bay-80-6946 has been researched along with Neoplasms* in 9 studies
2 review(s) available for bay-80-6946 and Neoplasms
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Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well. Topics: Antineoplastic Agents; Drug Design; Drug Resistance, Multiple; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors | 2019 |
Targeting the PI3K pathway in cancer: are we making headway?
The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive. Nevertheless, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers. Novel compounds with greater potency and selectivity, as well as improved therapeutic indices owing to reduced risks of toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit α isoform, must be identified and analytically and clinically validated. Finally, considering that oncogenic activation of the PI3K-AKT-mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment. Herein, we review the current experience with anticancer therapies that target the PI3K-AKT-mTOR pathway. Topics: Class I Phosphatidylinositol 3-Kinases; Everolimus; Humans; Molecular Targeted Therapy; Neoplasms; Oncogene Protein v-akt; Purines; Pyrimidines; Quinazolines; Quinazolinones; Signal Transduction; TOR Serine-Threonine Kinases | 2018 |
3 trial(s) available for bay-80-6946 and Neoplasms
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On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors.
Topics: Biopsy; Cell Line, Tumor; Female; Humans; Lymphoma; Male; Neoplasms; Phosphatidylinositol 3-Kinases; Pyrimidines; Quinazolines | 2020 |
A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors.
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.. 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. Safety was monitored throughout the study. Plasma copanlisib levels were measured for pharmacokinetic analysis.. Ten patients were enrolled and treated; three received copanlisib 0.4 mg/kg and seven received copanlisib 0.8 mg/kg. Overall, median duration of treatment was 6.2 weeks. No patients treated at 0.4 mg/kg experienced a dose-limiting toxicity, and the maximum tolerated dose in Japanese patients was determined to be 0.8 mg/kg. Adverse events were recorded in all ten patients; the most common were hyperglycemia, hypertension, and constipation. Copanlisib pharmacokinetic exposures displayed near dose-proportionality, with no accumulation. No patients achieved a complete or partial response, and disease control rate was 40.0%.. Copanlisib was well tolerated in Japanese patients with advanced or refractory solid tumors, and the maximum tolerated dose was determined to be 0.8 mg/kg. Copanlisib demonstrated near dose-proportional pharmacokinetics and preliminary disease control, warranting further investigation.. NCT01404390. Topics: Aged; Antineoplastic Agents; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Quinazolines | 2017 |
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.
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).. 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 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially.. Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years.. Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL.. NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611. Topics: Administration, Intravenous; Adult; Aged; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Staging; Neoplasms; Pyrimidines; Quinazolines | 2016 |
4 other study(ies) available for bay-80-6946 and Neoplasms
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ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Inhibitory Concentration 50; Mice, Nude; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; raf Kinases; ras Proteins; Xenograft Model Antitumor Assays | 2021 |
A closer look at copanlisib.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Decision-Making; Clinical Trials as Topic; Disease Management; Humans; Molecular Targeted Therapy; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Quinazolines; Signal Transduction; Treatment Outcome | 2018 |
Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling.
The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF-MEK-ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2(+) cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity. Topics: Apoptosis; Cell Line, Tumor; Heterocyclic Compounds, 3-Ring; Humans; Lapatinib; MAP Kinase Signaling System; MCF-7 Cells; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Quinazolines | 2014 |
BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models.
Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with sub-nanomolar IC50s against PI3Kα and PI3Kδ. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Kα compared with PI3Kβ in cells. BAY 80-6946 showed superior antitumor activity (>40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80-6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80-6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non-small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors. Topics: Administration, Intravenous; Animals; Apoptosis; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Molecular Targeted Therapy; Neoplasms; Neoplasms, Experimental; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Rats; Rats, Nude; Receptor, ErbB-2; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays | 2013 |