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https://www.readbyqxmd.com/read/29397193/the-poly-adp-ribose-polymerase-inhibitor-niraparib-management-of-toxicities
#1
Kathleen N Moore, Mansoor Raza Mirza, Ursula A Matulonis
Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA...
January 31, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29361470/prexasertib-a-cell-cycle-checkpoint-kinase-1-and-2-inhibitor-in-brca-wild-type-recurrent-high-grade-serous-ovarian-cancer-a-first-in-class-proof-of-concept-phase-2-study
#2
Jung-Min Lee, Jayakumar Nair, Alexandra Zimmer, Stanley Lipkowitz, Christina M Annunziata, Maria J Merino, Elizabeth M Swisher, Maria I Harrell, Jane B Trepel, Min-Jung Lee, Mohammad H Bagheri, Dana-Adriana Botesteanu, Seth M Steinberg, Lori Minasian, Irene Ekwede, Elise C Kohn
BACKGROUND: High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. METHODS: In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma...
January 17, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29352572/phase-i-combination-study-of-the-parp-inhibitor-veliparib-plus-carboplatin-and-gemcitabine-in-patients-with-advanced-ovarian-cancer-and-other-solid-malignancies
#3
Heidi J Gray, Katherine Bell-McGuinn, Gini F Fleming, Mihaela Cristea, Hao Xiong, Danielle Sullivan, Yan Luo, Mark D McKee, Wijith Munasinghe, Lainie P Martin
OBJECTIVE: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. METHODS: In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m2 on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy...
January 15, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29338080/phase-1-trial-evaluating-cisplatin-gemcitabine-and-veliparib-in-2-patient-cohorts-germline-brca-mutation-carriers-and-wild-type-brca-pancreatic-ductal-adenocarcinoma
#4
Eileen M O'Reilly, Jonathan W Lee, Maeve A Lowery, Marinela Capanu, Zsofia K Stadler, Malcolm J Moore, Neesha Dhani, Hedy L Kindler, Hayley Estrella, Hannah Maynard, Talia Golan, Amiel Segal, Erin E Salo-Mullen, Kenneth H Yu, Andrew S Epstein, Michal Segal, Robin Brenner, Richard K Do, Alice P Chen, Laura H Tang, David P Kelsen
BACKGROUND: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1...
January 16, 2018: Cancer
https://www.readbyqxmd.com/read/29238749/a-feasibility-study-of-neoadjuvant-talazoparib-for-operable-breast-cancer-patients-with-a-germline-brca-mutation-demonstrates-marked-activity
#5
J K Litton, M Scoggins, D L Ramirez, R K Murthy, G J Whitman, K R Hess, B E Adrada, S L Moulder, C H Barcenas, V Valero, J Schwartz Gomez, E A Mittendorf, A Thompson, T Helgason, G B Mills, H Piwnica-Worms, B K Arun
This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/29194191/brca-mutation-status-is-not-associated-with-increased-hematologic-toxicity-among-patients-undergoing-platinum-based-chemotherapy-for-ovarian-cancer
#6
Joanne Kotsopoulos, Karla Willows, Sandra Trat, Raymond H Kim, Alexandra Volenik, Ping Sun, Steven A Narod, Jeffrey Boyd, Taymaa May
OBJECTIVE: Women with an inherited BRCA1 or BRCA2 mutation may have an impaired ability to repair chemotherapy-induced damage as a result of a state of haploinsufficiency and may experience greater treatment-related toxicity. The objective of this study was to compare the hematologic adverse effect profiles associated with platinum-based chemotherapy in ovarian cancer patients with and without germline BRCA mutations. METHODS: We conducted a retrospective analysis of patients treated for high-grade serous ovarian cancer at Princess Margaret Cancer Center, Toronto, Ontario between January 2000 and December 2015...
November 30, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/29108297/phase-i-ib-study-of-olaparib-and-carboplatin-in-women-with-triple-negative-breast-cancer
#7
Jung-Min Lee, John L Hays, Victoria L Chiou, Christina M Annunziata, Elizabeth M Swisher, Maria I Harrell, Minshu Yu, Nicolas Gordon, Tristan M Sissung, Jiuping Ji, William D Figg, Lori Minasian, Stanley Lipkowitz, Bradford J Wood, James Doroshow, Elise C Kohn
PURPOSE: To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ≤ 8 cycles, with olaparib 400mg bid maintenance...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29045554/veliparib-with-temozolomide-or-carboplatin-paclitaxel-versus-placebo-with-carboplatin-paclitaxel-in-patients-with-brca1-2-locally-recurrent-metastatic-breast-cancer-randomized-phase-ii-study
#8
H S Han, V Diéras, M Robson, M Palácová, P K Marcom, A Jager, I Bondarenko, D Citrin, M Campone, M L Telli, S M Domchek, M Friedlander, B Kaufman, J E Garber, Y Shparyk, E Chmielowska, E H Jakobsen, V Kaklamani, W Gradishar, C K Ratajczak, C Nickner, Q Qin, J Qian, S P Shepherd, S J Isakoff, S Puhalla
Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, which interfere with DNA damage repair. Veliparib, a potent PARP inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer...
September 29, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28935542/phase-i-trial-of-veliparib-a-poly-adp-ribose-polymerase-inhibitor-plus-metronomic-cyclophosphamide-in-metastatic-her2-negative-breast-cancer
#9
Jesus Anampa, Alice Chen, John Wright, Margi Patel, Christine Pellegrino, Karen Fehn, Joseph A Sparano, Eleni Andreopoulou
BACKGROUND: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. METHODS: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer...
September 1, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/28637614/classical-inherited-bone-marrow-failure-syndromes-with-high-risk-for-myelodysplastic-syndrome-and-acute-myelogenous-leukemia
#10
REVIEW
Sharon A Savage, Carlo Dufour
The inherited marrow failure syndromes (IBMFS) are a heterogeneous group of diseases characterized by failure in the production of one or more blood lineage. The clinical manifestations of the IBMFS vary according to the type and number of blood cell lines involved, including different combinations of anemia, leukopenia, and thrombocytopenia. In some IBMFS, systemic non-hematologic manifestations, including congenital malformations, mucocutaneous abnormalities, developmental delay, and other medical complications, may be present...
April 2017: Seminars in Hematology
https://www.readbyqxmd.com/read/28454122/olaparib-in-combination-with-irinotecan-cisplatin-and-mitomycin-c-in-patients-with-advanced-pancreatic-cancer
#11
Mark Yarchoan, Melinda C Myzak, Burles A Johnson, Ana De Jesus-Acosta, Dung T Le, Elizabeth M Jaffee, Nilofer S Azad, Ross C Donehower, Lei Zheng, Paul E Oberstein, Robert L Fine, Daniel A Laheru, Michael Goggins
BACKGROUND: Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC)...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28388551/phase-i-ib-study-of-olaparib-and-carboplatin-in-women-with-triple-negative-breast-cancer
#12
Jung-Min Lee, John L Hays, Victoria L Chiou, Christina M Annunziata, Elizabeth M Swisher, Maria I Harrell, Minshu Yu, Nicolas Gordon, Tristan M Sissung, Jiuping Ji, William D Figg, Lori Minasian, Stanley Lipkowitz, Bradford J Wood, James Doroshow, Elise C Kohn
PURPOSE: To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ≤ 8 cycles, with olaparib 400mg bid maintenance...
March 25, 2017: Oncotarget
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
#13
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/27717299/niraparib-maintenance-therapy-in-platinum-sensitive-recurrent-ovarian-cancer
#14
RANDOMIZED CONTROLLED TRIAL
Mansoor R Mirza, Bradley J Monk, Jørn Herrstedt, Amit M Oza, Sven Mahner, Andrés Redondo, Michel Fabbro, Jonathan A Ledermann, Domenica Lorusso, Ignace Vergote, Noa E Ben-Baruch, Christian Marth, Radosław Mądry, René D Christensen, Jonathan S Berek, Anne Dørum, Anna V Tinker, Andreas du Bois, Antonio González-Martín, Philippe Follana, Benedict Benigno, Per Rosenberg, Lucy Gilbert, Bobbie J Rimel, Joseph Buscema, John P Balser, Shefali Agarwal, Ursula A Matulonis
BACKGROUND: Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS: In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily...
December 1, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27663600/sequence-specific-pharmacokinetic-and-pharmacodynamic-phase-i-ib-study-of-olaparib-tablets-and-carboplatin-in-women-s-cancer
#15
Jung-Min Lee, Cody J Peer, Minshu Yu, Lauren Amable, Nicolas Gordon, Christina M Annunziata, Nicole Houston, Andrew K L Goey, Tristan M Sissung, Bernard Parker, Lori Minasian, Victoria L Chiou, Robert F Murphy, Brigitte C Widemann, William D Figg, Elise C Kohn
Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination.Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1-7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance...
March 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26801247/phase-i-study-of-veliparib-abt-888-combined-with-cisplatin-and-vinorelbine-in-advanced-triple-negative-breast-cancer-and-or-brca-mutation-associated-breast-cancer
#16
Eve T Rodler, Brenda F Kurland, Melissa Griffin, Julie R Gralow, Peggy Porter, Rosa F Yeh, Vijayakrishna K Gadi, Jamie Guenthoer, Jan H Beumer, Larissa Korde, Sandra Strychor, Brian F Kiesel, Hannah M Linden, John A Thompson, Elizabeth Swisher, Xiaoyu Chai, Stacie Shepherd, Vincent Giranda, Jennifer M Specht
PURPOSE: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. EXPERIMENTAL DESIGN: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m(2) day 1) and vinorelbine (25 mg/m(2) days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy...
June 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25899311/olaparib-a-review-of-its-use-as-maintenance-therapy-in-patients-with-ovarian-cancer
#17
REVIEW
James E Frampton
Olaparib (Lynparza™) is a first-in-class, orally-active, small molecule, poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. In the EU, the capsule formulation of olaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive, relapsed, BRCA-mutated (germline and/or somatic), high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy...
April 2015: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/25818403/a-phase-ii-evaluation-of-the-potent-highly-selective-parp-inhibitor-veliparib-in-the-treatment-of-persistent-or-recurrent-epithelial-ovarian-fallopian-tube-or-primary-peritoneal-cancer-in-patients-who-carry-a-germline-brca1-or-brca2-mutation-an-nrg-oncology
#18
MULTICENTER STUDY
Robert L Coleman, Michael W Sill, Katherine Bell-McGuinn, Carol Aghajanian, Heidi J Gray, Krishnansu S Tewari, Steven C Rubin, Thomas J Rutherford, John K Chan, Alice Chen, Elizabeth M Swisher
BACKGROUND: Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA). METHODS: Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400mg orally BID with one cycle being 28days...
June 2015: Gynecologic Oncology
https://www.readbyqxmd.com/read/25481791/olaparib-combined-with-chemotherapy-for-recurrent-platinum-sensitive-ovarian-cancer-a-randomised-phase-2-trial
#19
RANDOMIZED CONTROLLED TRIAL
Amit M Oza, David Cibula, Ana Oaknin Benzaquen, Christopher Poole, Ron H J Mathijssen, Gabe S Sonke, Nicoletta Colombo, Jiří Špaček, Peter Vuylsteke, Holger Hirte, Sven Mahner, Marie Plante, Barbara Schmalfeldt, Helen Mackay, Jacqui Rowbottom, Elizabeth S Lowe, Brian Dougherty, J Carl Barrett, Michael Friedlander
BACKGROUND: The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. METHODS: In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group)...
January 2015: Lancet Oncology
https://www.readbyqxmd.com/read/25001612/tbcrc-018-phase-ii-study-of-iniparib-in-combination-with-irinotecan-to-treat-progressive-triple-negative-breast-cancer-brain-metastases
#20
Carey Anders, Allison M Deal, Vandana Abramson, Minetta C Liu, Anna M Storniolo, John T Carpenter, Shannon Puhalla, Rita Nanda, Amal Melhem-Bertrandt, Nancy U Lin, P Kelly Marcom, Catherine Van Poznak, Vered Stearns, Michelle Melisko, J Keith Smith, Olga Karginova, Joel Parker, Jonathan Berg, Eric P Winer, Amy Peterman, Aleix Prat, Charles M Perou, Antonio C Wolff, Lisa A Carey
Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks...
August 2014: Breast Cancer Research and Treatment
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