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https://www.readbyqxmd.com/read/28893315/heterogeneous-drug-penetrance-of-veliparib-and-carboplatin-measured-in-triple-negative-breast-tumors
#1
Imke H Bartelink, Brendan Prideaux, Gregor Krings, Lisa Wilmes, Pei Rong Evelyn Lee, Pan Bo, Byron Hann, Jean-Philippe Coppé, Diane Heditsian, Lamorna Swigart-Brown, Ella F Jones, Sergey Magnitsky, Ron J Keizer, Niels de Vries, Hilde Rosing, Nela Pawlowska, Scott Thomas, Mallika Dhawan, Rahul Aggarwal, Pamela N Munster, Laura J Esserman, Weiming Ruan, Alan H B Wu, Douglas Yee, Véronique Dartois, Radojka M Savic, Denise M Wolf, Laura van 't Veer
BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS: MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice...
September 11, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28875097/sustained-long-term-maintenance-of-remission-with-single-agent-veliparib-in-recurrent-triple-negative-breast-cancer
#2
Karthik Kota, Shannon Puhalla
Triple-negative breast cancers (TNBC) have poorer outcomes than hormone positive or human epidermal growth factor receptor 2 (HER2)-positive breast cancers, with chemotherapy being the usual standard of care. Veliparib, a poly ADP-ribose polymerase (PARP) inhibitor, has been studied in both breast cancer susceptibility genes 1 and 2 (BRCA)-mutation related and sporadic cancers as a single agent and in combination with chemotherapy. Here, we describe a patient whose metastatic recurrence of TNBC was treated with combination chemotherapy and veliparib followed by maintenance single-therapy veliparib...
July 4, 2017: Curēus
https://www.readbyqxmd.com/read/28851423/the-brca1ness-signature-is-associated-significantly-with-response-to-parp-inhibitor-treatment-versus-control-in-the-i-spy-2-randomized-neoadjuvant-setting
#3
Tesa M Severson, Denise M Wolf, Christina Yau, Justine Peeters, Diederik Wehkam, Philip C Schouten, Suet-Feung Chin, Ian J Majewski, Magali Michaut, Astrid Bosma, Bernard Pereira, Tycho Bismeijer, Lodewyk Wessels, Carlos Caldas, René Bernards, Iris M Simon, Annuska M Glas, Sabine Linn, Laura van 't Veer
BACKGROUND: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. METHODS: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project...
August 25, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28837250/a-phase-1-study-of-veliparib-with-carboplatin-and-weekly-paclitaxel-in-japanese-patients-with-newly-diagnosed-ovarian-cancer
#4
Shin Nishio, Munetaka Takekuma, Satoshi Takeuchi, Kouichirou Kawano, Naotake Tsuda, Kazuto Tasaki, Nobutaka Takahashi, Masakazu Abe, Aki Tanaka, Takayuki Nagasawa, Tadahiro Shoji, Hao Xiong, Silpa Nuthalapati, Terri Leahy, Hideyuki Hashiba, Tsukasa Kiriyama, Philip Komarnitsky, Yasuyuki Hirashima, Kimio Ushijima
This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics, and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg twice daily on days 1-21 with carboplatin (area under the concentration-time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 3 weeks for up to 6 21-day cycles. Dose escalation followed a 3+3 design to determine dose-limiting toxicities, maximum tolerated dose, and the recommended phase 2 dose...
August 24, 2017: Cancer Science
https://www.readbyqxmd.com/read/28770300/phase-i-study-of-veliparib-in-combination-with-gemcitabine
#5
Ronald Stoller, John C Schmitz, Fei Ding, Shannon Puhalla, Chandra P Belani, Leonard Appleman, Yan Lin, Yixing Jiang, Salah Almokadem, Daniel Petro, Julianne Holleran, Brian F Kiesel, R Ken Czambel, Benedito A Carneiro, Emmanuel Kontopodis, Pamela A Hershberger, Madani Rachid, Alice Chen, Edward Chu, Jan H Beumer
BACKGROUND: Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine. METHODS: Patients with advanced solid tumors received veliparib (10-40-mg PO BID) on chemotherapy weeks with gemcitabine 500-750-mg/m(2) IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle)...
August 2, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28763368/veliparib-monotherapy-to-patients-with-brca-germ-line-mutation-and-platinum-resistant-or-partially-platinum-sensitive-relapse-of-epithelial-ovarian-cancer-a-phase-i-ii-study
#6
Karina Dahl Steffensen, Parvin Adimi, Anders Jakobsen
OBJECTIVE: A new treatment principle, which seems to radically change the treatment approach in ovarian cancer (OC), has developed over the past few years. Poly(ADP-ribose) polymerase inhibitors work by interfering with mechanisms important to DNA damage repair. Cancer cells that already have defects in the BRCA genes are particularly sensitive to treatment with poly(ADP-ribose) polymerase inhibitors. The main purpose of this study was to investigate the effect of veliparib in patients with known BRCA1/2 mutations and with a platinum-resistant or intermediate sensitive relapse of OC...
August 1, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28751440/exposure-response-of-veliparib-to-inform-phase%C3%A2-ii-trial-design-in-refractory-or-relapsed-patients-with-hematological-malignancies
#7
Shailly Mehrotra, Mathangi Gopalakrishnan, Jogarao Gobburu, Jiuping Jay Ji, Jacqueline M Greer, Richard L Piekarz, Judith Karp, Keith W Pratz, Michelle A Rudek
Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure-response analysis to inform the phase II trial design. <p>Experimental Design: Pharmacokinetic, efficacy and safety data from 95 patients, who were administered 10 to 100 mg BID doses of veliparib for either 8, 14 or 21 days with T+C, were utilized for exposure-efficacy (objective response and overall survival) and exposure-safety (≥Grade 3  mucositis) analysis...
July 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28725277/sabcs-2016-systemic-therapy-for-metastatic-breast-cancer
#8
REVIEW
Simon Peter Gampenrieder, Gabriel Rinnerthaler, Richard Greil
At the 2016 San Antonio Breast Cancer Symposium, several interesting phase II and phase III studies investigating systemic therapies for metastatic breast cancer were presented. The PrEGOC 0102 trial demonstrated that the combination of fulvestrant plus everolimus is safe and effective and could be an alternative to exemestane plus everolimus for selected patients with hormone-receptor positive, HER2-negative disease. The pan-PI3K inhibitor buparlisib showed some activity in combination with fulvestrant after failure of everolimus in the BELLE-3 trial...
2017: Memo
https://www.readbyqxmd.com/read/28723663/a-network-meta-analysis-on-the-efficacy-of-targeted-agents-in-combination-with-chemotherapy-for-treatment-of-advanced-metastatic-triple-negative-breast-cancer
#9
Long Ge, Yan Tang, Qiu-Ning Zhang, Jin-Hui Tian, Xiao-Hu Wang, Dawid Pieper, Bei Pan, Lun Li, Juan Ling, Zhi-Tong Bing, Ke-Hu Yang
OBJECTIVE: Our network meta-analysis aimed to determine the assistant efficacy of targeted therapy in combined with chemotherapy for advanced/metastatic triple-negative breast cancer (TNBC). RESULTS: A total of 15 randomized controlled trials (RCTs), involving 2,410 patients, met our inclusion criteria. Eight targeted agents involving 11 treatment arms were included. The methodological quality of included RCTs was acceptable. The results of direct comparisons showed that progression-free survival (PFS) was significantly longer with bevacizumab+chemotherapy when compared to chemotherapy alone (hazard ratio [HR] = 0...
July 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28665051/phase-1-dose-escalation-study-of-single-agent-veliparib-in-japanese-patients-with-advanced-solid-tumors
#10
Tadaaki Nishikawa, Koji Matsumoto, Kenji Tamura, Hiroyuki Yoshida, Yuichi Imai, Aki Miyasaka, Takuma Onoe, Satoshi Yamaguchi, Chikako Shimizu, Kan Yonemori, Tatsunori Shimoi, Mayu Yunokawa, Hao Xiong, Silpa Nuthalapati, Hideyuki Hashiba, Tsukasa Kiriyama, Terri Leahy, Philip Komarnitsky, Keiichi Fujiwara
Veliparib (ABT-888) is a potent, orally bioavailable poly(ADP-ribose) polymerase-1 and -2 inhibitor. This phase 1 study evaluated the tolerability, pharmacokinetic profile, safety, and preliminary antitumor activity of single-agent veliparib in Japanese patients with advanced solid tumors. Eligible patients were assigned to treatment with veliparib at 200 or 400 mg dose; veliparib was self-administered orally twice daily on days 1-28 of 28-day cycles. Dose escalation, following a 3 + 3 design, defined dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose...
September 2017: Cancer Science
https://www.readbyqxmd.com/read/28497757/safety-and-tolerability-of-veliparib-combined-with-capecitabine-plus-radiotherapy-in-patients-with-locally-advanced-rectal-cancer-a-phase-1b-study
#11
Brian G Czito, Dustin A Deming, Gayle S Jameson, Mary F Mulcahy, Houman Vaghefi, Matthew W Dudley, Kyle D Holen, Angela DeLuca, Rajendar K Mittapalli, Wijith Munasinghe, Lei He, John R Zalcberg, Samuel Y Ngan, Philip Komarnitsky, Michael Michael
BACKGROUND: Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. METHODS: This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA)...
June 2017: Lancet. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28497258/clinical-pharmacokinetics-and-mass-balance-of-veliparib-in-combination-with-temozolomide-in-subjects-with-nonhematologic-malignancies
#12
Silpa Nuthalapati, Wijith Munasinghe, Vincent Giranda, Hao Xiong
BACKGROUND AND OBJECTIVES: Veliparib is an orally active potent poly(ADP-ribose) polymerase (PARP) inhibitor currently in phase III clinical trials in solid tumors. This phase I study evaluated the pharmacokinetics and mass balance of veliparib administered alone and in combination with temozolomide, and assessed any potential pharmacokinetic drug-drug interaction between veliparib and temozolomide. METHODS: This was an open-label, dose-escalation study of veliparib in combination with temozolomide in 42 subjects with nonhematologic malignancies...
May 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28461256/smoking-history-predicts-sensitivity-to-parp-inhibitor%C3%A2-veliparib-in-patients-with-advanced-non-small-cell-lung-cancer
#13
Martin Reck, Normand Blais, Erzsebet Juhasz, Vera Gorbunova, C Michael Jones, Laszlo Urban, Sergey Orlov, Fabrice Barlesi, Ebenezer Kio, Ulrich Keilholz, Qin Qin, Jiang Qian, Caroline Nickner, Juliann Dziubinski, Hao Xiong, Rajendar K Mittapalli, Martin Dunbar, Peter Ansell, Lei He, Mark McKee, Vincent Giranda, Suresh S Ramalingam
INTRODUCTION: Tobacco-related NSCLC is associated with reduced survival and greater genomic instability. Veliparib, a potent poly(adenosine diphosphate-ribose) polymerase inhibitor, augments platinum-induced DNA damage. A phase 2 trial of untreated advanced NSCLC showed a trend for improved outcomes (hazard ratio [HR] = 0.80, 95% confidence interval: 0.54-1.18, p = 0.27 for overall survival and HR = 0.72, 95% CI: 0.45-1.15, p = 0.17 for progression-free survival) when veliparib was added to carboplatin/paclitaxel...
July 2017: Journal of Thoracic Oncology
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
#14
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)...
August 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-california-cancer-consortium-trial-nct01149083
#15
George Somlo, Paul H Frankel, Banu K Arun, Cynthia X Ma, Agustin A Garcia, Tessa Cigler, Leah V Cream, Harold A Harvey, Joseph A Sparano, Rita Nanda, Helen K Chew, Timothy J Moynihan, Linda T Vahdat, Matthew P Goetz, Jan H Beumer, Arti Hurria, Joanne Mortimer, Richard Piekarz, Sharon Sand, Josef Herzog, Lily R Van Tongeren, Katherine V Ferry-Galow, Alice P Chen, Christopher Ruel, Edward M Newman, David R Gandara, Jeffrey N Weitzel
Purpose: We aimed to establish the 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 after progression, and to correlate PAR levels with clinical outcome.Experimental Design: Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib...
August 1, 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
#16
Jacob D Soumerai, Andrew D Zelenetz, Craig H Moskowitz, M Lia Palomba, Paul A Hamlin, Ariela Noy, David J Straus, Alison J Moskowitz, Anas Younes, Matthew J Matasar, Steven M Horwitz, Carol S Portlock, Jason A 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 I 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 twice a day, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m(2) intravenously, days 1 and 2)...
August 1, 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
#17
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
#18
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)...
June 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-haematological-malignancies
#19
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 leukaemia, 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...
August 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
#20
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
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