella J Lugtenburg, Paul A. Northcott, Maryline Barrie, Kenneth J. Cohen, Tanuj Saaraswat, Xiaobu Ye, Sandra Ruland, Diana M. Haninger, Surasak Phuphanich, Marc C. Chamberlain, Kenneth Aldape, Ewa Matczak, Phyo Kim, Peter Bartenstein, Lumir Hrabalek, Howard Y. Chang, Donatella Tampieri, Fumi Higuchi, Katherine S. Panageas, Allicia C. Girvan, Majid Khan, Stevie Threatt, Tareq Juratli, Mitchel S. Berger, Linda Dirven, Michele Nikolai, Emmanuelle DiTomaso, Sarah Leary, Jan H.M. Schellens, Chuanlu Jiang, Michael Glantz, Harald Sontheimer, Michael D. Prados, Mauricio Lema, Marie-Christine Guiot, Shesh N. Rai, Minhee Won, Carlos Vargas, Eva Galanis, Kazunori Arita, David I. Sandberg, Gianluca Ardolino, Sylvain Choquet, Ondrej Kalita, Michael Rytting, Lorenzo Bello, Luis Ley Urzaiz, Martin J.B. Taphoorn, Kourosh Jafari-Khouzani, Alfred Rademaker, Juan Martinez San Millan, Isabelle Aerts, Sergio Bracarda, John Norton, Mark D. Anderson, Barbara Zarino, Jun Ichi Kuratsu, Nicholas Butowski, Derek R. Johnson, James E. Herndon, Diana Giannarelli, Debra LaFrankie, Filippo Cogiamanian, Yasuyoshi Chiba, Hideo Nakamura, Agnes Jager, Caroline Chung, Paula Warren, Frans S. S. Leijten, Peter Hau, Yusuke Oji, Yuichi Hirose, Kathryn Gilliland, Sadao Kaneko, W. K. Alfred Yung, Roger Stupp, Amy Chung, Yutaka Hata, Mary Frances McAleer, Hee-Won Jung, Miloslava Zlevorová, Brendan Killory, Raymond Sawaya, Anita Chawla, John Trusheim, H. Ian Robins, Judy Lima, Prakash Ambady, Barbara O'Brien, Sonia Bermúdez, Howard Colman, Matthias Gromeier, Jean-Sébastien Guillamo, Maria C. Pietanza, Antonello Vidiri, Laura Guyman, Kristin Swanson, Paul Rosenblatt, Joshua L. Dowling, Lakshmi Nayak, Ashlee Drawz, Yu Jung Kim, Mikael L. Rinne, Shlomit Yust-Katz, Jessi Stevens, Katharine J. Drummond, Patricia Wing, Sarah Taylor, Joshua E. Allen, Ron Schaafsma, John DeGroot, Shigetoshi Yano, Paula Rauschkolb, Anupam Kumar, Soichiro Shibui, M. E. van Linde, Shirish M. Gadgeel, Yoshitaka Narita, Nicholas G. Avgeropoulos, Luca Bertero, Hongjun Wang, Jason K. Rockhill, Suriya Jeyapalan, Yukihiko Sonoda, Hikaru Sasaki, Shirley L. Markant, Masamitsu Nishihara, Daniel J. Brat, Alexandra Flowers, Monica Sierra del Rio, Morgan Prust, Adam M. Sonabend, Pierre A. Robe, James J. Dignam, Julia C. Chisholm, Gregory J. Riely, Mary Gerard, Sajeel Chowdhary, Natalie Jäger, Giovanna M. D'Abaco, James J. Culhane, Tatsunori Okamura, Erik P. Sulman, L. Adriana Esparza, Ivo W. Tremont-Lukats, Emily Porensky, Yoshihiro Oka, Marcelo De Carvalho, Brigitte C. Widemann, Stacey Kalambakas, Rolf D. Kortmann, Stewart Goldman, Jaap C. Reijneveld, Andrew Brenner, Jacob Mandel, Riccardo Draghi, Yunus Arik, Shinji Yamashita, Torsten Pietsch, Tanweer Zaidi, Dawid Schellingerhout, Marta Penas-Prado, Veronica Villani, Adriana Olar, Vanessa L. Merker, Matthias Holdhoff, Joke W. Baars, Katrina H. Smith, Arnab Chakravarti, Giorgio Carrabba, Gertjan J.L. Kaspers, Susan Boulton, Peter A. Forsyth, David T.W. Jones, Anne Baldock, Meier Hsu, Soham Dasgupta, Jeremy Rudnick, Arun Rai, Jessica Sun, Naoki Shinojima, Christian Mawrin, Eita Uchida, Jaswinder Jutla, Koichi Ichimura, Alona Muzikansky, Jean Philippe Maire, Louis B. Nabors, Yuko Matsushita, Emilie Le Rhun, Annick Desjardins, Magali Lecavalier-Barsoum, Laurie Rice, Bradford A. Moffat, Kelly Hempfling, Andrew A. Kanner, Mark W. Kieran, Stephanie M. Robert, Hervé Ghesquières, Alba A. Brandes, E. Sander Connolly, Jingxia Liu, David T. Dicker, Katherine B. Peters, Gregory S. Burzynski, Charles Sweeley, Deborah T. Blumenthal, Nicolás Useche, Tulika Ranjan, Thierry Muanza, Mercedes Garcia Villanueva, Fernando Hakim, Yana Krutoshinskaya, Shintaro Fukushima, Ryo Nishikawa, Damien C. Weber, Michael R. Chicoine, Motomasa Furuse, André Busson, Joseph R. Simpson, Gabriele Röhn, Susanne Koeppen, Arjun Sahgal, Fabio M. Iwamoto, Leland Graves, Sarah Iglseder, Taro Yanagawa, Michael Lahn, Ramaswamy Govindan, Eduardo Roberts Cervantes, Eric S. Wong, Nadine Kliese, Feng Tai, Katja von Hoff, Vincenzo Anelli, Trevor J. Pugh, Andrés F. Cardona, Gebra Cuyun Carter, Yuko Watanabe, Bogdana Suchorska, Manuela Caroli, José Luis Asencio, Eudocia Q. Lee, John Floyd, Lucas Moreno, Samantha J Mills, Jun-ichiro Kuroda, Susan Chi, David N. Louis, Aanchal Kakkar, Elizabeth R. Gerstner, Annika Schlamann, Robert Cavaliere, John L. Villano, Asha Das, Petr Kavan, Takaaki Yanagisawa, Luc Taillandier, Jonathan Fratkin, Günther Stockhammer, Tomasz Janicki, Sherese Fralin, Wafik Zaky, Lisa Scarpace, Kazunari Yoshida, Magalie Hilton, Andrey Korshunov, Aliasgar Moiyadi, Alexandra Gorelick, Alfredo Carrato Mena, Yuya Nishiyama, Riccardo Soffietti, Marina Donativi, Andrew S. Chi, Lauren Schaff, Andrew P. Morokoff, Sophie E. M. Veldhuijzen van Zanten, Hans-Joachim Reimers, John G. Stewart, Clare Ferrigno, Jackson Hamilton, Do-Hyun Nam, Samantha Hammond, Regina Krel, Mika Watanabe, Anna K. Nowak, Elina Tsyvkin, Michael W. McDermott, Jacoline E C Bromberg, Teiji Tominaga, Laila M. Poisson, Lisa Doherty, Alessia Lodi, Vino Apok, Magdalena Kneblova, Michelle Bell, Carl Jaffe, Sunita Dahr, Maria Koh, Pedro Garciarena, J. Gregory Cairncross, Ana Gómez Rueda, Augustus Perez, Ho Jun Seol, Frank Saran, Camillo Porta, Grace Elzinga, Michael Cloney, and Charles P. Hart
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Cancer Research ,medicine.medical_specialty ,business.industry ,010403 inorganic & nuclear chemistry ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,Abstracts ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Medical physics ,Neurology (clinical) ,business - Published
- 2013
48. Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): Results from the confirmatory phase 3 ASCEND-5 study
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Patrick Urban, Alice T. Shaw, Enriqueta Felip, David R. Spigel, G.V. Scagliotti, C. Gridelli, Cheng Zheng, L. Crinò, Makoto Nishio, Silvia Novello, Oliver Gautschi, Tae Min Kim, S. Deudon, Tony Mok, Alessandra Bearz, K. Kiura, and G. Liu
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Chemotherapy ,Ceritinib ,Crizotinib ,business.industry ,medicine.medical_treatment ,non-small cell lung cancer (NSCLC) ,Hematology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Anaplastic lymphoma kinase ,In patient ,business ,Previously treated ,medicine.drug - Published
- 2016
49. Abstract S6-01: PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial
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S-A Im, M. Campone, J. Baselga, Yoshinori Ito, M. De Laurentiis, Agnieszka Jagiełło-Gruszfeld, J. Cortes, Walter Jonat, Patrick Urban, Cristian Massacesi, S Hurvitz, Noriyuki Masuda, E. di Tomaso, H. Iwata, Soulef Hachemi, CL Arteaga, Ahmad Awada, L-M Tseng, Zefei Jiang, S Le Mouhaër, S Chia, Mark Clemons, and Barbara Pistilli
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Population ,Buparlisib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Clinical endpoint ,Medicine ,education ,Chemotherapy ,education.field_of_study ,Aromatase inhibitor ,Fulvestrant ,business.industry ,Cancer ,medicine.disease ,Surgery ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Background: PI3K pathway activation is a hallmark of hormone receptor-positive (HR+) BC cells resistant to endocrine therapy (ET). Preclinical and early clinical data suggest that combining the pan-PI3K inhibitor BUP (BKM120) with ET may provide clinical benefits in this setting. BELLE-2 (NCT01610284) is the first randomized Phase III trial to assess the efficacy and safety of a PI3K inhibitor combined with FULV in HR+ advanced BC, including a prospective analysis of whether PI3K pathway activation status measured in archival tumor tissue and ctDNA is predictive of clinical benefit. Methods: Postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to aromatase inhibitor therapy were enrolled. After a 14-day run-in with FULV (500 mg), patients (pts) were randomized (1:1) to receive oral BUP (100 mg/day) or placebo (PBO) with FULV (500 mg per standard of care). Randomization of all pts was stratified by PI3K pathway status measured in archival tumor tissue (PIK3CA mutation or PTEN loss; activated, non-activated, unknown) and visceral disease status (present, absent). Baseline PIK3CA mutation status in ctDNA was assessed in a subset of 587 pts at trial entry. The primary endpoint was locally-assessed progression-free survival (PFS; RECIST v1.1) in the full population and PI3K pathway-activated group. Secondary endpoints included overall survival, safety, overall response rate (ORR), and clinical benefit rate (CBR). Results: 1147 pts received FULV with BUP or PBO, with 187 (16%) ongoing at data cut-off. Baseline characteristics were well balanced between the two arms: median age was 62 years, 98% had ECOG performance status of 0/1, 61% had visceral disease, 69% were sensitive to prior ET, 28% had received prior chemotherapy for metastatic BC. BELLE-2 met its primary endpoint in the full population (Table). In pts with PI3K pathway-activated tumor tissue, PFS increase for BUP+FULV vs PBO+FULV did not meet the planned endpoint. Among pts with PIK3CA status measured in ctDNA, median PFS, ORR, and CBR were significantly improved for BUP+FULV vs PBO+FULV in pts with PIK3CA-mutant tumors but not pts without. Median PFS, monthsHR95% CI; P valueORRCBR BUP+FULVPBO+FULV Full population N=11476.95.00.780.67–0.89;P The most common Grade 3/4 adverse events (AEs; ≥5% of pts; BUP+FULV vs PBO+FULV) in all pts were increased alanine aminotransferase (26 vs 1%), increased aspartate aminotransferase (18 vs 3%), hyperglycemia (15 vs 0.2%), and rash (8 vs 0%). The most common reasons for treatment discontinuation were disease progression (54 vs 73%) and AEs (13 vs 2%). Conclusions: BELLE-2 met its primary endpoint in the full population. Prespecified analyses showed that characterizing PIK3CA mutation in ctDNA at trial entry identifies pts with endocrine- resistant HR+/HER2–advanced BC, for whom BUP+FULV results in meaningful clinical benefits. Citation Format: Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng L-M, Hurvitz S, Masuda N, Cortés J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Hachemi S, Le Mouhaër S, Di Tomaso E, Urban P, Massacesi C, Campone M. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-01.
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- 2016
50. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design
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Emmanuelle di Tomaso, Bharani Dharan, C. Germa, Lucia Trandafir, Cornelia Quadt, Samit Hirawat, Patrick Urban, Cristian Massacesi, Ranjana Tavorath, Nathalie Fretault, and Paola Aimone
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Buparlisib ,Review ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Carcinoma ,medicine ,Pharmacology (medical) ,PI3K/AKT/mTOR pathway ,business.industry ,Clinical study design ,biomarkers ,Cancer ,PI3K inhibitors ,medicine.disease ,Head and neck squamous-cell carcinoma ,clinical trial design ,Lymphoma ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,PI3K–AKT–mTOR pathway ,business ,patient selection - Abstract
The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.
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- 2016
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