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Veliparib

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https://www.readbyqxmd.com/read/28387939/parent-metabolite-pharmacokinetic-modeling-and-pharmacodynamics-of-veliparib-abt-888-a-parp-inhibitor-in-patients-with-brca-1-2-mutated-cancer-or-parp-sensitive-tumor-types
#1
Jing Niu, Christie Scheuerell, Shailly Mehrotra, Sharon Karan, Shannon Puhalla, Brian F Kiesel, Jiuping Ji, Edward Chu, Mathangi Gopalakrishnan, Vijay Ivaturi, Jogarao Gobburu, Jan H Beumer
Veliparib (ABT-888) is a novel oral poly-ADP-ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib have been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics (PK) of chronically dosed single-agent veliparib in patients with either BRCA 1/2-mutated cancer or PARP-sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly-ADP-ribose (PAR) level observed in peripheral blood mononuclear cells (PBMCs)...
April 7, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28356425/efficacy-of-the-parp-inhibitor-veliparib-with-carboplatin-or-as-a-single-agent-in-patients-with-germline-brca1-or-brca2-associated-metastatic-breast-cancer
#2
George Somlo, Paul Frankel, Banu Arun, Cynthia X Ma, Agustin Garcia, Tessa Cigler, Leah Cream, Harold Harvey, Joseph A Sparano, Rita Nanda, Helen K Chew, Timothy Moynihan, Matthew P Goetz, Linda Vahdat, Jan H Beumer, Arti Hurria, Joanne Mortimer, Richard Piekarz, Sharon Sand, Josef Herzog, Lily R Van Tongeren, Katherine Ferry-Galow, Alice Chen, Christopher Ruel, Edward Newman, David R Gandara, Jeffrey N Weitzel
We aimed to establish the maximum tolerated dose (MTD) of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2-(BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment post-progression, and to correlate PAR levels with clinical outcome. <br /><br />Experimental Design:Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses of oral twice-daily (BID) veliparib...
March 29, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28314788/the-parp-inhibitor-veliparib-can-be-safely-added-to-bendamustine-and-rituximab-and-has-preliminary-evidence-of-activity-in-b-cell-lymphoma
#3
Jacob D Soumerai, Andrew D Zelenetz, Craig Moskowitz, M Lia Palomba, Paul A Hamlin, Ariela Noy, David J Straus, Alison J Moskowitz, Anas Younes, Matthew J Matasar, Steven Horwitz, Carol Portlock, Jason Konner, Mrinal M Gounder, David M Hyman, Martin H Voss, Matthew G Fury, Devika Gajria, Richard D Carvajal, Alan L Ho, Jan H Beumer, Brian Kiesel, Zhigang Zhang, Alice Chen, Richard F Little, Christine Jarjies, Thu O Dang, Fallon France, Nishant Mishra, John F Gerecitano
PURPOSE: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase 1 study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. EXPERIMENTAL DESIGN: This dose-escalation study evaluated safety, pharmacokinetics and preliminary efficacy of veliparib (20-400 mg BID, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 IV, days 1 and 2)...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28314386/veliparib-in-combination-with-radiotherapy-for-the-treatment-of-mgmt-unmethylated-glioblastoma
#4
Toni Rose Jue, Kyoko Nozue, Ashleigh J Lester, Swapna Joshi, Lisette B W Schroder, Shane P Whittaker, Sheri Nixdorf, Robert W Rapkins, Mustafa Khasraw, Kerrie L McDonald
BACKGROUND: The O (6) -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM. METHODS: The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors...
March 17, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28243955/development-of-a-level-a-in-vitro-in-vivo-correlation-for-veliparib-abt-888-extended-release-tablet-formulation
#5
Rajendar K Mittapalli, Silpa Nuthalapati, Alyssa E Delke DeBord, Hao Xiong
PURPOSE: The aim of the current manuscript is to develop and validate a level A in vitro-in vivo correlation (IVIVC) for veliparib extended-release (ER) tablet formulations. METHODS: The in vitro release profiles of veliparib formulations were determined using USP Dissolution Apparatus 2 with 900 mL of 0.1 N HCl at 75 rpm. In a clinical study, 24 subjects with solid tumors received one of the ER formulations (200 mg): fast (Formulation A), intermediate (Formulation B), and slow (Formulation C), and two 100 mg immediate release capsules (Formulation D)...
February 27, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28156017/population-pharmacokinetics-and-site-of-action-exposures-of-veliparib-with-topotecan-plus-carboplatin-in-patients-with-hematological-malignancies
#6
Shailly Mehrotra, Mathangi Gopalakrishnan, Jogarao Gobburu, Jacqueline M Greer, Richard Piekarz, Judith E Karp, Keith Pratz, Michelle A Rudek
AIMS: Veliparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzyme. The objectives of the analysis were to evaluate the effect of baseline covariates and co-administration of topotecan plus carboplatin (T + C) on pharmacokinetics of veliparib in patients with refractory acute leukemia, and compare veliparib concentration in various biological matrices. METHODS: A population pharmacokinetic model was developed and effect of age, body size indices, sex, creatinine clearance (CrCL), and co-administration of T + C on the pharmacokinetics of veliparib were evaluated...
February 3, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28109627/a-final-report-of-a-phase-i-study-of-veliparib-abt-888-in-combination-with-low-dose-fractionated-whole-abdominal-radiation-therapy-ldfwar-in-patients-with-advanced-solid-malignancies-and-peritoneal-carcinomatosis-with-a-dose-escalation-in-ovarian-and-fallopian
#7
Kim A Reiss, Joseph M Herman, Deborah Armstrong, Marianna Zahurak, Anthony Fyles, Anthony Brade, Michael Milosevic, Laura A Dawson, Angela Scardina, Patricia Fischer, Amy Hacker-Prietz, Robert J Kinders, Lihua Wang, Alice Chen, Sarah Temkin, Naomi Horiba, Lee-Anne Stayner, Lillian L Siu, Nilofer S Azad
BACKGROUND: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). METHODS: Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients...
March 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28032120/inhibition-of-poly-adp-ribosylation-fails-to-increase-axonal-regeneration-or-improve-functional-recovery-after-adult-mammalian-cns-injury
#8
Xingxing Wang, Yuichi Sekine, Alexandra B Byrne, William B J Cafferty, Marc Hammarlund, Stephen M Strittmatter
After traumatic damage of the brain or spinal cord, many surviving neurons are disconnected, and recovery of function is limited by poor axon regeneration. Recent data have suggested that poly ADP-ribosylation plays a role in limiting axonal regrowth such that inhibition of poly (ADP-ribose) polymerase (PARP) may have therapeutic efficacy for neurological recovery after trauma. Here, we tested systemic administration of the PARP inhibitor, veliparib, and showed effective suppression of PARylation in the mouse CNS...
November 2016: ENeuro
https://www.readbyqxmd.com/read/28031413/let-7-status-is-crucial-for-parp1-expression-in-her2-overexpressing-breast-tumors
#9
Monica E Wielgos, Rajani Rajbhandari, Tiffiny S Cooper, Shi Wei, Susan Nozell, Eddy S Yang
HER2(+) breast tumors have been shown to express elevated levels of PARP1 protein. Yet, the mechanism by which PARP1 is upregulated in HER2(+) breast cancer is unknown. Here, knockdown of HER2 (ERBB2) in HER2(+) breast cancer cells resulted in a reduction in PARP1 protein. Conversely, ectopic overexpression of HER2 in a non-HER2-overexpressing cell line resulted in increased PARP1 protein levels. Alterations in HER2 expression had no significant effect on PARP1 transcript levels. Instead, HER2 mRNA status was inversely correlated with let-7a miRNA levels in breast cancer cells...
March 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28001384/structural-basis-for-potency-and-promiscuity-in-poly-adp-ribose-polymerase-parp-and-tankyrase-inhibitors
#10
Ann-Gerd Thorsell, Torun Ekblad, Tobias Karlberg, Mirjam Löw, Ana Filipa Pinto, Lionel Trésaugues, Martin Moche, Michael S Cohen, Herwig Schüler
Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27998970/a-phase-i-trial-of-paclitaxel-cisplatin-and-veliparib-in-the-treatment-of-persistent-or-recurrent-carcinoma-of-the-cervix-an-nrg-oncology-study-nct-01281852
#11
P H Thaker, R Salani, W E Brady, H A Lankes, D E Cohn, D G Mutch, R S Mannel, K M Bell-McGuinn, P A Di Silvestro, D Jelovac, J S Carter, W Duan, K E Resnick, D S Dizon, C Aghajanian, P M Fracasso
Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled...
March 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27866910/proteome-wide-profiling-of-clinical-parp-inhibitors-reveals-compound-specific-secondary-targets
#12
Claire E Knezevic, Gabriela Wright, Lily L Remsing Rix, Woosuk Kim, Brent M Kuenzi, Yunting Luo, January M Watters, John M Koomen, Eric B Haura, Alvaro N Monteiro, Caius Radu, Harshani R Lawrence, Uwe Rix
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively...
December 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27831000/targeted-therapies-for-the-treatment-of-non-small-cell-lung-cancer-monoclonal-antibodies-and-biological-inhibitors
#13
REVIEW
Ana P S Silva, Priscila V Coelho, Maristella Anazetti, Patricia U Simioni
The usual treatments for patients with non-small-cell lung cancer (NSCLC), such as advanced lung adenocarcinoma, are unspecific and aggressive, and include lung resection, radiotherapy and chemotherapy. Recently, treatment with monoclonal antibodies and biological inhibitors has emerged as an effective alternative, generating effective results with few side effects. In recent years, several clinical trials using monoclonal antibodies presented potential benefits to NSCLC, and 4 of them are already approved for the treatment of NSCLC, such as cetuximab, bevacizumab, nivolumab and pembrolizumab...
April 3, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/27811964/the-poly-adp-ribose-polymerase-inhibitor-veliparib-and-radiation-cause-significant-cell-line-dependent-metabolic-changes-in-breast-cancer-cells
#14
Vijesh J Bhute, Yan Ma, Xiaoping Bao, Sean P Palecek
Breast tumors are characterized into subtypes based on their surface marker expression, which affects their prognosis and treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in clinical trials, both as single agents and in combination with other chemotherapeutics, in several subtypes of breast cancer patients. Here, we used NMR-based metabolomics to probe cell line-specific effects of the PARP inhibitor Veliparib and radiation on metabolism in three breast cancer cell lines...
November 4, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27803064/randomized-placebo-controlled-phase-ii-study-of-veliparib-in-combination-with-carboplatin-and-paclitaxel-for-advanced-metastatic-non-small-cell-lung-cancer
#15
Suresh S Ramalingam, Normand Blais, Julien Mazieres, Martin Reck, C Michael Jones, Erzsebet Juhasz, Laszlo Urban, Sergey Orlov, Fabrice Barlesi, Ebenezer Kio, Ulrich Keiholz, Qin Qin, Jiang Qian, Caroline Nickner, Juliann Dziubinski, Hao Xiong, Peter Ansell, Mark McKee, Vincent Giranda, Vera Gorbunova
Purpose: PARP plays an important role in DNA repair. Veliparib, a PARP inhibitor, enhances the efficacy of platinum compounds and has been safely combined with carboplatin and paclitaxel. The primary endpoint of this phase II trial determined whether addition of veliparib to carboplatin and paclitaxel improved progression-free survival (PFS) in previously untreated patients with advanced/metastatic non-small cell lung cancer.Experimental Design: Patients were randomized 2:1 to carboplatin and paclitaxel with either veliparib or placebo...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27739325/a-randomized-phase-ii-study-of-veliparib-with-temozolomide-or-carboplatin-paclitaxel-versus-placebo-with-carboplatin-paclitaxel-in-brca1-2-metastatic-breast-cancer-design-and-rationale
#16
RANDOMIZED CONTROLLED TRIAL
Steven J Isakoff, Shannon Puhalla, Susan M Domchek, Michael Friedlander, Bella Kaufman, Mark Robson, Melinda L Telli, Véronique Diéras, Hyo Sook Han, Judy E Garber, Eric F Johnson, David Maag, Qin Qin, Vincent L Giranda, Stacie P Shepherd
Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609)...
February 2017: Future Oncology
https://www.readbyqxmd.com/read/27716873/the-current-status-of-parp-inhibitors-in-ovarian-cancer
#17
REVIEW
Jennifer McLachlan, Angela George, Susana Banerjee
Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach...
October 13, 2016: Tumori
https://www.readbyqxmd.com/read/27709282/effect-of-veliparib-abt-888-on-cardiac-repolarization-in-patients-with-advanced-solid-tumors-a-randomized-placebo-controlled-crossover-study
#18
Wijith Munasinghe, Sven Stodtmann, Anthony Tolcher, Emiliano Calvo, Michael Gordon, Mathilde Jalving, Judith de Vos-Geelen, Diane Medina, Dennis Bergau, Silpa Nuthalapati, David Hoffman, Stacie Shepherd, Hao Xiong
PURPOSE: Veliparib (ABT-888) is an orally bioavailable potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and PARP-2. This phase 1 study evaluated the effect of veliparib on corrected QT interval using Fridericia's formula (QTcF). METHODS: Eligible patients with advanced solid tumors received single-dose oral veliparib (200 mg or 400 mg) or placebo in a 6-sequence, 3-period crossover design. The primary endpoint was the difference in the mean baseline-adjusted QTcF between 400 mg veliparib and placebo (∆∆QTcF) at six post-dose time points...
November 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27686254/the-poly-adp-ribosyl-ation-of-foxo3-mediated-by-parp1-participates-in-isoproterenol-induced-cardiac-hypertrophy
#19
Jing Lu, Renwei Zhang, Huiqi Hong, Zuolong Yang, Duanping Sun, Shuya Sun, Xiaolei Guo, Jiantao Ye, Zhuoming Li, Peiqing Liu
The Forkhead box-containing protein, O subfamily 3 (FoxO3) transcription factor negatively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, methylation and glycosylation. Here, we introduce a novel modification of the FoxO3 protein in cardiomyocytes: poly(ADP-ribosyl)ation (PARylation) mediated by poly(ADP-ribose) polymerase-1 (PARP1). This process catalyzes the NAD(+)-dependent synthesis of polymers of ADP-ribose (PAR) and their subsequent attachment to target proteins by PARPs...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27663478/promise-and-limits-of-the-cellsearch-platform-for-evaluating-pharmacodynamics-in-circulating-tumor-cells
#20
REVIEW
Lihua Wang, Priya Balasubramanian, Alice P Chen, Shivaani Kummar, Yvonne A Evrard, Robert J Kinders
Circulating tumor cells (CTCs), which are captured from blood with anti-epithelial cell adhesion molecule (EpCAM) antibodies, have established prognostic value in specific epithelial cancers, but less is known about their utility for assessing patient response to molecularly targeted agents via measurement of pharmacodynamic (PD) endpoints. We discuss the use of CellSearch (Janssen Diagnostics, LLC, Raritan, NJ) CTC isolation technology for monitoring PD response in early phase trials. We present representative data from three clinical trials with the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) suggesting that CTCs can be used to measure PD effects...
August 2016: Seminars in Oncology
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