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Taofeek K Owonikoko - One of the best experts on this subject based on the ideXlab platform.
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patient reported tolerability of Veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer neurotoxicity and adherence data from the ecog acrin cancer research group e2511 phase ii randomized trial
Cancer Medicine, 2020Co-Authors: Laurie E Mclouth, Fengmin Zhao, Taofeek K Owonikoko, Josephine Feliciano, Nisha Mohindra, Suzanne E Dahlberg, James L Wade, Gordan Srkalovic, Bradley Walter Lash, Joseph W LeachAbstract:Objectives The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of Veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the Veliparib arm, and tolerability of the addition of Veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared. Materials and methods Patients randomized to Veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms. Results and conclusion No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the Veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of Veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS. Gov identifier NCT01642251.
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randomized double blind phase ii study of temozolomide in combination with either Veliparib or placebo in patients with relapsed sensitive or refractory small cell lung cancer
Journal of Clinical Oncology, 2018Co-Authors: Catherine M Pietanza, Taofeek K Owonikoko, Saiama N Waqar, Lee M Krug, Afshin Dowlati, Christine L Hann, Alberto Chiappori, Kaitlin M Woo, Robert J Cardnell, Junya FujimotoAbstract:Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor Veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral Veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m2/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of Veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/Veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/Veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/Veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/Veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/Veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/Veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/Veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.
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randomized phase ii trial of cisplatin and etoposide in combination with Veliparib or placebo for extensive stage small cell lung cancer ecog acrin 2511 study
Journal of Clinical Oncology, 2017Co-Authors: Taofeek K Owonikoko, Suzanne E Dahlberg, James L Wade, Gordan Srkalovic, Bradley Walter Lash, Joseph W Leach, Gabriel Sica, Lynne I Wagner, Ticiana Leal, Charu AggarwalAbstract:PurposeVeliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of Veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC).Materials and MethodsPatients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with Veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate.ResultsA total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 f...
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a multi center randomized double blind phase ii study comparing temozolomide tmz plus either Veliparib abt 888 a parp inhibitor or placebo as 2nd or 3rd line therapy for patients pts with relapsed small cell lung cancers sclcs
Journal of Clinical Oncology, 2016Co-Authors: Maria Catherine Pietanza, Taofeek K Owonikoko, Saiama N Waqar, Lee M Krug, Afshin Dowlati, Christine L Hann, Alberto Chiappori, Kaitlin M Woo, Yevgeniya Bensman, Brenda HurtadoAbstract:8512Background: Preclinical data indicate that the combination of Veliparib, an oral PARP-1/2 inhibitor, and TMZ result in synergistic tumor growth delay or regression. We hypothesized that adding Veliparib to TMZ will improve outcomes in pts with relapsed sensitive and refractory SCLCs. Methods: Relapsed SCLC pts treated with 1 or 2 prior regimens were randomized 1:1 to receive oral TMZ 150-200mg/m2/day on days 1-5 of a 28-day cycle along with either Veliparib or placebo 40mg twice daily, orally, on days 1-7. Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in pts with sensitive disease (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Correlative studies included immunohistochemistry to evaluate MGMT and PARP and circulating tumor cell enumeration. Results: Between Aug 2012 and Feb 2015, 104 pts were enrolled and 100 pts were treated. Baseline characteristics were balanced b...
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a phase 1 safety study of Veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer a trial of the ecog acrin cancer research group e2511
Lung Cancer, 2015Co-Authors: Taofeek K Owonikoko, Chandra P Belani, Suzanne E Dahlberg, Christine L Hann, Saad A Khan, David E Gerber, Jonathan E Dowell, Rebecca A Moss, Charu Aggarwal, Suresh S RamalingamAbstract:Objectives Veliparib (V) potentiated therapeutic efficacy of cisplatin (C) and etoposide (E) in preclinical models of SCLC. We conducted this phase 1 study to establish the safety of the combination in human subjects.
Melinda L Telli - One of the best experts on this subject based on the ideXlab platform.
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abstract es12 1 clinical indications of parp1 inhibitors and other targets
Cancer Research, 2020Co-Authors: Melinda L TelliAbstract:Two PARP1 inhibitors, olaparib and talazoparib, garnered regulatory approvals for the treatment of advanced HER2-negative breast cancer associated with a germline BRCA1 or BRCA2 mutation in 2018. The approvals were based on a prolongation of progression-free survival with PARP inhibitor monotherapy compared to non-DNA damaging single agent chemotherapy in the 1st - 4th line metastatic setting. While the availability of these therapies has increased therapeutic options for this group of patients, median progression-free survival ranged from 7 - 8.6 months and no overall survival advantage has been observed to date. While response rates with PARP inhibitor monotherapy are high, development of resistance remains a significant clinical problem. Further, how PARP inhibitor monotherapy compares with platinum-based chemotherapy in this group of patients has been unclear. The recently reported phase III BROCADE 3 clinical trial examining carboplatin and paclitaxel with the addition of Veliparib or placebo added important insights. This was the first phase III trial in patients with advanced germline BRCA1 and BRCA2 mutation-associated HER2-negative breast cancer that examined the use of a PARP inhibitor combined with DNA damaging chemotherapy in the 1st-3rd line setting followed by blinded monotherapy after discontinuation of chemotherapy. The median progression-free survival was significantly prolonged with the addition of Veliparib (14.5 versus 12.6 months) with 26% of patients in the Veliparib arm remaining progression-free at 36 months. Median overall survival was 33.5 months in the Veliparib arm compared to 28.2 months in placebo with 44% of patients in the placebo arm crossing over to receive Veliparib after disease progression. While important differences exist between these three trials, BROCADE 3 has reported the longest progression-free and overall survival to date with PARP inhibitor therapy in advanced germline BRCA1 and BRCA2 mutation-associated breast cancer. Beyond BRCA1 and BRCA2, PARP inhibitors are also being investigated in homologous recombination deficient advanced breast cancer in a number of clinical trials. In the Talazoparib Beyond BRCA study, high clinical activity was noted in germline PALB2 mutation carriers. The Olaparib Expanded trial is ongoing. Citation Format: ML Telli. Clinical indications of PARP1 inhibitors and other targets [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES12-1.
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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
Annals of Oncology, 2018Co-Authors: H S Han, V Dieras, Mark E Robson, M Palacova, P K Marcom, Agnes Jager, Igor Bondarenko, D Citrin, Mario Campone, Melinda L TelliAbstract:ABSTRACT Background Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase 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. Patients and methods Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1:1:1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536–1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503–1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278–2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032–2.131; P = 0.032), and ORR 28.6% (P Conclusion Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of Veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with Veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information NCT01506609
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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
Annals of Oncology, 2018Co-Authors: H S Han, V Dieras, Mark E Robson, M Palacova, P K Marcom, Agnes Jager, Igor Bondarenko, D Citrin, Mario Campone, Melinda L TelliAbstract:Background:Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase 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. Patients and methods:Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results:Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion:Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of Veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with Veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information:NCT01506609.
Douglas A Levine - One of the best experts on this subject based on the ideXlab platform.
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abstract 335 variable off target effects of clinically advanced parp inhibitors
Cancer Research, 2018Co-Authors: Monica E Wielgos, Petar Jelinic, Jay R Patibandla, Michelle Firlit, Elke Van Oudenhove, Paulina Cybulska, Douglas A LevineAbstract:High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of ovarian cancer with low 5-year survival rates. Inhibitors of poly (ADP-ribose) polymerase (PARP) are promising novel agents that uniquely target HGSOCs with DNA repair deficiencies. The majority of patients with DNA repair proficient HGSOCs do not respond to PARP inhibitor monotherapy, highlighting the need for novel treatment approaches for these women. The goal of this study was to expand the patient population that could benefit from PARP inhibition by identifying the off-target effects that are favorable in combination with CHK1 inhibitors among the five most clinically advanced PARP inhibitors. Cell cycle and western blot analysis revealed that the four most potent PARP trappers (rucaparib, olaparib, niraparib, and talazoparib) have a strong effect on the cell cycle. The PARP trappers in particular activated CHK1 through phosphorylation at the serine 345 residue, decreased total protein levels of CDC25C, and arrested cells in the S/G2 phase of the cell cycle. These results were not observed after treatment with Veliparib, the least potent PARP trapper. We created phospo-CHK1 mutants to confirm CHK1 activation at serine 345 and to further investigate whether potent PARP trappers activate CHK1 on serine 317, another residue that is also phosphorylated in response to replication stress. The data suggest that PARP trappers activate CHK1 at both the serine 317 and 345 phosphorylation sites. Next, we examined whether PARP inhibition-induced activation of CHK1 is a determinant of synergy between PARP and CHK1 inhibitors. We exposed one of our established BRCA wild-type, TP53 mutant HGSOC patient-derived xenograft models to a PARP1 inhibitor (Veliparib or talazoparib) or to the CHK1 inhibitor (MK-8776) or a combination of PARP and CHK1 inhibitors. CHK1 inhibition slightly increased sensitivity to talazoparib compared to single agent therapy. However, the tumor volume was significantly reduced by the combination of CHK1 inhibition and Veliparib treatment compared to either single agent alone. This study suggests that there are off-target cell cycle effects that vary among the five most clinically-advanced PARP inhibitors that likely influence the response to combinatorial treatment. We propose the use of PARP and CHK1 inhibition as a strategy for HGSOC patients who would otherwise have minimal benefit to PARP inhibitor monotherapy. Citation Format: Monica E. Wielgos, Jay Patibandla, Michelle Firlit, Elke Van Oudenhove, Paulina Cybulska, Petar Jelinic, Douglas A. Levine. Variable off-target effects of clinically advanced PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 335.
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new insights into parp inhibitors effect on cell cycle and homology directed dna damage repair
Molecular Cancer Therapeutics, 2014Co-Authors: Petar Jelinic, Douglas A LevineAbstract:In preclinical and clinical studies, olaparib and Veliparib are the most represented PARP inhibitors (PARPi), which mainly target homologous DNA damage repair pathway-deficient cancer cells. Their off-target effects are not fully understood, especially with regard to cell cycle and homology-directed DNA damage repair. Our objective was to comparatively evaluate olaparib and Veliparib in this context and correlate our findings with their therapeutic potential. We used a well-established direct repeat GFP (DR-GFP) reporter assay in U2OS(DR-GFP) and H1299(DR-GFP) cells and measured DNA damage repair activity upon drug treatment. Olaparib-treated U2OS(DR-GFP) cells showed a dramatic decrease in DNA damage repair versus Veliparib irrespective of inhibitory potency. We demonstrate that this effect was a result of olaparib's strong effect on the cell cycle. Unlike in Veliparib-treated U2OS(DR-GFP) cells, in olaparib-treated cells S-phase decreased and G(2)-phase increased sharply, indicating a G(2)-phase arrest-like state and replicative stress. This was further confirmed by upregulation of p53 and p21 and accumulation of cyclin A. Lack of the same effect in p53-null H1299(DR-GFP) cells suggested that olaparib's effect is p53 related, which was confirmed in p53-depleted U2OS(DR-GFP) and p53-null HCT116 cells. Importantly, we also demonstrate that olaparib, but not Veliparib, induced a robust phosphorylation of Chk1, a crucial component of the replicative stress response pathway. Our data show olaparib and Veliparib differ in their off-target effects; olaparib, unlike Veliparib, mitigates DNA damage repair activity via G(2) cell-cycle arrest-like effect in a p53-dependent manner. These off-target effects may add to PARPis' anticancer properties.
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new insights into parp inhibitors effect on cell cycle and homology directed dna damage repair
Molecular Cancer Therapeutics, 2014Co-Authors: Petar Jelinic, Douglas A LevineAbstract:In preclinical and clinical studies, olaparib and Veliparib are the most represented PARP inhibitors (PARPi), which mainly target homologous DNA damage repair pathway-deficient cancer cells. Their off-target effects are not fully understood, especially with regard to cell cycle and homology-directed DNA damage repair. Our objective was to comparatively evaluate olaparib and Veliparib in this context and correlate our findings with their therapeutic potential. We used a well-established direct repeat GFP (DR-GFP) reporter assay in U2OSDR-GFP and H1299DR-GFP cells and measured DNA damage repair activity upon drug treatment. Olaparib-treated U2OSDR-GFP cells showed a dramatic decrease in DNA damage repair versus Veliparib irrespective of inhibitory potency. We demonstrate that this effect was a result of olaparib's strong effect on the cell cycle. Unlike in Veliparib-treated U2OSDR-GFP cells, in olaparib-treated cells S-phase decreased and G2-phase increased sharply, indicating a G2-phase arrest-like state and replicative stress. This was further confirmed by upregulation of p53 and p21 and accumulation of cyclin A. Lack of the same effect in p53-null H1299DR-GFP cells suggested that olaparib's effect is p53 related, which was confirmed in p53-depleted U2OSDR-GFP and p53-null HCT116 cells. Importantly, we also demonstrate that olaparib, but not Veliparib, induced a robust phosphorylation of Chk1, a crucial component of the replicative stress response pathway. Our data show olaparib and Veliparib differ in their off-target effects; olaparib, unlike Veliparib, mitigates DNA damage repair activity via G2 cell-cycle arrest-like effect in a p53-dependent manner. These off-target effects may add to PARPis' anticancer properties. Mol Cancer Ther; 13(6); 1645–54. ©2014 AACR .
Kathleen N. Moore - One of the best experts on this subject based on the ideXlab platform.
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A phase I study of intravenous or intraperitoneal platinum based chemotherapy in combination with Veliparib and bevacizumab in newly diagnosed ovarian, primary peritoneal and fallopian tube cancer.
Gynecologic oncology, 2019Co-Authors: Kathleen N. Moore, Russell J. Schilder, Austin Miller, Katherine M. Bell-mcguinn, Joan L. Walker, Roisin E. O'cearbhaill, Saketh R. Guntupalli, Deborah K. Armstrong, Andrea R. Hagemann, Heidi J. GrayAbstract:Abstract Background Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi Veliparib in combination with chemotherapy for EOC. Methods A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1–2. Once Findings Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg Veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. Interpretation The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). Funding National Cancer Institute.
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Veliparib with first line chemotherapy and as maintenance therapy in ovarian cancer
The New England Journal of Medicine, 2019Co-Authors: Robert L Coleman, Kathleen N. Moore, Gini F Fleming, Mark F Brady, Elizabeth Swisher, Karina Dahl Steffensen, Michael Friedlander, Aikou Okamoto, Noa Benbaruch, Theresa L WernerAbstract:Abstract Background Data are limited regarding the use of poly(adenosine diphosphate [ADP]–ribose) polymerase inhibitors, such as Veliparib, in combination with chemotherapy followed by maintenance...
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a phase i trial of pegylated liposomal doxorubicin pld carboplatin bevacizumab and Veliparib in recurrent platinum sensitive ovarian primary peritoneal and fallopian tube cancer an nrg oncology gynecologic oncology group study
Gynecologic Oncology, 2015Co-Authors: Lisa M Landrum, Kathleen N. Moore, Deborah K. Armstrong, William E Brady, Paul Disilvestro, David M Omalley, Meaghan Tenney, Peter G Rose, Paula M FracassoAbstract:Objective To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab.
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a phase i ii evaluation of Veliparib nsc 737664 topotecan and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix an nrg oncology gynecologic oncology group study
International Journal of Gynecological Cancer, 2015Co-Authors: Charles A. Kunos, Heidi J. Gray, Wei Deng, Dawn M Dawson, Jayanthi S Lea, Kristine M Zanotti, David P Bender, Perry P Guaglianone, Jori S Carter, Kathleen N. MooreAbstract:Purpose The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by Veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. Experimental Design This phase I-II trial examined twice-daily oral Veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m2) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. Results Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%–22%]). Four patients had a disease progression date more than 6 months after the start of Veliparib-topotecan therapy. Patients with low immunohistochemical expression (0–1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after Veliparib-topotecan therapy. Conclusions Clinical activity of a Veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.
Ian F Pollack - One of the best experts on this subject based on the ideXlab platform.
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a phase i trial of Veliparib abt 888 and temozolomide in children with recurrent cns tumors a pediatric brain tumor consortium report
Neuro-oncology, 2014Co-Authors: Patrick A Thompson, Arzu Onarthomas, Adekunle M Adesina, Lindsay Kilburn, Mehmet Kocak, Brenda Chyla, Evelyn M Mckeegan, Katherine E Warren, Stewart Goldman, Ian F PollackAbstract:Most cytotoxic chemotherapy drugs induce single-strand DNA breaks, and radiation treatment induces double-strand DNA breaks. Repair of single-strand DNA breaks is mediated by multiple mechanisms, including the base-excision repair pathway, while double-strand DNA breaks are repaired by the homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways.1,2 Poly(ADP-ribose) polymerase (PARP) recognizes single- and double-strand DNA breaks3 and recruits and activates repair proteins from the base-excision,4 NHEJ,5,6 and HR repair pathways.4,7 Elevated PARP expression and/or activity may therefore mediate chemotherapy and radiation resistance and have indeed been demonstrated in numerous human cancers, including pediatric brain tumors.8–11 Veliparib (ABT-888) is an oral PARP inhibitor that potentiates anticancer activity of chemotherapy drugs,12,13 including temozolomide (TMZ), and enhances radiation efficacy.14–17 Several adult trials of Veliparib and various chemotherapy agents,18–20 including TMZ,21,22 are ongoing. To explore the potential of Veliparib as a novel treatment strategy in pediatric brain tumors, we previously showed that in a nonhuman primate model, the CSF-to-plasma ratio of Veliparib was 57% ± 7%.23 We also demonstrated by immunohistochemistry (IHC) that PARP is highly expressed in pediatric medulloblastoma (MB) and glioblastoma multiforme (GBM) tumors but absent in postnatal normal brains, and Veliparib treatment potently inhibited PARP activity in mouse orthotopic xenografts of pediatric MB and GBM and enhanced TMZ efficacy (X-N.L. and J.M.S., unpublished data). TMZ treatment in children with recurrent brain tumors showed only modest activity,24–26 with objective response rates ranging 5%–14%; although prior clinical data suggested a high rate of TMZ resistance in pediatric brain tumors, we hypothesized that such resistance to TMZ may be partially mediated by elevated PARP activity, and Veliparib treatment may therefore abrogate PARP activity and improve response to TMZ. Here we report the results of our phase I trial of Veliparib and TMZ in children with recurrent brain tumors. The primary objectives of the trial were: (i) to estimate the maximum tolerated dose (MTD) of Veliparib and TMZ in children with recurrent brain tumors; (ii) to study Veliparib pharmacokinetic (PK) and PARP inhibition in peripheral blood mononuclear cells (PBMCs); and (iii) to describe the toxicities of this regimen in children. The secondary objectives were: (i) to study PARP and other DNA repair protein expression by IHC in formalin-fixed, paraffin-embedded (FFPE) tumors; and (ii) to document tumor response to this regimen.
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a phase i clinical trial of Veliparib and temozolomide in children with recurrent central nervous system tumors a pediatric brain tumor consortium report
Journal of Clinical Oncology, 2013Co-Authors: Patrick A Thompson, Arzu Onarthomas, Adekunle M Adesina, Lindsay Kilburn, Mehmet Kocak, Brenda Chyla, Evelyn M Mckeegan, Katherine E Warren, Stewart Goldman, Ian F PollackAbstract:2036 Background: A phase I trial of Veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of Veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after Veliparib treatment. Methods: TMZ was given once daily and Veliparib twice daily for 5 days, every 28 days. Five Veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m2/dose, respectively. Baseline and serial Veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. ...
