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Copanlisib

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https://www.readbyqxmd.com/read/29383036/development-of-a-personalized-therapeutic-strategy-for-erbb-gene-mutated-cancers
#1
Malgorzata Milewska, Mattia Cremona, Clare Morgan, John O'Shea, Aoife Carr, Sri H Velanki, Ann M Hopkins, Sinead Toomey, Stephen F Madden, Bryan T Hennessy, Alex J Eustace
Background: The application of genomic technologies to patient tumor samples identified groups of signaling pathways which acquire activating mutations. Some cancers are dependent on these mutations and the aberrant proteins resulting from these mutations can be targeted by novel drugs which can eradicate the cancer. Methods: We used www.cbioportal.org to determine the frequency of ERBB mutations in solid tumors. We then determined the sensitivity of a panel of cell lines to clinically available PI3K inhibitors...
2018: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29348486/phase-i-dose-escalation-study-of-copanlisib-in-combination-with-gemcitabine-or-cisplatin-plus-gemcitabine-in-patients-with-advanced-cancer
#2
R D Kim, S R Alberts, C Peña, I Genvresse, A Ajavon-Hartmann, C Xia, A Kelly, J E Grilley-Olson
BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo...
January 18, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29222281/improved-biological-insight-and-influence-on-management-in-indolent-lymphoma-talk-3-update-on-nodal-and-splenic-marginal-zone-lymphoma
#3
REVIEW
Catherine Thieblemont
Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are rare indolent chronic B-cell lymphomas. Prognosis is typically good with median survival around 10-15 years. Management is generally based on the presence of symptoms or high tumor burden. There are no standard treatments for these 2 entities, and therapeutic strategies are rapidly evolving. Clinical developments for these 2 entities are oriented by genomic studies, with largely overlapping mutational profiles involving the NOTCH, B-cell receptor (BcR) and nuclear factor κB (NF-κB) signaling, chromatin remodeling, and the cytoskeleton...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29216806/an-industry-update-the-latest-developments-in-therapeutic-delivery
#4
Iain Simpson
This industry update covers the period from 1 September through 30 September 2017, and is based on information sourced from company press releases, scientific literature, patents and various news websites. The month saw the US FDA approve three new molecular entities, Aliqopa (copanlisib dihydrochloride) (Bayer Healthcare); Solosec (secnidazole) (Symbiomix Therapeutics) and Verzenio (abemaciclib) (Eli Lilly and Co). Intarcia Therapeutics Inc. has its application for approval of a novel drug device combination of exenatide for the treatment of diabetes rejected by FDA but said that it will work to address the concerns and refile the application...
January 2018: Therapeutic Delivery
https://www.readbyqxmd.com/read/29179250/pi3k-inhibitors-understanding-toxicity-mechanisms-and-management
#5
REVIEW
I Brian Greenwell, Andrew Ip, Jonathon B Cohen
The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms...
November 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/29156708/a-preclinical-evaluation-of-the-mek-inhibitor-refametinib-in-her2-positive-breast-cancer-cell-lines-including-those-with-acquired-resistance-to-trastuzumab-or-lapatinib
#6
John O'Shea, Mattia Cremona, Clare Morgan, Malgorzata Milewska, Frankie Holmes, Virginia Espina, Lance Liotta, Joyce O'Shaughnessy, Sinead Toomey, Stephen F Madden, Aoife Carr, Naomi Elster, Bryan T Hennessy, Alex J Eustace
Purpose: The MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an in vitro preclinical evaluation of refametinib, an allosteric MEK1/2 inhibitor, in HER2-positive breast cancer cell lines including models of acquired resistance to trastuzumab or lapatinib. Methods: A panel of HER2-positive breast cancer cells were profiled for mutational status and also for anti-proliferative response to refametinib alone and in combination with the PI3K inhibitor (PI3Ki) copanlisib and the HER2-targeted therapies trastuzumab and lapatinib...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29127587/copanlisib-first-global-approval
#7
Anthony Markham
Bayer are developing copanlisib (Aliqopa™)-a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor-as a treatment for various haematological and solid malignancies. The US FDA has granted copanlisib accelerated approval for the treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies based on the results of a phase II trial. Phase III trials are underway evaluating copanlisib as treatment for relapsed/refractory diffuse large B-cell lymphoma and in combination with rituximab or rituximab-based chemotherapy or standard immunochemotherapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma...
December 2017: Drugs
https://www.readbyqxmd.com/read/29070613/copanlisib-produces-prolonged-responses-in-lymphoma
#8
(no author information available yet)
A phase II trial of the pan-class I PI3K inhibitor copanlisib demonstrated that it induces objective responses in 59% of patients with relapsed or refractory indolent lymphoma. The responses lasted a median of 22.6 months. Although the drugs weren't compared head to head, researchers suspect that the side effects of copanlisib may be less severe than those of idelalisib, another PI3K inhibitor.
October 25, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29033198/copanlisib-in-heavily-pretreated-indolent-lymphoma
#9
Manjulika Das
No abstract text is available yet for this article.
October 12, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28976790/phosphatidylinositol-3-kinase-inhibition-by-copanlisib-in-relapsed-or-refractory-indolent-lymphoma
#10
Martin Dreyling, Armando Santoro, Luigina Mollica, Sirpa Leppä, George A Follows, Georg Lenz, Won Seog Kim, Arnon Nagler, Panayiotis Panayiotidis, Judit Demeter, Muhit Özcan, Marina Kosinova, Krimo Bouabdallah, Franck Morschhauser, Don A Stevens, David Trevarthen, Marius Giurescu, Lisa Cupit, Li Liu, Karl Köchert, Henrik Seidel, Carol Peña, Shuxin Yin, Florian Hiemeyer, Jose Garcia-Vargas, Barrett H Childs, Pier Luigi Zinzani
Purpose Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle...
October 4, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28946015/peripheral-t-cell-lymphomas-focusing-on-novel-agents-in-relapsed-and-refractory-disease
#11
REVIEW
Alessandro Broccoli, Lisa Argnani, Pier Luigi Zinzani
Patients with relapsed or refractory peripheral T-cell lymphoma display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory PTCL. Four recently approved compounds are used as single agents: pralatrexate, a novel antifolate agent; romidepsin and belinostat, both histone deacetylase (HDAC) inhibitors; brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody...
November 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28942659/novel-synthetic-drugs-currently-in-clinical-development-for-chronic-lymphocytic-leukemia
#12
REVIEW
Pawel Robak, Tadeusz Robak
Over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28714036/pharmacokinetics-of-intravenous-pan-class-i-phosphatidylinositol-3-kinase-pi3k-inhibitor-14-c-copanlisib-bay-80-6946-in-a-mass-balance-study-in-healthy-male-volunteers
#13
Michael Gerisch, Thomas Schwarz, Dieter Lang, Gabriele Rohde, Stefanie Reif, Isabelle Genvresse, Susanne Reschke, Dorina van der Mey, Camille Granvil
PURPOSE: To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. METHODS: A single dose of 12 mg copanlisib containing 2.76 MBq [(14)C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites...
July 11, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28633365/phase-ii-study-of-copanlisib-a-pi3k-inhibitor-in-relapsed-or-refractory-indolent-or-aggressive-lymphoma
#14
M Dreyling, F Morschhauser, K Bouabdallah, D Bron, D Cunningham, S E Assouline, G Verhoef, K Linton, C Thieblemont, U Vitolo, F Hiemeyer, M Giurescu, J Garcia-Vargas, I Gorbatchevsky, L Liu, K Koechert, C Peña, M Neves, B H Childs, P L Zinzani
Background: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. Patients and methods: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. Results: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28288710/possible-novel-agents-in-marginal-zone-lymphoma
#15
REVIEW
Pier Luigi Zinzani, Alessandro Broccoli
Efficacy, safety and mechanisms of action of novel agents in marginal zone lymphoma patients, both with a nodal and extranodal presentation, are reviewed. Data on lenalidomide, bortezomib and 90yttrium-ibrutumomab tiuxetan are obtained from trials specifically designed for patients affected by marginal zone lymphoma and with various disease presentations. The role of targeted agents, such as obinutuzumab, ibrutinib and idelalisib, and of some very new drugs (venetoclax, copanlisib, ublituximab and TGR-1202) is also discussed, taking into account the most relevant experiences in patients with indolent non-Hodgkin's lymphomas...
March 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/28073005/simultaneous-inhibition-of-pi3k%C3%AE-and-pi3k%C3%AE-induces-abc-dlbcl-regression-by-blocking-bcr-dependent-and-independent-activation-of-nf-%C3%AE%C2%BAb-and-akt
#16
Juliane Paul, Maurice Soujon, Antje M Wengner, Sabine Zitzmann-Kolbe, Andrea Sturz, Katja Haike, Koh Hui Keng Magdalene, Sze Huey Tan, Martin Lange, Soo Yong Tan, Dominik Mumberg, Soon Thye Lim, Karl Ziegelbauer, Ningshu Liu
Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/27915408/a-phase-i-study-of-intravenous-pi3k-inhibitor-copanlisib-in-japanese-patients-with-advanced-or-refractory-solid-tumors
#17
Toshihiko Doi, Nozomu Fuse, Takayuki Yoshino, Takashi Kojima, Hideaki Bando, Hideaki Miyamoto, Masato Kaneko, Motonobu Osada, Atsushi Ohtsu
PURPOSE: To evaluate the safety, tolerability, pharmacokinetics, and efficacy of the intravenously administered pan-PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors. METHODS: A Phase I open-label study in Japanese patients with advanced or refractory solid tumors was carried out. Patients received a single intravenous dose of either copanlisib 0.4 mg/kg or copanlisib 0.8 mg/kg, dosed intermittently on days 1, 8, and 15 of a 28-day cycle...
January 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27672108/first-in-human-phase-i-study-of-copanlisib-bay-80-6946-an-intravenous-pan-class-i-phosphatidylinositol-3-kinase-inhibitor-in-patients-with-advanced-solid-tumors-and-non-hodgkin-s-lymphomas
#18
A Patnaik, L J Appleman, A W Tolcher, K P Papadopoulos, M Beeram, D W Rasco, G J Weiss, J C Sachdev, M Chadha, M Fulk, S Ejadi, J M Mountz, M T Lotze, F G S Toledo, E Chu, M Jeffers, C Peña, C Xia, S Reif, I Genvresse, R K Ramanathan
BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0...
October 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27437766/combination-therapy-with-copanlisib-and-abl-tyrosine-kinase-inhibitors-against-philadelphia-chromosome-positive-resistant-cells
#19
Seiichi Okabe, Tetsuzo Tauchi, Yuko Tanaka, Juri Sakuta, Kazuma Ohyashiki
ABL tyrosine kinase inhibitor (TKI) therapy has improved the survival of patients with Philadelphia (Ph) chromosome-positive leukemia. However, ABL TKIs cannot eradicate leukemia stem cells. Therefore, new therapeutic approaches for Ph-positive leukemia are needed. Aberrant activation of phosphoinositide 3-kinase (PI3K) signaling is important for the initiation and maintenance of human cancers. Copanlisib (BAY80-6946) is a potent inhibitor of PI3Kα and PI3K-δ. Here we investigated the efficacy of combination therapy of copanlisib with an ABL TKI (imatinib, nilotinib, or ponatinib) using BCR-ABL-positive cells...
August 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27310202/discovery-and-sar-of-novel-2-3-dihydroimidazo-1-2-c-quinazoline-pi3k-inhibitors-identification-of-copanlisib-bay-80-6946
#20
William J Scott, Martin F Hentemann, R Bruce Rowley, Cathy O Bull, Susan Jenkins, Ann M Bullion, Jeffrey Johnson, Anikó Redman, Arthur H Robbins, William Esler, R Paul Fracasso, Timothy Garrison, Mark Hamilton, Martin Michels, Jill E Wood, Dean P Wilkie, Hong Xiao, Joan Levy, Enrico Stasik, Ningshu Liu, Martina Schaefer, Michael Brands, Julien Lefranc
The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens...
July 19, 2016: ChemMedChem
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