246 results on '"Bruce J. Dezube"'
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2. Author Correction: Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
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Anniina Färkkilä, Doga C. Gulhan, Julia Casado, Connor A. Jacobson, Huy Nguyen, Bose Kochupurakkal, Zoltan Maliga, Clarence Yapp, Yu-An Chen, Denis Schapiro, Yinghui Zhou, Julie R. Graham, Bruce J. Dezube, Pamela Munster, Sandro Santagata, Elizabeth Garcia, Scott Rodig, Ana Lako, Dipanjan Chowdhury, Geoffrey I. Shapiro, Ursula A. Matulonis, Peter J. Park, Sampsa Hautaniemi, Peter K. Sorger, Elizabeth M. Swisher, Alan D. D’Andrea, and Panagiotis A. Konstantinopoulos
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Science - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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3. IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer
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Wei Guo, Manish R Patel, Nashat Gabrail, Jordi Rodon, Erika Hamilton, Timothy A Yap, Meghan Duncan, Alberto Bessudo, Jasgit Sachdev, Lena Evilevitch, Sujatha Kumar, Sharon Lu, and Bruce J Dezube
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin–paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer.Methods IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin–paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination.Results A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin–paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin–paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A–D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A–D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A–D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%.Conclusions Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens.Trial registration number NCT03307785.
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- 2022
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4. Supplementary Figure 1 from A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
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Bruce J. Dezube, Geoffrey I. Shapiro, Hillard Lazarus, Donald Kufe, Michael Andreeff, Sergej Konoplev, Marina Konopleva, James Mier, Deborah A. Ferguson, Colin J. Meyer, Joseph Paul Eder, Donald Lawrence, Jennifer Wheler, Aung Naing, Xiaoying He, Jeffrey G. Supko, Razelle Kurzrock, and David S. Hong
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PDF file, 19K, Line graph representing the mean change in eGFR for nine patients that received bardoxolone methyl treatment for at least six cycles. Error bars represent the SEM.
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- 2023
5. Supplementary Tables 1-2, Supplementary Methods, Supplementary Figure Legend from Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors
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R. Donald Harvey, Bruce J. Dezube, George Mulligan, Kristine Burke, Allison J. Berger, Hélène M. Faessel, Michael D. Pickard, Devalingam Mahalingam, James M. Cleary, Glen J. Weiss, John S. Kauh, Jeffrey W. Clark, Roger B. Cohen, Geoffrey I. Shapiro, and John Sarantopoulos
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Supplemental Table 1: Treatment-related AEs experienced by {greater than or equal to}10% of patients on any schedule, and treatmentrelated grade {greater than or equal to}3 AEs reported in at least 1 patient; Supplemental Table 2: Summary of hepatotoxicities reported with pevonedistat on each dosing schedule and overa ll
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- 2023
6. Data from Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors
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R. Donald Harvey, Bruce J. Dezube, George Mulligan, Kristine Burke, Allison J. Berger, Hélène M. Faessel, Michael D. Pickard, Devalingam Mahalingam, James M. Cleary, Glen J. Weiss, John S. Kauh, Jeffrey W. Clark, Roger B. Cohen, Geoffrey I. Shapiro, and John Sarantopoulos
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Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies.Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0.Results: Schedule A MTD was 50 mg/m2; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m2, respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies.Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m2 and 67 mg/m2. DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. Clinical trials are ongoing. Clin Cancer Res; 22(4); 847–57. ©2015 AACR.
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- 2023
7. Supplementary Tables 1-6, Supplementary Figure Legend from Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma
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Sagar Lonial, Bruce J. Dezube, Stephen Tirrell, Hélène M. Faessel, George Mulligan, Allison J. Berger, Zhaowei Hua, Kevin Kelly, Catherine Diefenbach, Daniel Lebovic, Mitchell R. Smith, R. Donald Harvey, Robert Z. Orlowski, Owen A. O'Connor, Andrzej J. Jakubowiak, and Jatin J. Shah
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Table A1. Prior therapies received (agents received by >5 patients); Table A2. Summary of pevonedistat plasma pharmacokinetic parameters on days 1 and 9 of cycle 1 on schedule A (administration on days 1, 2, 8, 9 of 21-day cycles); Table A3. Summary of pevonedistat plasma pharmacokinetic parameters on days 1 and 4 (or, alternatively, day 11) of cycle 1 on schedule B (administration on days 1, 4, 8, 11 of 21-day cycles); Table A4. Changes from baseline in gene expression levels for NAEregulated transcriptional targets on cycle 1, day 1 following pevonedistat administration at the MTDs on schedules A and B; Table A5. Patients achieving partial responses; Table A6. Patients achieving stable disease and receiving at least 5 cycles of pevonedistat.
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- 2023
8. Supplementary Figure 1 from Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma
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Sagar Lonial, Bruce J. Dezube, Stephen Tirrell, Hélène M. Faessel, George Mulligan, Allison J. Berger, Zhaowei Hua, Kevin Kelly, Catherine Diefenbach, Daniel Lebovic, Mitchell R. Smith, R. Donald Harvey, Robert Z. Orlowski, Owen A. O'Connor, Andrzej J. Jakubowiak, and Jatin J. Shah
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Representative images (20 x magnification) of formalin-fixed paraffin-embedded clots prepared from bone marrow aspirates.
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- 2023
9. Supplementary Figure Legend from A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
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Bruce J. Dezube, Geoffrey I. Shapiro, Hillard Lazarus, Donald Kufe, Michael Andreeff, Sergej Konoplev, Marina Konopleva, James Mier, Deborah A. Ferguson, Colin J. Meyer, Joseph Paul Eder, Donald Lawrence, Jennifer Wheler, Aung Naing, Xiaoying He, Jeffrey G. Supko, Razelle Kurzrock, and David S. Hong
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PDF file, 43K.
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- 2023
10. Supplementary Table 1 from A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
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Bruce J. Dezube, Geoffrey I. Shapiro, Hillard Lazarus, Donald Kufe, Michael Andreeff, Sergej Konoplev, Marina Konopleva, James Mier, Deborah A. Ferguson, Colin J. Meyer, Joseph Paul Eder, Donald Lawrence, Jennifer Wheler, Aung Naing, Xiaoying He, Jeffrey G. Supko, Razelle Kurzrock, and David S. Hong
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PDF file, 63K, Changes in Serum Creatinine Following Treatment with Bardoxolone Methyl.
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- 2023
11. Data from Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma
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Sagar Lonial, Bruce J. Dezube, Stephen Tirrell, Hélène M. Faessel, George Mulligan, Allison J. Berger, Zhaowei Hua, Kevin Kelly, Catherine Diefenbach, Daniel Lebovic, Mitchell R. Smith, R. Donald Harvey, Robert Z. Orlowski, Owen A. O'Connor, Andrzej J. Jakubowiak, and Jatin J. Shah
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Purpose: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma.Experimental Design: Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m2 on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m2 on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles.Results: Maximum tolerated doses were 110 mg/m2 (schedule A) and 196 mg/m2 (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat–NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease.Conclusions: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma. Clin Cancer Res; 22(1); 34–43. ©2015 AACR.
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- 2023
12. Data from A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
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Bruce J. Dezube, Geoffrey I. Shapiro, Hillard Lazarus, Donald Kufe, Michael Andreeff, Sergej Konoplev, Marina Konopleva, James Mier, Deborah A. Ferguson, Colin J. Meyer, Joseph Paul Eder, Donald Lawrence, Jennifer Wheler, Aung Naing, Xiaoying He, Jeffrey G. Supko, Razelle Kurzrock, and David S. Hong
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Purpose: Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity.Experimental Design: Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies.Results: The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased.Conclusions: Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. Clin Cancer Res; 18(12); 3396–406. ©2012 AACR.
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- 2023
13. Supplemental Figure 1 from Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors
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R. Donald Harvey, Bruce J. Dezube, George Mulligan, Kristine Burke, Allison J. Berger, Hélène M. Faessel, Michael D. Pickard, Devalingam Mahalingam, James M. Cleary, Glen J. Weiss, John S. Kauh, Jeffrey W. Clark, Roger B. Cohen, Geoffrey I. Shapiro, and John Sarantopoulos
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Individual dose-normalized exposures of pevonedistat (as assessed by Cmax and AUC24) obtained on Day 1 and Day 5 for schedule B (with dexamethasone) and schedule C (without dexamethasone).
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- 2023
14. Data from Novel Cellular Genes Essential for Transformation of Endothelial Cells by Kaposi's Sarcoma–Associated Herpesvirus
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Ashlee V. Moses, Klaus Früh, Bruce J. Dezube, Henry Koon, Shane McAllister, Rebecca Ruhl, and Camilo Raggo
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Kaposi's sarcoma–associated herpesvirus (KSHV) is involved in the development of lymphoproliferative diseases and Kaposi's sarcoma. The oncogenicity of this virus is reflected in vitro by its ability to transform B cells and endothelial cells. Infection of dermal microvascular endothelial cells (DMVEC) transforms the cells from a cobblestone-like monolayer to foci-forming spindle cells. This transformation is accompanied by dramatic changes in the cellular transcriptome. Known oncogenes, such as c-Kit, are among the KSHV-induced host genes. We previously showed that c-Kit is an essential cellular component of the KSHV-mediated transformation of DMVEC. Here, we test the hypothesis that the transformation process can be used to discover novel oncogenes. When expression of a panel of KSHV-induced cellular transcripts was inhibited with antisense oligomers, we observed inhibition of DMVEC proliferation and foci formation using antisense molecules to RDC1 and Neuritin. We further showed that transformation of KSHV-infected DMVEC was inhibited by small interfering RNA directed at RDC1 or Neuritin. Ectopic expression of Neuritin in NIH 3T3 cells resulted in changes in cell morphology and anchorage-independent growth, whereas RDC1 ectopic expression significantly increased cell proliferation. In addition, both RDC1- and Neuritin-expressing cells formed tumors in nude mice. RDC1 is an orphan G protein–coupled receptor, whereas Neuritin is a growth-promoting protein known to mediate neurite outgrowth. Neither gene has been previously implicated in tumorigenesis. Our data suggest that KSHV-mediated transformation involves exploitation of the hitherto unrealized oncogenic properties of RDC1 and Neuritin.
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- 2023
15. Supplementary Table 1 from Novel Cellular Genes Essential for Transformation of Endothelial Cells by Kaposi's Sarcoma–Associated Herpesvirus
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Ashlee V. Moses, Klaus Früh, Bruce J. Dezube, Henry Koon, Shane McAllister, Rebecca Ruhl, and Camilo Raggo
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Supplementary Table 1 from Novel Cellular Genes Essential for Transformation of Endothelial Cells by Kaposi's Sarcoma–Associated Herpesvirus
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- 2023
16. IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer
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Timothy A Yap, Alberto Bessudo, Erika Hamilton, Jasgit Sachdev, Manish R Patel, Jordi Rodon, Lena Evilevitch, Meghan Duncan, Wei Guo, Sujatha Kumar, Sharon Lu, Bruce J Dezube, and Nashat Gabrail
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Pharmacology ,Vascular Endothelial Growth Factor A ,Cancer Research ,Indazoles ,Paclitaxel ,Immunology ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Carboplatin ,Bevacizumab ,Oncology ,Piperidines ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Molecular Medicine ,Immunology and Allergy ,Humans - Abstract
BackgroundDoublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin–paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer.MethodsIOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin–paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination.ResultsA total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin–paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin–paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A–D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A–D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A–D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%.ConclusionsDostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens.Trial registration numberNCT03307785.
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- 2022
17. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
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Yinghui Zhou, Bose Kochupurakkal, Anniina Färkkilä, Dipanjan Chowdhury, Bruce J. Dezube, Geoffrey I. Shapiro, Huy V. Nguyen, Scott J. Rodig, Alan D. D'Andrea, Pamela N. Munster, Ursula A. Matulonis, Connor A. Jacobson, Sandro Santagata, Yu-An Chen, Ana Lako, Clarence Yapp, Panagiotis A. Konstantinopoulos, Zoltan Maliga, Elizabeth M. Swisher, Doga Gulhan, Julie R. Graham, Denis Schapiro, Elizabeth P. Garcia, Peter J. Park, Julia Casado, Sampsa Hautaniemi, Peter K. Sorger, Research Program in Systems Oncology, HUS Gynecology and Obstetrics, Clinicum, Research Programs Unit, University of Helsinki, Sampsa Hautaniemi / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Bioinformatics, and Department of Biochemistry and Developmental Biology
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EXPRESSION ,Cancer microenvironment ,0301 basic medicine ,Genome instability ,Combination therapy ,Science ,3122 Cancers ,General Physics and Astronomy ,Pembrolizumab ,THERAPY ,BREAST ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Cancer genomics ,Medicine ,PEMBROLIZUMAB ,lcsh:Science ,Cancer ,Tumor microenvironment ,Multidisciplinary ,business.industry ,1184 Genetics, developmental biology, physiology ,General Chemistry ,Translational research ,medicine.disease ,Immune checkpoint ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,PARP inhibitor ,Cancer research ,lcsh:Q ,Immunotherapy ,business ,Ovarian cancer ,GENOMIC INSTABILITY - Abstract
Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second., A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.
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- 2020
18. High Efficacy and Low Toxicity of MB-106, a Third Generation CD20 Targeted CAR-T for Treatment of Relapsed/Refractory B-NHL and CLL
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Mazyar Shadman, Cecilia CS Yeung, Mary Redman, Sang Yun Lee, Dong Hoon Lee, Susan Ra, Chaitra S Ujjani, Bruce J Dezube, Christina Poh, Edus H. Warren, Aude G. Chapuis, Damian J. Green, Andrew J. Cowan, Ryan D. Cassaday, Hans-Peter Kiem, Jordan Gauthier, Cameron J. Turtle, Ryan C. Lynch, Stephen D. Smith, Ajay K. Gopal, David G. Maloney, and Brian G. Till
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
19. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma.
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John C Morris, Antoinette R Tan, Thomas E Olencki, Geoffrey I Shapiro, Bruce J Dezube, Michael Reiss, Frank J Hsu, Jay A Berzofsky, and Donald P Lawrence
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Medicine ,Science - Abstract
In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks).GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.Clinicaltrials.gov NCT00356460.
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- 2014
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20. Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors
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A. Craig Lockhart, Afshin Dowlati, Bruce J. Dezube, Charu Aggarwal, Carrie B. Lee, Roger B. Cohen, Tsz Keung Nip, Hélène M. Faessel, Todd M. Bauer, R. Donald Harvey, Douglas V. Faller, Farhad Sedarati, and Ajeeta B Dash
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Male ,0301 basic medicine ,Oncology ,Docetaxel ,Deoxycytidine ,Carboplatin ,Clinical research ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Phase I Studies ,Antineoplastic Combined Chemotherapy Protocols ,Tissue Distribution ,Pharmacology (medical) ,Aged, 80 and over ,Pevonedistat ,Middle Aged ,Prognosis ,Standard-of-care chemotherapies ,Paclitaxel ,Tolerability ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,medicine.drug ,Adult ,medicine.medical_specialty ,Maximum Tolerated Dose ,NEDD8 Protein ,Nausea ,Cyclopentanes ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Adverse effect ,Aged ,Pharmacology ,business.industry ,medicine.disease ,Gemcitabine ,Pyrimidines ,030104 developmental biology ,chemistry ,Advanced solid tumors ,business ,Phase Ib study ,Febrile neutropenia ,Follow-Up Studies - Abstract
Summary Purpose This phase Ib study (NCT01862328) evaluated the maximum tolerated dose (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care chemotherapies in patients with solid tumors. Methods Patients received pevonedistat with docetaxel (arm 1, n = 22), carboplatin plus paclitaxel (arm 2, n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment. Results Pevonedistat MTD was 25 mg/m2 (arm 1) or 20 mg/m2 (arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) patients experienced dose-limiting toxicities during cycle 1 (grade ≥3 liver enzyme elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most common AEs included fatigue (56%) and nausea (50%). One drug-related death occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with carboplatin plus paclitaxel; no obvious changes were observed when co-administered with docetaxel or gemcitabine. Among 54 response-evaluable patients, two had complete responses (arm 2) and 10 had partial responses (three in arm 1, one in arm 2a, six in arm 2); overall response rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression correlated with clinical benefit in arm 2. Conclusion Pevonedistat with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity. Sustained clinical responses were observed in pretreated patients receiving pevonedistat with carboplatin and paclitaxel. ClinicalTrials.gov identifier: NCT01862328.
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- 2018
21. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML
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Jesus G. Berdeja, Ronan T. Swords, Farhad Sedarati, Michael R. Savona, Iwona Pawlikowska-Dobler, Bruce J. Dezube, Ajeeta B Dash, Joshua F. Zeidner, Douglas V. Faller, Steven Coutre, Jose C. Cruz, James M. Foran, Hélène M. Faessel, Saran Vardhanabhuti, Wayne Tam, Harry P. Erba, and Michael B. Maris
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Myeloid ,Anemia ,Immunology ,Azacitidine ,Cyclopentanes ,Biochemistry ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Pharmacokinetics ,Risk Factors ,Internal medicine ,medicine ,Humans ,Enzyme Inhibitors ,Adverse effect ,Aged ,Aged, 80 and over ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Neoplasm Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,Pyrimidines ,030104 developmental biology ,medicine.anatomical_structure ,Tolerability ,030220 oncology & carcinogenesis ,Ubiquitin-Conjugating Enzymes ,Female ,business ,medicine.drug - Abstract
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.
- Published
- 2018
22. Safety and Efficacy of Third Generation CD20 Targeted CAR-T (MB-106) for Treatment of Relapsed/Refractory B-NHL and CLL
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Edus H. Warren, Dong Hoon Lee, Chaitra S. Ujjani, Christina Poh, Ryan C. Lynch, Cecilia Yeung, Aude G. Chapuis, Susan Ra, Mary W. Redman, Sang Yun Lee, Brian G. Till, Cameron J. Turtle, Bruce J. Dezube, Ajay K. Gopal, Stephen D. Smith, Mazyar Shadman, Andrew J. Cowan, Jordan Gauthier, Ryan D. Cassaday, David G. Maloney, Hans-Peter Kiem, and Damian J. Green
- Subjects
Oncology ,CD20 ,medicine.medical_specialty ,biology ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Third generation ,Internal medicine ,Relapsed refractory ,medicine ,biology.protein ,Car t cells ,business - Abstract
Background: Autologous CD19-targeting chimeric antigen receptor T cell (CAR-T) products are approved as standard treatment options for patients (pts) with relapsed diffuse large cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). Their long-term efficacy for DLBCL is ~40% and is unknown for other histologies. Additionally, associated toxicities including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain a challenge. CD20 is a proven target for treatment of B-NHLs/CLL with demonstrated high clinical efficacy of unmodified, radiolabeled, and bispecific antibodies. Therefore, CD20-targeted CAR-T represents a promising adoptive immunotherapy option that could be utilized to treat relapsed/refractory (R/R) B-NHLs and CLL. MB-106 is a fully human 3rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains. We present results of our ongoing phase I/II clinical trial investigating safety and efficacy of CD20 CAR-T for high-risk B-NHLs and CLL (NCT03277729). Methods: Pts with R/R CD20+ B-cell malignancies are eligible, including but not limited to DLBCL, FL, MCL, and CLL. Prior treatment with CD19 CAR-T is permitted. Lymphodepletion (LD) consists of cyclophosphamide (Cy) ± fludarabine (Flu). CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x10 5, DL2: 1x10 6, DL3: 3.3x10 6, DL4: 1x10 7 CAR T cells/kg. A continual reassessment method dose escalation design was used to find the maximally tolerated dose. CAR-T is infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Treatment response is assessed on day 28. CRS and ICANS are graded per ASTCT consensus grading. The study underwent a major cell manufacturing modification after treating 7 pts with no objective responses as previously reported (Shadman, ASH 2020, #1443). This abstract includes pts who were treated under the modified process. Results: Between Dec 2019 and July 2021, 16 pts (12 FL, 2 MCL, 1 CLL, 1 DLBCL) were treated after LD with Cy-Flu and had day 28 assessment. All DLs were reached (see table), with no dose-limiting toxicities to date. CRS occurred in 7 pts (44%): 4 pts with grade (Gr) 1 and 3 with Gr 2. ICANS was observed in 1 pt (6.2%) at Gr 2. There were no Gr 3 or Gr 4 CRS or ICANS. Median time to CRS was 6.5 days (range, 0-12); the 1 ICANS event occurred on day 12. One pt (CLL) developed Gr 3 temporary neuropathic pain which, in the absence of other explanation, was attributed to the CAR-T. No pts had tumor lysis syndrome or Gr 3-4 infections. Thrombocytopenia (Gr 3-4: 19%) and neutropenia (Gr 3-4: 94%) were common but there were no bleeding complications, and the rate of febrile neutropenia was 19%. Overall response (ORR) was 94% (15/16) with complete response (CR) rate of 62% (10/16). In FL pts (n =12), ORR was 92% (11/12) and CR rate was 75% (9/12). Among FL pts who received DL 3 or 4, the CR rate was 86%. The CLL pt had a PET-negative CR and undetectable measurable residual disease in peripheral blood and bone marrow by flow cytometry (10 -4) (uMRD4) on day 28. The pt with DLBCL achieved a partial response (PR) on day 28 and a repeat PET on day ~ 90 showed continued improvement but still indicating a PR. Among pts who achieved a CR, only one pt (FL) relapsed after 9 months. All other CRs are ongoing (range: 3-18 months). CAR-T persistence was lost at day 95 in 1 pt who had progression and proceeded to other anti-lymphoma treatment; 2 other patients lost CAR-T engraftment by day 181 and 201 with B cell recovery. All other patients continue to have detectable CAR-T cells as of last follow-up (max 13 months post-infusion). Conclusion: Treatment with MB-106 shows a favorable safety profile with no Gr 3 or Gr 4 CRS or ICANS. In addition, we observed a high rate of ORR and CR with ongoing CRs and high rate of CAR-T persistence. Enrollment is currently ongoing; data will be updated at the time of presentation. Figure 1 Figure 1. Disclosures Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Yeung: Merck,Celgene: Consultancy. Ujjani: ACDT: Honoraria; Gilead: Honoraria; TG Therapeutics: Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dezube: Mustang Bio: Current Employment, Current holder of individual stocks in a privately-held company. Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Chapuis: Karkinos Therapeutics: Other: Ownership; Lonza: Other: Intellectual Property; Cullian: Other: Intellectual Property; TScan Therapeutics, Inc.: Consultancy, Other: Ownership; SignalOne Bio: Consultancy, Other: Ownership; Bluebird bio: Other: Intellectual Property; Juno therapeutics: Other: Intellectual Property; Adapyive Biotechnologies Corporation: Other: Ownership/Intellectual Property; Pfizer: Other: Intellectual Property; Affini-T: Other: Ownership; Ridgeline: Consultancy; BioNTech: Consultancy. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Cowan: Abbvie: Consultancy, Research Funding; Harpoon: Research Funding; Janssen: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Nektar: Research Funding; GSK: Consultancy; Secura Bio: Consultancy; Cellectar: Consultancy. Cassaday: Amgen: Consultancy, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Pfizer: Consultancy, Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding. Kiem: Homology Medicines: Consultancy; VOR Biopharma: Consultancy; Ensoma Inc.: Consultancy, Current holder of individual stocks in a privately-held company. Gauthier: Janssen: Membership on an entity's Board of Directors or advisory committees; Multerra Bio: Consultancy; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Larvol: Consultancy; JMP: Consultancy; Eusapharma: Consultancy. Turtle: T-CURX: Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Nektar Therapeutics: Consultancy, Research Funding; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; AstraZeneca: Consultancy, Research Funding; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Amgen: Consultancy; PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Allogene: Consultancy. Lynch: TG Therapeutics: Research Funding; Bayer: Research Funding; Incyte: Research Funding; Juno Therapetics: Research Funding; Morphosys: Consultancy; Genentech: Research Funding; SeaGen: Research Funding; Cyteir: Research Funding. Smith: Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; Incyte Corporation: Research Funding; AstraZeneca: Consultancy, Research Funding; Incyte: Consultancy; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Research Funding; Bristol Myers Squibb (spouse): Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; KITE pharm: Consultancy; Millenium/Takeda: Consultancy; Bayer: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy, Research Funding; Genentech: Research Funding. Gopal: Gilead: Consultancy, Honoraria, Research Funding; Genetech: Consultancy, Honoraria, Research Funding; SeaGen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Research Funding; Bristol Meyers Squibb: Research Funding; Agios: Research Funding; MorphoSys: Honoraria; IGM Biosciences: Research Funding; ADC Therapeutics: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Nurix Inc: Consultancy, Honoraria; Takeda: Research Funding; Teva: Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Incyte: Honoraria; Beigene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Cellectar: Consultancy, Honoraria. Maloney: BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Consultancy; Kite, a Gilead Company, Juno, and Celgene: Research Funding; Juno: Patents & Royalties; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding.
- Published
- 2021
23. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma
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Alan D. D'Andrea, Dmitri Bobilev, Gregory A. Vidal, John W. Moroney, Linda Van Le, Jing Wang, Bruce J. Dezube, Panagiotis A. Konstantinopoulos, Pamela N. Munster, Anniina Färkkilä, Steven E. Waggoner, Sujata Arora, Erica Stringer-Reasor, Robert W. Holloway, Ursula A. Matulonis, Elizabeth M. Swisher, Young B. Kim, Kathleen N. Moore, Nathan Buerstatte, Richard T. Penson, Julie R. Graham, Monica M. Mita, Jasgit C. Sachdev, Eloise Chapman-Davis, Gerardo Colon-Otero, Clinicum, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and University of Helsinki
- Subjects
Oncology ,EPITHELIAL OVARIAN ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Population ,BEVACIZUMAB ,3122 Cancers ,Pembrolizumab ,POLY(ADP-RIBOSE) POLYMERASE ,MUTATION CARRIERS ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,3123 Gynaecology and paediatrics ,Internal medicine ,Ovarian carcinoma ,GERMLINE ,medicine ,030212 general & internal medicine ,education ,education.field_of_study ,BRCA2 MUTATION ,business.industry ,OLAPARIB ,CHEMOTHERAPY ,medicine.disease ,OPEN-LABEL ,CANCER ,3. Good health ,Editorial Commentary ,chemistry ,030220 oncology & carcinogenesis ,Ovarian cancer ,business ,Recurrent Ovarian Carcinoma ,Progressive disease ,medicine.drug - Abstract
ImportancePatients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. ObjectiveTo evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. Design, Setting, and ParticipantsThe TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to >= 23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. InterventionsThe recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main Outcomes and MeasuresThe primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. ResultsFourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to >= 14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Conclusions and RelevanceNiraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. Trial RegistrationClinicalTrials.gov identifier: NCT02657889
- Published
- 2019
24. Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors
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Glen J. Weiss, John S. Kauh, Bruce J. Dezube, Jeffrey W. Clark, Roger B. Cohen, Devalingam Mahalingam, James M. Cleary, Hélène M. Faessel, Allison Berger, Michael D. Pickard, George Mulligan, Kristin E. Burke, R. Donald Harvey, Geoffrey I. Shapiro, and John Sarantopoulos
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Maximum Tolerated Dose ,Antineoplastic Agents ,Cyclopentanes ,Ubiquitin-Activating Enzymes ,Pharmacology ,03 medical and health sciences ,Protein neddylation ,0302 clinical medicine ,Pharmacokinetics ,Neoplasms ,Humans ,Medicine ,Adverse effect ,Dexamethasone ,Aged ,Aged, 80 and over ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Tumor Burden ,Clinical trial ,Pyrimidines ,Treatment Outcome ,030104 developmental biology ,Pevonedistat ,Oncology ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Female ,business ,medicine.drug - Abstract
Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. Results: Schedule A MTD was 50 mg/m2; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m2, respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m2 and 67 mg/m2. DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. Clinical trials are ongoing. Clin Cancer Res; 22(4); 847–57. ©2015 AACR.
- Published
- 2016
25. Author Correction: Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
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Yinghui Zhou, Clarence Yapp, Doga Gulhan, Sandro Santagata, Julie R. Graham, Anniina Färkkilä, Dipanjan Chowdhury, Ursula A. Matulonis, Connor A. Jacobson, Alan D. D'Andrea, Yu-An Chen, Ana Lako, Sampsa Hautaniemi, Scott J. Rodig, Huy V. Nguyen, Peter K. Sorger, Pamela N. Munster, Denis Schapiro, Bose Kochupurakkal, Geoffrey I. Shapiro, Bruce J. Dezube, Zoltan Maliga, Elizabeth M. Swisher, Elizabeth P. Garcia, Panagiotis A. Konstantinopoulos, Julia Casado, and Peter J. Park
- Subjects
Cancer microenvironment ,Indazoles ,Science ,Poly ADP ribose polymerase ,DNA Mutational Analysis ,Programmed Cell Death 1 Receptor ,General Physics and Astronomy ,CD8-Positive T-Lymphocytes ,Poly(ADP-ribose) Polymerase Inhibitors ,Antibodies, Monoclonal, Humanized ,B7-H1 Antigen ,General Biochemistry, Genetics and Molecular Biology ,Piperidines ,Antineoplastic Combined Chemotherapy Protocols ,Cancer genomics ,Tumor Microenvironment ,Humans ,Medicine ,Profiling (information science) ,Author Correction ,lcsh:Science ,Cancer ,Aged ,Aged, 80 and over ,Ovarian Neoplasms ,Multidisciplinary ,business.industry ,Macrophages ,Ovary ,Gene Amplification ,Recombinational DNA Repair ,General Chemistry ,Translational research ,Middle Aged ,Programmed Cell Death 1 Ligand 2 Protein ,medicine.disease ,Treatment Outcome ,Cancer research ,Female ,lcsh:Q ,Immunotherapy ,Interferons ,Drug Monitoring ,Neoplasm Recurrence, Local ,Single-Cell Analysis ,business ,Ovarian cancer - Abstract
Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
- Published
- 2020
26. Open-label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer
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Andrea E. Wahner-Hendrickson, Corrine Zarwan, Patrick M. Dillon, Filipa Lynce, Monica M. Mita, Nathan Buerstatte, Carey K. Anders, Gerburg M. Wulf, Sara M. Tolaney, Julie R. Graham, Antoinette R. Tan, Lee S. Schwartzberg, Georgia A. McCann, Bruce J. Dezube, Shaveta Vinayak, Melinda L. Telli, Yinghui Zhou, Sujata Arora, John K. Erban, and Andres Forero
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,BRCA mutation ,Population ,Phases of clinical research ,Pembrolizumab ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Internal medicine ,Clinical endpoint ,Medicine ,030212 general & internal medicine ,business ,education ,Progressive disease - Abstract
Importance Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC). Objective To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC. Design, setting, and participants This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019. Interventions Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main outcomes and measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival. Results Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected. Conclusions and relevance Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation. Trial registration ClinicalTrials.gov identifier: NCT02657889.
- Published
- 2019
27. Abstract 4487: Association of the tumor-immune microenvironment with response to niraparib and pembrolizumab in relapsed, platinum-resistant ovarian cancer
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Gini F. Fleming, Steven E. Waggoner, Panagiotis A. Konstantinopoulos, Huy Nguyen, Jia R. Lin, Julia Casado, Sandro Santagata, Ursula A. Matulonis, Bruce J. Dezube, Yinghui Zhou, Elizabeth M. Swisher, Julie R. Graham, Alan D. D'Andrea, Pamela N. Munster, Anniina Farkkila, and Peter K. Sorger
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,T cell ,Pembrolizumab ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Interferon ,Internal medicine ,biology.protein ,Medicine ,Cytotoxic T cell ,Antibody ,business ,Ovarian cancer ,CD8 ,medicine.drug - Abstract
Introduction: TOPACIO/Keynote-162 is a multi-center, open-label, single-arm phase 1/2 trial of Poly-ADP Ribose Polymerase (PARP) inhibitor niraparib combined with an anti-PD-1 antibody pembrolizumab. One cohort enrolled patients with recurrent ovarian cancer (OC). As tumor BRCA1/2 mutation (tBRCA), Homologous Recombination Deficiency (HRD) test (Myriad), or PD-L1 testing by immunohistochemistry were unable to predict clinical responses, we set out to examine additional DNA repair and immune biomarkers for response. Methods: We analyzed pre-trial Formalin Fixed Paraffin Embedded (FFPE) tumor samples from 49 patients with recurrent OC. The samples were collected either at diagnosis, or a median of 4.3 months (range 1.5 - 91.1) after the diagnosis. The median time from diagnosis to trial entry was 35.8 months (range 11.4 - 136.5). To further assess HRD we performed BROCA sequencing of 69 DNA repair genes as previously reported. NanoString gene expression analysis was performed using an IO360 panel complemented with 30 DNA repair genes and analyzed with the NSolver software. Findings were correlated with clinical response evaluated based on RECIST v1.1. Results: Overall, the confirmed objective response (OR) rate was 18% with a clinical benefit (complete response + partial response + stable disease; CB) rate of 65%. HRD as assessed by BROCA sequencing did not associate with OR or CB. In the Nanostring mRNA expression analyses, the samples taken at the time of diagnosis (n=23) had significantly lower abundance score for several immune cell lineages, including cytotoxic cells, macrophages, dendritic cells, and NK-cells compared to samples collected after the diagnosis. In addition, in the at-diagnosis samples, lower abundance scores for overall immune cells (CD45), tumor-infiltrating lymphocytes, CD8+T-cells, and macrophages were associated with clinical benefit. Pathway analysis demonstrated that increased scores for Cytosolic DNA sensing- and interferon pathways significantly correlated with OR, particularly in the platinum-resistant patients. In contrast, the samples collected after diagnosis (n=21), had increased mRNA expression levels of PD-L1, PD-L2 and PD-1, and a higher score for exhausted CD8+ T-cells than the samples collected at diagnosis. In these samples, a low exhausted CD8+T cell/T-regulatory cell score ratio was associated with OR. Conclusions: Increased interferon signaling, and exhausted T/regulatory T-cell ratio are associated with response to the combination of niraparib and pembrolizumab. We are in the process of performing further profiling of the tumor microenviroment with a highly multiplexed tissue immunofluorescence (tCycIF) providing a comprehensive analysis of cell types, functional states, and spatial interactions at single-cell resolution. Citation Format: Anniina Farkkila, Jia R. Lin, Julia Casado, Huy Nguyen, Yinghui Zhou, Julie R. Graham, Bruce J. Dezube, Steven Waggoner, Pamela Munster, Gini F. Fleming, Sandro Santagata, Ursula A. Matulonis, Peter K. Sorger, Elizabeth M. Swisher, Alan D. D’Andrea, Panagiotis Konstantinopoulos. Association of the tumor-immune microenvironment with response to niraparib and pembrolizumab in relapsed, platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4487.
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- 2019
28. IOLite: Multipart, phase 1b, dose-finding study of the PD-1 inhibitor dostarlimab in combination with the PARP inhibitor niraparib ± bevacizumab (bev), or with platinum-based chemotherapy ± bev for advanced cancer
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Bruce J. Dezube, Sharon Lu, Erika Hamilton, Jordi Rodon Ahnert, Manish R. Patel, Jasgit C. Sachdev, Alberto Bessudo, Lena Evilevitch, Nashat Y. Gabrail, Meghan Duncan, Wei Guo, and Timothy A. Yap
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,biology ,Bevacizumab ,business.industry ,medicine.medical_treatment ,Advanced cancer ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Programmed cell death 1 ,PARP inhibitor ,medicine ,biology.protein ,In patient ,business ,neoplasms ,Standard therapy ,030215 immunology ,medicine.drug - Abstract
2560 Background: Novel combinations of drugs may overcome resistance in patients (pts) with solid tumors who had progressed on standard therapy. Methods: IOLite (NCT03307785) is a multicenter, open label, multipart study to determine dosing and evaluate safety and efficacy of dostarlimab in combination with approved therapies in pts with advanced solid tumors. Pts were enrolled in each part based on tumor histology, prior treatment (tx) history, and physician preference. Primary endpoint is dose-limiting toxicities (DLTs) deemed as tx-related per investigator, and safety and tolerability of the combination. Tumor responses were assessed per RECIST v1.1. Results: Parts A-D (see Table) are fully enrolled. One complete response was reported in part B (endometrial); confirmed partial responses in part A (ovarian, small cell lung [SCLC], gastrointestinal stromal [GIST]); part B (breast [2], bladder, SCLC); part C (prostate, fallopian tube), and part D (endometrial, non-SCLC). Stable disease was reported in part A (colorectal, prostate [2], breast, GIST, gastric); part B (SCLC, squamous cell, head and neck, prostate); part C (pancreatic, ovarian, GIST, breast [2], liver, endometrial); part D (ovarian, head & neck, cholangiocarcinoma). At data cutoff, 24 pts remain on treatment. PK’s of dostarlimab and niraparib (nir) were not altered by any of the combination agents tested. Conclusions: Dostarlimab is well tolerated in combination with nir ± bev, or carbo-pac ± bev. Preliminary efficacy data show responses in various histologies. No new safety signals were identified. Clinical trial information: NCT03307785. [Table: see text]
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- 2019
29. Abstract OT3-03-01: Open-label, single-arm study evaluating the antitumor activity and safety of niraparib as neoadjuvant treatment in patients with localized, HER2-negative, BRCA-mutant breast cancer
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Meghan Duncan, MC Liu, David B. Page, Erika Hamilton, Andre K. D. Liem, Bruce J. Dezube, Hyo S. Han, J.R. Graham, D Jelovac, Cesar A. Santa-Maria, Steven J. Isakoff, James Reeves, Laura Spring, Hanna Irie, A Milillo, J Chen, and Julie R. Nangia
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Oncology ,Antitumor activity ,Cancer Research ,medicine.medical_specialty ,business.industry ,Mutant ,HER2 negative ,medicine.disease ,Breast cancer ,Neoadjuvant treatment ,Internal medicine ,medicine ,In patient ,Open label ,business ,Single Arm Study - Abstract
Background: Neoadjuvant chemotherapy is administered to patients with operable breast cancer to downstage the tumor to allow for less extensive surgery and to provide prognostic information about drug efficacy and risk of disease recurrence. Patients who achieve a pathological complete response (pCR) following neoadjuvant treatment have a more favorable outcome than patients with residual invasive disease. Single-agent poly(ADP-ribose) polymerase (PARP) inhibitors have clinical efficacy in BRCA-mutated breast cancer. Niraparib, a potent and selective PARP1/2 inhibitor, is approved for maintenance treatment of patients with recurrent ovarian cancer and has demonstrated strong antitumor activity in in vivo studies with BRCA1-mutant breast cancer. The objective of this study is to evaluate the antitumor activity of single-agent niraparib in the neoadjuvant treatment of patients with localized, human epidermal growth factor receptor 2 (HER2)-negative, BRCAmut breast cancer. Trial Design: This is an open-label, single-arm pilot study with a target enrollment of 20 evaluable patients. Eligible patients are those ≥18 years old with histologically-confirmed HER2-negative localized breast cancer and either a BRCA1 or BRCA2 mutation (germline or somatic) and no prior anti-cancer therapies for the current malignancy. Patients will receive 200 mg of oral niraparib once daily for 2 months, after which they may either proceed directly to surgery or receive chemotherapy at the discretion of the physician. The primary endpoint is tumor response rate based on the change in tumor volume as measured by breast MRI after 2 months of treatment with niraparib; a response is defined as ≥30% reduction of tumor volume from baseline. Secondary endpoints include pCR rate, tumor response rate based on the change in tumor volume as measured by breast ultrasound, and safety and tolerability. Data will be summarized in a descriptive nature by frequency distributions (number and percentage of patients) for categorical variables and by the mean, median, and standard deviation for continuous variables. Tumor response rate will be tabulated together with its 95% binomial exact confidence interval. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Han H, Hamilton E, Irie H, Isakoff S, Jelovac D, Liem A, Liu MC, Milillo A, Nangia J, Page D, Reeves J, Santa-Maria C, Duncan M, Graham JR, Chen J, Dezube BJ, Spring L. Open-label, single-arm study evaluating the antitumor activity and safety of niraparib as neoadjuvant treatment in patients with localized, HER2-negative, BRCA-mutant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-01.
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- 2019
30. Abstract PD5-02: Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162)
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Corrine Zarwan, Carey K. Anders, Shaveta Vinayak, Yinghui Zhou, John K. Erban, Melinda L. Telli, Georgia A. McCann, A Wahner Hendrickson, Gerburg M. Wulf, Patrick M. Dillon, Lee S. Schwartzberg, Ar Tan, JR Graham, Sujata Arora, Sara M. Tolaney, Andres Forero, Monica M. Mita, Anniina Farkkila, Bruce J. Dezube, Nathan Buerstatte, and Filipa Lynce
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,DNA repair ,PALB2 ,BRCA mutation ,Pembrolizumab ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,PARP inhibitor ,medicine ,CHEK1 ,business ,Triple-negative breast cancer - Abstract
Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC >6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.
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- 2019
31. Management of AIDS-related Kaposi's sarcoma
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Giuseppe Di Lorenzo, Bruce J. Dezube, Rossella Di Trolio, Panagiotis A. Konstantinopoulos, Sabino De Placido, Liron Pantanowitz, Giuseppe Di, Lorenzo, Panagiotis A., Konstantinopoulo, Liron, Pantanowitz, Rossella Di, Trolio, DE PLACIDO, Sabino, and Bruce J., Dezube
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Oncology ,Acquired Immunodeficiency Syndrome ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,virus diseases ,Antineoplastic Agents ,Disease ,medicine.disease ,Antiretroviral therapy ,Aids-related kaposi's sarcoma ,Antiretroviral Therapy, Highly Active ,Internal medicine ,Immunology ,medicine ,Molecular targets ,Humans ,Sarcoma ,business ,Sarcoma, Kaposi - Abstract
The advent of highly active antiretroviral therapy (HAART) has lead to a substantial reduction in the prevalence, morbidity, and mortality associated with AIDS-related Kaposi's sarcoma. Similarly, concomitant advances in chemotherapy and supportive-care protocols have allowed for Kaposi's sarcoma to be managed more effectively in comparison with the pre-HAART era. Furthermore, developments in our understanding of the pathogenesis of Kaposi's sarcoma have identified several molecular targets that can potentially provide new therapeutic strategies. This Review discusses the role of conventional chemotherapeutic and immunomodulatory agents in the treatment of Kaposi's sarcoma and summarises the current status and future prospects of novel molecularly targeted agents in the treatment of this disease.
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- 2007
32. An Evaluation of Treatment Patterns and Outcomes in Elderly Patients Newly Diagnosed With Acute Myeloid Leukemia: A Retrospective Analysis of Electronic Medical Records From US Community Oncology Practices
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Esprit Ma, Ronan T. Swords, Anita Chawla, Marie Hélène Lafeuille, Patrick Lefebvre, Bruce J. Dezube, Jonathan Fortier, Vijayveer Bonthapally, Mei Sheng Duh, and Bruno Emond
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Pediatrics ,Community oncology practices ,03 medical and health sciences ,0302 clinical medicine ,Observational study ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Outcome Assessment, Health Care ,medicine ,Electronic Health Records ,Humans ,Blood Transfusion ,Community Health Services ,Practice Patterns, Physicians' ,Treatment patterns ,Aged ,Retrospective Studies ,Aged, 80 and over ,Leukemia ,Performance status ,business.industry ,Medical record ,Age Factors ,Myeloid leukemia ,Cancer ,Disease Management ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,United States ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Population Surveillance ,Cohort ,Female ,business ,Descriptive analysis ,030215 immunology - Abstract
Background Many elderly patients with acute myeloid leukemia (AML) are considered ineligible for standard intensive induction therapy due to performance status and comorbidities. We analyzed treatment patterns and outcomes among elderly patients newly diagnosed with AML in the US community oncology setting. Methods A retrospective observational study was conducted using patient-level data from a network of US community oncology practices provided by Altos Solutions. Patients aged ≥ 60 years, diagnosed with AML between November 2005 and February 2014, with ≥ 1 recorded visit and ≥ 6 months between diagnosis and data cutoff, were included. Only patients who received active treatment or best supportive care (BSC) per National Comprehensive Cancer Network (NCCN) AML Guidelines were analyzed. Results Of 1139 patients meeting the inclusion criteria, 922 (median age 76 years) received NCCN-recommended treatments: standard induction (n = 5), low-intensity therapy (n = 425), BSC with hydroxyurea (HU) (n = 36), or BSC without HU (n = 455). For the low-intensity therapy cohort, median time from diagnosis to treatment initiation was 17 days; median duration of therapy was 5.1 months. Median overall survival (OS) from diagnosis in the low-intensity, BSC with HU, and BSC without HU groups was 12.3, 7.0, and 49.4 months, respectively. Median time to next therapy/death was 10.1 months in patients receiving low-intensity therapy. A higher proportion of patients receiving low-intensity therapy required transfusion or other supportive care versus those receiving BSC. Conclusions As expected, OS in patients receiving low-intensity therapy or BSC with HU is poor for elderly patients with AML. Remarkably, intensive induction strategies are rarely used for older patients in community oncology practice.
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- 2016
33. A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
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Michael Andreeff, Donald P. Lawrence, Jennifer J. Wheler, Marina Konopleva, Xiaoying He, Razelle Kurzrock, Sergej Konoplev, Bruce J. Dezube, James W. Mier, David S. Hong, Donald Kufe, Hillard M. Lazarus, Colin J. Meyer, Geoffrey I. Shapiro, Joseph Paul Eder, Deborah A. Ferguson, Aung Naing, and Jeffrey G. Supko
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Lymphoma ,Maximum Tolerated Dose ,NF-E2-Related Factor 2 ,Phases of clinical research ,Antineoplastic Agents ,Pharmacology ,Peripheral blood mononuclear cell ,Drug Administration Schedule ,Article ,Young Adult ,Pharmacokinetics ,Neoplasms ,Internal medicine ,NAD(P)H Dehydrogenase (Quinone) ,medicine ,Humans ,Cyclin D1 ,RNA, Messenger ,Thyroid Neoplasms ,Bardoxolone methyl ,Oleanolic Acid ,Carcinoma, Renal Cell ,Melanoma ,Aged ,Janus Kinases ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,NF-kappa B ,Cancer ,Middle Aged ,Cell cycle ,medicine.disease ,Kidney Neoplasms ,STAT Transcription Factors ,Endocrinology ,Oncology ,Pharmacodynamics ,Female ,Mantle cell lymphoma ,Colorectal Neoplasms ,business - Abstract
Purpose: Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Experimental Design: Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. Results: The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Conclusions: Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. Clin Cancer Res; 18(12); 3396–406. ©2012 AACR.
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- 2012
34. Plasmablastic Lymphoma is Treatable in the HAART Era. A 10 year Retrospective by the AIDS Malignancy Consortium (AMC)
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Amy Chadburn, Joseph A. Sparano, Alexandra M. Levine, Dimitrios Tzachanis, William Wachsman, Bruce J. Dezube, Lee Ratner, Lawrence D. Kaplan, Scot C. Remick, Richard F. Ambinder, Page C. Moore, Ariela Noy, Neel K. Gupta, Shelly Lensing, Robert A. Baiocchi, David M. Aboulafia, Erin Reid, David H. Henry, and Ronald T. Mitsuyasu
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Adult ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Anti-HIV Agents ,CHOP ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,International Prognostic Index ,Chemoimmunotherapy ,Median follow-up ,Internal medicine ,Antiretroviral Therapy, Highly Active ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,EPOCH (chemotherapy) ,Lymphoma, AIDS-Related ,Retrospective Studies ,Acquired Immunodeficiency Syndrome ,business.industry ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Surgery ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Plasmablastic Lymphoma ,business ,Diffuse large B-cell lymphoma ,030217 neurology & neurosurgery ,Febrile neutropenia ,Plasmablastic lymphoma - Abstract
Plasmablastic lymphoma (PBL) is an aggressive CD20 negative diffuse large B cell lymphoma over-represented in patients with HIV infection. CD45 expression is weak, but immunoglobulin genes are rearranged and plasma cell markers are expressed.[1] In 1997, 95% of the cases were reported to be from HIV + patients, all with oral cavity involvement, 68% stage I. In this pre-HAART era report, 9//11 patients with follow-up died within a year of diagnosis. Most other case reports and case series have typically described poor survival for patients with PBL, particularly those infected with HIV,[2] while others were more optimistic.[3] We sought to characterize patients with PBL diagnosed and treated solely in the HAART era. We identified 12 patients with newly diagnosed PBL treated at the AIDS Malignancy Consortium (AMC) sites from 1999 to 2008. This retrospective analysis suggests these patients had better outcomes than those identified pre-HAART, perhaps due to use of aggressive chemotherapy made possible because of better supportive care and antiretroviral therapy. All AMC sites, which participated in this retrospective review were queried for cases of PBL diagnosed from 1998–2008. Two of the authors (AC and AN) reviewed the pathology reports for the criteria for plasmablastic lymphoma described in the 2008 WHO Classification.[4] Twelve cases from 9 AMC sites were included in this study. Descriptive statistics were computed for demographic and clinical characteristics. Overall survival (OS) was calculated from date of initial diagnosis to death or last follow-up. Kaplan-Meier estimates of 1-year survival were computed. All AMC sites had an Institutional Review Board waiver of authorization. Baseline clinical characteristics at study entry are presented in Table 1. The median CD4 + count at HIV diagnosis was 256 cells/uL (range 45–750) and was lower at initial PBL diagnosis with a median of 136 cells/uL (range of 2–514). Sixty-seven percent of the patients had had a prior opportunistic infection. Most (58%) of patients were not on HAART at lymphoma diagnosis, however, they had all previously taken HAART at some point. Of 7 patients not on HAART, 6 started HAART, typically at diagnosis or chemoimmunotherapy initiation. Stage at initial diagnosis was I (25%), II (25%), III (0%) and IV (50%). Four of 7 patients with extranodal disease had more than one site of involvement. Extranodal sites of disease at initial diagnosis included bone without bone marrow (4), bone marrow (1), liver (2), kidney (2), sinus (1), cerebrospinal fluid (1), colon (1), skin (1), adrenal (1), nasopharynx (1) and stomach (1). Table 1 Clinical characteristics at study entry of 12 HIV-positive patients with initial diagnosis of plasmablastic lymphoma. Surprisingly, no patients had oral involvement. LDH was elevated in 5/8 where the value was known. The International Prognostic Index could not be calculated for the group as a whole as performance status assessment data was not available in one third of the patients. Not all cases had uniform immunophenotypic data available [Table 1]. As per the definition of plasmablastic lymphoma, all 12 cases tested were negative for the B cell marker CD20. Similarly, markers of terminal B cell differentiation, CD138 and MUM-1/IFR4, were positive in 6/6 cases and in 4/4 cases tested, respectively Epstein-Barr virus (EBV) was present in 8/8 cases based on in situ hybridization (EBER). At initial diagnosis, 10/12 patients received chemotherapy, although HAART alone was attempted without success in one patient. Treatment was CHOP on a 14 day cycle (n=1) [5] or 21 day cycle (n=3), [6] (cyclophosphamide, doxorubicin, vincristine, prednisone), infusional CDE (n=1), (cyclophosphamide, doxorubicin, etoposide); [7] infusional EPOCH (n=2) (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone),[8,9] or other (n=5). The other therapies included EPOCH with high dose methotrexate and zidovudine, either alternating (n=2), or sequential (n=2). Three patients with stage I/II disease received radiation in combination with chemotherapy. Two of the ten treated patients experienced grade 3/4 toxicity. No patient died of treatment. One patient experienced grade 3/4 fatigue, anemia, thrombocytopenia, febrile neutropenia, nausea, vomiting, diarrhea, and weight loss, and the other patient experienced renal insufficiency. Responses were complete (CR) in 7, partial (PR) in 2 and refractory in 1. CRs were seen with CHOP (n=4), EPOCH (n=2), and EPOCH alternating with high dose methotrexate and zidovudine (n=1). PRs were seen after EPOCH alternating with high dose methotrexate and zidovudine (n=2). The one patient treated with CDE had refractory disease. Overall survival is shown in Fig. 1. At a median follow up of 73 weeks (range, 40–165), the median survival was not reached. The one-year survival was 66.7% (SE, 13.6). No patients died in the follow up period after year one. Figure 1 Survival of plasmablastic lymphoma patients. We report the first case series of plasmablastic lymphoma patients, under the care of dedicated HIV malignancy oncologists in a consortium setting, diagnosed and treated exclusively in the HAART era. In this study we demonstrate relatively long disease free survival despite earlier reports showing nearly all HIV + patients with PBL were destined to die from progressive lymphoma. In the initial, pre-HAART study of PBL by Delecluse, et al.[1] 9 of the 11 patients died within 16 months of diagnosis including 3 patients with stage I disease treated with external beam radiation, poly-chemotherapy or a combination of both. In the HAART era, intensive treatment of aggressive lymphomas, such as Burkitt and diffuse large B cell lymphoma, can result in CR and long-term survival for HIV infected patients.[9–11] Cohort studies suggest that plasmablastic lymphoma has an inferior survival to Burkitt and DLBCL.[12] We demonstrate that PBL may be curable, even in patients with higher stage disease and more extranodal involvement compared to the cases described by Delecluse, et al. where the disease was primarily localized to the jaw in the majority of patients. Recently, Ibrahim et al. reported in abstract form, their single institution experience with 25 patients during the HAART era.[13] Similar to our study, only 32% were on HAART and the median CD4 + cell count was 87cells/uL. Only 76% received chemotherapy, with EPOCH being the most common treatment choice (56%), and 28% received radiotherapy. The response rate was 84% and the median OS observed in all patients who received chemotherapy was 11.6 months (range, 2–63 months). Those who were treated with EPOCH demonstrated a better median overall survival (17 months) compared to those treated with CHOP and CHOP-like regimens (7 months, p=0.04). Castillo et al. reviewed 112 cases in the literature and noted a median overall survival of 15 months with a 3 year OS of only 25%. In contrast, Cattaneo et al. reported their single institution experience of 13 patients treated during the HAART era with a 67% 3 year OS.[14] 15 patients were treated, all with CHOP or CHOP-like regiments, with involved field consolidation in seven. Five received high dose therapy with autologus stem cell transplant as first CR consolidation. The initial goal of this AMC retrospective study was to identify which first line therapy might be the most promising for HIV positive patients with plasmablastic lymphoma. The rarity of this lymphoma resulted in a very small cohort, possibly as a result of incomplete retrieval from institutional databases. In this regard, we were unable to draw specific conclusions due to the sample size, the disparate number of lymphoma regimens, and the retrospective nature of the study. However, it is notable that CR was achieved with CHOP or EPOCH based regimens. The literature on regimens more intensive than CHOP is inconsistent. Two earlier retrospective studies did not demonstrate an advantage of therapies more intensive than CHOP for PBL.[15,16] Loghavi et al. noted a series of 50 patients (20 HIV+) tended to have a better OS with CHOP than hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) (p=0.078).[17] Nonetheless, many experts do consider CHOP inadequate and favor intensive therapies including EPOCH.[18] As an aside, we cannot comment on the efficacy of HAART therapy alone, as only one patient was treated with this strategy with disease progression. In addition to intensive chemotherapy, it is probable that our patients fared better than those in the pre- HAART era due in part to better supportive care and more robust immune status. However, we cannot be certain, as the median CD4 + cell count of 256 cells/uL at initial PBL diagnosis was relatively low. Moreover, 59% had had a prior opportunistic infection and only 29% were on HAART at PBL diagnosis. Currently Clinical Trials Support Unit (CTSU) 9177 is prospectively studying EPOCH therapy for patients diagnosed with PBL irrespective of HIV status. Given the biologic similarity to multiple myeloma, drug classes like immune modulatory agents (IMiDs) and protease inhibitors [19] might also be promising agents for future study. The nearly ubiquitous finding of Epstein Barr in tumor tissue (11of 12 evaluable cases in our study) may provide a rationale for viral-based strategies. Finally, the role for autologous stem cell transplant in the setting of relapsed/refractory disease is also worthy of exploration.
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- 2015
35. Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies
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Sang Hoon Sin, William J. Harrington, Wolfgang Vahrson, Bruce J. Dezube, Debasmita Roy, Dirk P. Dittmer, Michelle R. Staudt, and Juan Carlos Ramos
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Cancer Research ,Biology ,Real-Time Polymerase Chain Reaction ,Complement factor B ,Article ,Virus ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,RNA, Messenger ,Biomarker discovery ,Sarcoma, Kaposi ,Lymphoma, AIDS-Related ,Bortezomib ,Gene Expression Profiling ,NF-kappa B ,medicine.disease ,Lymphoma ,Gene expression profiling ,Real-time polymerase chain reaction ,Oncology ,Immunology ,Primary effusion lymphoma ,Signal Transduction ,medicine.drug - Abstract
The nuclear factor kappa B (NFκB) pathway is essential for many human cancers. Therapeutics such as bortezomib (Velcade™) that interfere with NFκB signaling are of great clinical interest. NFκB signaling, however, is multifaceted and variable among tissues, developmental and disease entities. Hence, targeted biomarkers of NFκB pathways are of prime importance for clinical research. We developed a novel real-time qPCR-based NFκB array. Only mechanistically validated NFκB targets were included. We then used random-forest classification to define individual genes and gene combinations within the NFκB pathways that define viral lymphoma subclasses as well as Kaposi sarcoma (KS). Few NFκB targets emerged that were universally present in all tumor types tested, underscoring the need for additional tumor-type specific biomarker discovery. (i) We uncovered tissue of origin-specific tumor markers, specifically CD69, CSF-1 and complement factor B (C1QBP) for primary effusion lymphoma (PEL); IL1-beta, cyclinD3 and CD48 for KS. We found that IL12, jun-B, msx-1 and thrombospondin 2 were associated with EBV co-infection in PEL. (ii) We defined the NFκB signature of Epstein-Barr virus (EBV) positive AIDS-associated Burkitt lymphoma (BL). This signature identified CCR5 as the key marker. (iii) This signature differed from EBV negative BL consistent with the idea that EBV not only activates NFκB activity but that this virus also reprograms NFκB signaling toward different targets.
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- 2011
36. Pilot study evaluating the interaction between paclitaxel and protease inhibitors in patients with human immunodeficiency virus-associated Kaposi’s sarcoma: an Eastern Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium (AMC) trial
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Joseph A. Sparano, Mary Cianfrocca, Jamie H. Von Roenn, Susan E. Krown, Bruce J. Dezube, Sandra J. Lee, and Michelle A. Rudek
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Paclitaxel ,medicine.medical_treatment ,AIDS-Related Opportunistic Infections ,HIV Infections ,Pilot Projects ,Toxicology ,Disease-Free Survival ,Article ,chemistry.chemical_compound ,Acquired immunodeficiency syndrome (AIDS) ,Internal medicine ,medicine ,Humans ,HIV Protease Inhibitor ,Drug Interactions ,Pharmacology (medical) ,Sarcoma, Kaposi ,Kaposi's sarcoma ,Pharmacology ,chemistry.chemical_classification ,Protease ,business.industry ,virus diseases ,HIV Protease Inhibitors ,Middle Aged ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Enzyme ,chemistry ,Area Under Curve ,Female ,Sarcoma ,business - Abstract
Paclitaxel, a cytotoxic agent metabolized by cytochrome P450 hepatic enzymes, is active for the treatment of human immunodeficiency (HIV) associated Kaposi's sarcoma. Protease inhibitors are commonly used to treat HIV infection and are known to inhibit cytochrome P450. We sought to determine whether protease inhibitors alter the pharmacokinetics of paclitaxel.Patients with advanced HIV-associated KS received paclitaxel (100 mg/m(2)) by intravenous infusion over 3 h, and plasma samples were collected to measure paclitaxel concentration. The area under the curve (AUC) was calculated using a combination of the log and linear trapezoidal rule, and clearance was calculated as the dose/AUC. Pharmacokinetics were compared with respect to antiretroviral therapy and toxicity,Thirty-four patients received paclitaxel, of whom 20 had no prior paclitaxel therapy and were assessable for response. Twenty-seven had pharmacokinetic studies performed. Paclitaxel exposure was higher in patients taking protease inhibitors compared to those who were not taking protease inhibitors. The increased exposure did not correlate with efficacy or toxicity. Of the 20 patients assessable for response, 6 (30%) had an objective response and median progression-free survival was 7.8 months (95% confidence interval, 5.6, 21.0 months).Despite higher exposure to paclitaxel, patients on protease inhibitors did not experience enhanced toxicity or efficacy.
- Published
- 2011
37. Activity and Safety of Pegylated Liposomal Doxorubicin as First-Line Therapy in the Treatment of Non-Visceral Classic Kaposi's Sarcoma: A Multicenter Study
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C. Romano, Attilio Guarini, Sabino De Placido, Rossella Di Trolio, Norbert H. Brockmeyer, Vincenzo Montesarchio, Bruce J. Dezube, Alexander Kreuter, Mark Bower, Giuseppe Di Lorenzo, Giuseppe Di, Lorenzo, Alexander, Kreuter, Rossella Di, Trolio, Attilio, Guarini, Carmela, Romano, Vincenzo, Montesarchio, Norbert H., Brockmeyer, DE PLACIDO, Sabino, Mark, Bower, and Bruce J., Dezube
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Treatment outcome ,Dermatology ,Medical Oncology ,Biochemistry ,Polyethylene Glycols ,Pegylated Liposomal Doxorubicin ,First line therapy ,Internal medicine ,medicine ,Humans ,Doxorubicin ,Sarcoma, Kaposi ,Molecular Biology ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Classic Kaposi's sarcoma ,Retrospective cohort study ,Cell Biology ,Middle Aged ,medicine.disease ,Treatment Outcome ,Multicenter study ,Disease Progression ,Female ,Sarcoma ,business ,medicine.drug - Published
- 2008
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38. Human Immunodeficiency Virus–Associated Primary Lung Cancer in the Era of Highly Active Antiretroviral Therapy: A Multi-Institutional Collaboration
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Bruce J. Dezube, Erin Greco, Gabriela A. D’Jaen, Nancy Neil, Jonathan Stem, Liron Pantanowitz, Justin Stebbing, David H. Henry, Timothy P. Cooley, Susan E. Buskin, Mark Bower, and David M. Aboulafia
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Adolescent ,Databases, Factual ,Survival ,International Cooperation ,Population ,Antineoplastic Agents ,HIV Infections ,Adenocarcinoma ,Young Adult ,Acquired immunodeficiency syndrome (AIDS) ,Antiretroviral Therapy, Highly Active ,Internal medicine ,medicine ,Carcinoma ,Surveillance, Epidemiology, and End Results ,Humans ,Age of Onset ,Young adult ,Child ,Lung cancer ,education ,Aged ,Neoplasm Staging ,Aged, 80 and over ,education.field_of_study ,business.industry ,Age Factors ,virus diseases ,Middle Aged ,medicine.disease ,CD4 Lymphocyte Count ,Treatment Outcome ,Oncology ,Immunology ,Carcinoma, Squamous Cell ,Female ,Age of onset ,business ,SEER Program - Abstract
Human immunodeficiency virus (HIV)-infected individuals are at increased risk for primary lung cancer (LC). We wished to compare the clinicopathologic features and treatment outcome of HIV-LC patients with HIV-indeterminate LC patients. We also sought to compare behavioral characteristics and immunologic features of HIV-LC patients with HIV-positive patients without LC.A database of 75 HIV-positive patients with primary LC in the HAART era was established from an international collaboration. These cases were drawn from the archives of contributing physicians who subspecialize in HIV malignancies. Patient characteristics were compared with registry data from the Surveillance Epidemiology and End Results program (SEER; n = 169,091 participants) and with HIV-positive individuals without LC from the Adult and Adolescent Spectrum of HIV-related Diseases project (ASD; n = 36,569 participants).The median age at HIV-related LC diagnosis was 50 years compared with 68 years for SEER participants (P.001). HIV-LC patients, like their SEER counterparts, most frequently presented with stage IIIB/IV cancers (77% vs. 70%), usually with adenocarcinoma (46% vs. 47%) or squamous carcinoma (35% vs. 25%) histologies. HIV-LC patients and ASD participants had comparable median nadir CD4+ cell counts (138 cells/µL vs. 160 cells/µL). At LC diagnosis, their median CD4+ count was 340 cells/µL and 86% were receiving HAART. Sixty-three HIV-LC patients (84%) received cancer-specific treatments, but chemotherapy-associated toxicity was substantial. The median survival for both HIV-LC patients and SEER participants with stage IIIB/IV was 9 months.Most HIV-positive patients were receiving HAART and had substantial improvement in CD4+ cell count at time of LC diagnosis. They were able to receive LC treatments; their tumor types and overall survival were similar to SEER LC participants. However, HIV-LC patients were diagnosed with LC at a younger age than their HIV-indeterminate counterparts. Future research should explore how screening, diagnostic and treatment strategies directed toward the general population may apply to HIV-positive patients at risk for LC.
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- 2010
39. Topacio: Preliminary activity and safety in patients (pts) with platinum-resistant ovarian cancer (PROC) in a phase 1/2 study of niraparib in combination with pembrolizumab
- Author
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Jing Wang, Shaveta Vinayak, Panagiotis A. Konstantinopoulos, Wei Guo, Bruce J. Dezube, Ursula A. Matulonis, Pamela N. Munster, Robert W. Holloway, Lee S. Schwartzberg, and Andres Forero-Torez
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Obstetrics and Gynecology ,Pembrolizumab ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,In patient ,business ,Ovarian cancer ,Platinum resistant - Published
- 2018
40. Fine needle aspiration of breast masses in HIV-infected patients
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Bruce J. Dezube, Liron Pantanowitz, and Pam Michelow
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Biopsy, Fine-Needle ,Population ,Breast Neoplasms ,HIV Infections ,Breast Diseases ,Breast cancer ,Humans ,Medicine ,Child ,skin and connective tissue diseases ,education ,Galactocele ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Dermatology ,Surgery ,Fine-needle aspiration ,Oncology ,Gynecomastia ,Cytopathology ,Female ,Breast disease ,business - Abstract
BACKGROUND: There are limited studies investigating the cytopathology of HIV-related breast disease. The aim of the current study was to evaluate a large series of fine needle aspirations (FNA) performed on breast lesions in HIV-positive patients. METHODS: A retrospective review at the National Health Laboratory Service (NHLS) in Johannesburg, South Africa, was performed on confirmed HIV-positive patients who underwent breast FNA. Cases were evaluated for patient age and sex, presence of a clinical breast lesion, antiretroviral therapy use, specimen adequacy, and cytologic diagnosis. RESULTS: A total of 152 breast FNA procedures were recorded in patients of average age 36 years (range, 10-64 years). Cytologic findings in 100 females patients included 28 inadequate aspirates, 29 cases with a benign diagnosis, 25 abscesses, 3 with reactive intramammary lymphadenopathy, 3 with fat necrosis, 1 galactocele, 1 papillary lesion, 8 breast carcinomas, and 2 non-Hodgkin lymphomas. Fifty-two males underwent breast FNA, of which 6 were inadequate, and 43 (82.7%) showed gynecomastia. In 17 (40%) males with gynecomastia, a history of antiretroviral therapy was recorded. Two males were diagnosed with breast abscess and 1 with Kaposi sarcoma. Microbiology culture revealed 7 Mycobacterium tuberculosis infections in this patient population. CONCLUSIONS: FNA is a procedure to evaluate breast lesions and is capable of rendering results useful for a broad range of diagnoses likely to be encountered in an human immunodeficiency virus (HIV)-positive population. Unlike HIV-infected females who may present with a wide range of benign and neoplastic breast entities, HIV-positive males may have breast lesions that will most likely be attributed to gynecomastia associated with antiretroviral therapy. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.
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- 2010
41. TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial
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Sara M. Tolaney, Corrine Zarwan, Sujata Arora, Georgia A. McCann, Andres Forero-Torres, Andrea E. Wahner Hendrickson, Lee S. Schwartzberg, Bruce J. Dezube, Shaveta Vinayak, Melinda L. Telli, Antoinette R. Tan, John K. Erban, Nathan Buerstatte, Yinghui Zhou, Patrick M. Dillon, Haroun Achour, Filipa Lynce, Monica M. Mita, Gerburg M. Wulf, and Carey K. Anders
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Pembrolizumab ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,PARP1 ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,Programmed death 1 ,business ,Previously treated ,Objective response ,Triple-negative breast cancer - Abstract
1011Background: Chemotherapy is a standard of care for TNBC despite its suboptimal efficacy. ≈15–20% of TNBC have BRCA1/2 mutations (mut); ≈75% of BRCA1 mut BCs are TN. Single agent poly(ADP-ribose) polymerase (PARP) inhibitors have clinical activity in pts with BRCA1/2 mutations (BRCAmut) BC and provide median PFS of 6 mos in pts with BRCAmut TNBC vs 3.5 mos for chemotherapy. Single-agent pembrolizumab (pembro), a programmed death 1(PD–1) inhibitor, has shown objective response rates (ORR) of 5–18% in previously treated TNBC. TOPACIO (NCT02657889) is a fully enrolled study evaluating the safety and efficacy of combination treatment with selective PARP1/2 inhibitor niraparib + pembro in pts with met TNBC. Methods: Pts received niraparib 200 mg orally once daily + pembro 200 mg IV on day 1 of each 21-day cycle. Primary efficacy endpoint was ORR and secondary endpoints included disease control rate (DCR = CR+PR+SD [stable disease]). Results: As of Jan 2018, 12 of 54 enrolled TNBC pts (22%) had deleterious B...
- Published
- 2018
42. Human immunodeficiency virus-associated anaplastic large cell lymphoma
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Bruce J. Dezube, Jorge J. Castillo, Kimberly Perez, and Liron Pantanowitz
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Adolescent ,CD30 ,medicine.medical_treatment ,Ki-1 Antigen ,HIV Infections ,Virus ,hemic and lymphatic diseases ,medicine ,Humans ,Anaplastic lymphoma kinase ,Child ,Extranodal Involvement ,Anaplastic large-cell lymphoma ,Aged ,Chemotherapy ,business.industry ,Large cell ,Infant ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Lymphoma ,Oncology ,Child, Preschool ,Lymphoma, Large-Cell, Anaplastic ,Female ,business - Abstract
Anaplastic large cell lymphoma (ALCL) is a distinct subtype of peripheral T-cell lymphoma (PTCL) characterized by the expression of CD30 in lymphoma cells. Like aggressive B-cell non-Hodgkin lymphoma, the risk of developing PTCL is also increased in the setting of HIV infection. To date, the occurrence of ALCL in HIV-positive individuals is limited to a few case reports and small case series. A total of 37 cases of HIV-associated ALCL were identified after reviewing the available published literature. Analysis of these cases showed that this group of HIV-infected patients was on average 38 years of age with a male-to-female ratio of 4:1, and a reported median CD4 cell count of 83 cells/mm(3). HIV-associated ALCL cells rarely expressed anaplastic lymphoma kinase. Epstein-Barr virus infection was associated with one-third of the cases. These lymphomas manifested almost exclusively with extranodal involvement and exhibited a very aggressive clinical course. The median overall survival was 5 months. The administration of chemotherapy and early stages at presentation were identified as good prognostic factors, while the use of HAART showed a statistical trend toward improved survival in HIV-associated ALCL.
- Published
- 2010
43. Immunohistochemistry in Kaposiâs sarcoma
- Author
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Bruce J. Dezube, Christopher N. Otis, and Liron Pantanowitz
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Pathology ,medicine.medical_specialty ,business.industry ,Cancer ,Anatomical pathology ,Dermatology ,Disease ,Histogenesis ,medicine.disease ,medicine ,Immunohistochemistry ,Neoplasm staging ,Sarcoma ,business ,Kaposi's sarcoma - Abstract
The importance of immunohistochemistry (IHC) to our understanding, ability to confidently diagnose and treat Kaposi's sarcoma (KS) has grown steadily in the past few decades. IHC has been performed on many KS specimen types, with > 100 different primary antibodies. Therefore, it is not surprising that IHC has helped unravel the histogenesis, understand the pathogenesis and facilitate the diagnosis of KS and identify novel therapeutic targets in the disease. This paper reviews the literature on the use of IHC in the study of KS.
- Published
- 2010
44. Studying Rac1-induced tumorigenesis suggests antioxidants may help prevent and treat Kaposi’s sarcoma
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Bruce J. Dezube, Liron Pantanowitz, and Ryan J. Sullivan
- Subjects
Cancer Research ,Angiogenesis ,Cell growth ,Transgene ,RAC1 ,General Medicine ,Biology ,medicine.disease ,medicine.disease_cause ,Virology ,Oncology ,Downregulation and upregulation ,medicine ,Cancer research ,Receptor ,Carcinogenesis ,Kaposi's sarcoma - Abstract
Evaluation of: Ma Q, Cavallin LE, Yan B et al.: Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi’s sarcoma. Proc. Natl Acad. Sci. USA 106, 8683–8688 (2009). The development of Kaposi’s sarcoma (KS) is preceded by the upregulation of several key gene products of human herpesvirus 8/Kaposi’s sarcoma-associated herpesvirus. Some of these virally-encoded proteins are cellular homologs of oncogenes that play a critical role in cell-cycle regulation and apoptosis. Among these, the viral G-protein-coupled receptor, when constitutively activated, leads to robust signaling through the phosphotidyl-inositol-3-kinase pathway, thereby promoting cellular growth, transformation, angiogenesis and anti-apoptosis. Importantly, recent evidence suggests that activation of this complex cellular machinery downstream of the viral G-protein-coupled receptor occurs, at least in part, through the activation of the small G-protein, Rac1. Building upon this, Ma and colleagues describe their development of a mouse model where constitutively active Rac1 leads to the formation of KS-like tumors. Furthermore, it appears that Rac1 signaling leads to reactive oxygen species formation, which appears to be the major driver of tumorigenesis in this model. The potential therapeutic implications of these findings are the incorporation of reactive oxygen species-scavenging agents, such as N-acetyl-cysteine, into the treatment armamentarium for KS. In addition, these agents may be equally or more important in the prevention of KS development in at-risk populations.
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- 2009
45. Future treatment for non-AIDS-defining cancers in HIV-infected patients
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Liron Pantanowitz, Bruce J. Dezube, and John F. Deeken
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Pharmacology ,Oncology ,medicine.medical_specialty ,business.industry ,Integrase inhibitor ,Dermatology ,Raltegravir ,medicine.disease ,Virus ,Reverse transcriptase ,Metastasis ,Infectious Diseases ,Immune system ,Acquired immunodeficiency syndrome (AIDS) ,Virology ,Internal medicine ,Relative risk ,Drug Discovery ,medicine ,Pharmacology (medical) ,business ,medicine.drug - Abstract
ISSN 1758-4310 10.2217/HIV.09.14 © 2009 Future Medicine Ltd HIV Ther. (2009) 3(4), 311–314 at higher risk for some cancers compared with African–Americans and patients of other ethnic groups [7]. Additional risk factors include behavioral aspects, such as an increased use of tobacco and alcohol in patients with HIV [8]. Research has demonstrated that HIV itself may have direct effects that contribute to the development of NADC. For example, the HIV Tat protein may cause transactivation of protooncogenes [9]. Other genes within the HIV virus may inhibit tumor suppressor genes, including p53. HIV infection may cause microsatellite gene instability and genetic alterations leading towards onco genesis. Tissue infection with HIV may make these t issues more sensitive to the effects of carcinogens from the environment. Finally, HIV infection can cause endothelial abnormalities including pro angiogenesis, which may enhance the development of tumor growth and metastasis [1]. There have been conflicting data regarding whether HAART is associated with the risk of developing NADCs. Some studies have demonstrated a decreased risk of developing a NADC while patients are on HAART, compared with patients who are not receiving antiretroviral therapy or are only on single agent or dual agent antiretroviral therapy [7]. Other studies have demonstrated a possible increased risk if patients are on HAART [4], and specifically if they are on a non-nucleoside reverse transcriptase inhibitorbased therapy [5]. A concerning, recent finding in the large Phase III trial that led to the approval of raltegravir (an integrase inhibitor also known as Isentress [Merck] and MK-0518) was that during the period of the study, patients on raltegravir had a higher risk of developing a NADC compared with those taking placebo [10]. Clearly more research is needed to elucidate the role of antiretroviral therapy, immune reconstitution and the relative risk of developing NADCs. Editorial
- Published
- 2009
46. Tumor suppressor microRNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma
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Blossom Damania, Andrea J. O'Hara, Dirk P. Dittmer, William J. Harrington, Bruce J. Dezube, and Ling Wang
- Subjects
Pathology ,medicine.medical_specialty ,Lymphoid Neoplasia ,Tumor suppressor gene ,Gene Expression Profiling ,Immunology ,Cancer ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,law.invention ,MicroRNAs ,law ,RNA interference ,Lymphoma, Primary Effusion ,microRNA ,medicine ,Suppressor ,Gene silencing ,Genes, Tumor Suppressor ,Sarcoma ,Primary effusion lymphoma ,Sarcoma, Kaposi - Abstract
The presence of tumor-specific microRNAs reflects tissue of origin and tumor stage. We show that the absence of miRNAs likewise can be used to determine tumor origin (miR-155) and proliferation state because tumor suppressor miRNAs (miR-222/221, let-7 family) were significantly down-regulated in primary effusion lymphoma (PEL) and in Kaposi sarcoma (KS), an endothelial cell tumor. PEL and KS are associated with KS-associated herpesvirus infection. We identified 15 virally regulated miRNAs in latently infected, nontumorigenic endothelial cells. MiR-143/145 were elevated only in KS tumors, not virally infected endothelial cells. Thus, they represent tumor-specific, rather than virus-specific, miRNAs. Because many tumor suppressor proteins are wild-type in KS and PEL, down-regulation of multiple tumor suppressor miRNAs provides a novel, alternative mechanism of transformation.
- Published
- 2009
47. Targeted Therapy for Kaposi Sarcoma
- Author
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Bruce J. Dezube, Ryan J. Sullivan, and Liron Pantanowitz
- Subjects
AIDS-Related Opportunistic Infections ,medicine.medical_treatment ,Antineoplastic Agents ,HIV Infections ,Virus Replication ,Antiviral Agents ,Article ,Targeted therapy ,Immune reconstitution inflammatory syndrome ,Antiretroviral Therapy, Highly Active ,medicine ,Humans ,Immunologic Factors ,Anthracyclines ,Pharmacology (medical) ,Protein Kinase Inhibitors ,Sarcoma, Kaposi ,Kaposi's sarcoma ,Pharmacology ,business.industry ,virus diseases ,General Medicine ,medicine.disease ,Transplantation ,Sirolimus ,Herpesvirus 8, Human ,Liposomes ,Immunology ,Cancer research ,Sarcoma ,Primary effusion lymphoma ,business ,Immunosuppressive Agents ,Signal Transduction ,Biotechnology ,medicine.drug - Abstract
Kaposi sarcoma (KS) occurs as a result of Kaposi sarcoma-associated herpesvirus (KSHV) infection, typically in the context of one of several immunodeficient states. In the US, patients with KS may either be co-infected with HIV or receiving immunosuppressant therapy following solid-organ transplantation. Systemic treatment of KS has traditionally involved one of several chemotherapeutic agents administered either in combination or as single agents, which typically provide reasonable response rates and short-term control. However, recurrence of KS is common, and progression-free intervals are under 1 year. For these reasons, new therapies have been sought and with the elucidation of novel pathogenic mechanisms of KS infection, rational therapeutic targets have been identified. These include KSHV replication, restoration of immune competence, and signal transduction pathways utilized by KSHV in the propagation of KS. This review focuses on these emerging targets in the treatment of patients with KS and also highlights important clinicopathologic characteristics.
- Published
- 2009
48. Effects of Chemotherapy in AIDS-Associated Non-Hodgkin's Lymphoma on Kaposi's Sarcoma Herpesvirus DNA in Blood
- Author
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Ariela Noy, Susan E. Krown, Jeannette Y. Lee, Lan Lin, Lawrence D. Kaplan, Yanxing Yu, Alexandra M. Levine, Bruce J. Dezube, Richard F. Ambinder, and Gary S. Hayward
- Subjects
Cancer Research ,viruses ,Antineoplastic Agents ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Herpesviridae ,Virus ,Original Reports ,medicine ,Humans ,Gammaherpesvirinae ,Sarcoma, Kaposi ,Kaposi's sarcoma ,Lymphoma, AIDS-Related ,Acquired Immunodeficiency Syndrome ,Clinical Trials as Topic ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Lymphoma, Non-Hodgkin ,virus diseases ,medicine.disease ,biology.organism_classification ,Virology ,Non-Hodgkin's lymphoma ,Lymphoma ,Real-time polymerase chain reaction ,Oncology ,DNA, Viral ,Herpesvirus 8, Human ,Leukocytes, Mononuclear ,business - Abstract
Purpose To determine the relative frequency with which Kaposi's sarcoma–associated herpesvirus/HHV-8 (KSHV) DNA is detected in peripheral-blood mononuclear cells (PBMCs) and in plasma of patients with AIDS-KS and AIDS-associated non-Hodgkin's lymphoma (NHL; AIDS-NHL); to determine whether the presence of viral DNA in plasma reflects lysis of tumor cells or reflects the presence of viremia (ie, virion-encapsidated DNA); and to determine the effect of lymphoma therapy on KSHV DNA. Patients and Methods Samples were obtained from patients enrolled in AIDS Malignancy Consortium clinical trials and from healthy donors. Real time PCR was used to quantify KSHV DNA in peripheral blood mononuclear cells (PBMC) and plasma. DNase digestion and fragment size determination studies were used to characterize the DNA detected. Results In patients with AIDS-KS, KSHV DNA was detected in PBMC (54%) and in plasma (62%). In patients with AIDS-NHL, KSHV DNA was detected in PBMC (19%) and in plasma (22%). Median copy numbers also differed. KSHV DNA in plasma appeared to be encapsidated. In six patients with AIDS-NHL who were treated with chemotherapy (with or without rituximab), KSHV copy number declined in PBMC and in plasma. Conclusion KSHV DNA is sometimes detected in PBMC or in plasma of patients with AIDS-NHL without KS. Among patients with KSHV DNA detected in PBMC or in plasma, copy number does not distinguish between patients with AIDS-NHL and AIDS-KS. KSHV DNA in plasma likely reflects viremia and not simply lysis of tumor or other KSHV-infected cells. KSHV DNA copy number in PBMC and in plasma declined with lymphoma-directed cytotoxic chemotherapy in each of the six patients studied.
- Published
- 2009
49. Frequency and Significance of HIV Infection among Patients Diagnosed with Thrombotic Thrombocytopenic Purpura
- Author
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Gene W. Voskuhl, Deirdra R. Terrell, Sara K. Vesely, James N. George, Bernhard Lämmle, Melody Benjamin, Johanna A. Kremer Hovinga, and Bruce J. Dezube
- Subjects
Adult ,Male ,Microbiology (medical) ,medicine.medical_specialty ,Thrombotic thrombocytopenic purpura ,Prevalence ,ADAMTS13 Protein ,HIV Infections ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Acquired immunodeficiency syndrome (AIDS) ,hemic and lymphatic diseases ,Internal medicine ,Coagulopathy ,Humans ,Medicine ,heterocyclic compounds ,Registries ,Sida ,neoplasms ,Retrospective Studies ,Purpura, Thrombotic Thrombocytopenic ,biology ,business.industry ,Retrospective cohort study ,Middle Aged ,respiratory system ,medicine.disease ,biology.organism_classification ,3. Good health ,ADAM Proteins ,Infectious Diseases ,030220 oncology & carcinogenesis ,Immunology ,Female ,Viral disease ,Differential diagnosis ,business ,therapeutics - Abstract
BACKGROUND: Case series of patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) have reported different frequencies of human immunodeficiency virus (HIV) infection; some series suggest that HIV infection may cause TTP. METHODS: We systematically reviewed all reports of HIV infection in case series of patients with TTP. We analyzed data from the Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry, an inception cohort of 362 consecutive patients, for 1989-2007. RESULTS: Nineteen case series reported the occurrence of HIV infection at the time of diagnosis of TTP in 0%-83% of patients; individual patient data were rarely described. The Oklahoma TTP-HUS Registry determined the HIV status at the time of diagnosis of TTP in 351 (97%) of 362 patients. HIV infection was documented in 6 (1.84%; 95% CI, 0.68%-4.01%) of 326 adult patients (age, 26-51 years); follow-up data were complete for all 6 patients. The period prevalence of HIV infection among all adults in the Oklahoma TTP-HUS Registry region for 1989-2007 was 0.30%. One patient had typical features of TTP with 5 relapses. Five patients had single episodes; in 4, the clinical features that had initially suggested the diagnosis of TTP were subsequently attributed to malignant hypertension (in 3 patients) and disseminated Kaposi sarcoma (in 1 patient). CONCLUSIONS: HIV infection, similar to other inflammatory conditions, may trigger acute episodes of TTP in susceptible patients. More commonly, acquired immunodeficiency syndrome-related disorders may mimic the clinical features of TTP. If the diagnosis of TTP is suggested in a patient with HIV infection, there should be careful evaluation for alternative diagnoses and cautious consideration of plasma exchange, the required treatment for TTP.
- Published
- 2009
50. Detection of JC Virus DNA and Proteins in the Bone Marrow of HIV‐Positive and HIV‐Negative Patients: Implications for Viral Latency and Neurotropic Transformation
- Author
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Janice S. Miller, Chen S. Tan, Patrick Autissier, Parul Bhargava, Igor J. Koralnik, Bruce J. Dezube, and Christian Wüthrich
- Subjects
viruses ,JC virus ,Urine ,Biology ,medicine.disease_cause ,Article ,Virus ,law.invention ,Viral Proteins ,Antigens, CD ,Bone Marrow ,law ,HIV Seronegativity ,HIV Seropositivity ,Virus latency ,medicine ,Humans ,Immunology and Allergy ,Polymerase chain reaction ,Progressive multifocal leukoencephalopathy ,virus diseases ,medicine.disease ,Immunohistochemistry ,JC Virus ,Virology ,Virus Latency ,Blood ,Infectious Diseases ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,DNA, Viral ,Immunology ,Viral disease ,Bone marrow - Abstract
Background We sought to determine the prevalence of JC virus (JCV) in bone marrow samples from human immunodeficiency virus (HIV)-positive and HIV-negative patients and to determine whether bone marrow is a site of latency and neurotropic transformation of JCV, the agent of progressive multifocal leukoencephalopathy (PML). Methods We collected bone marrow aspirates, archival bone marrow samples, and blood and urine samples from 75 HIV-negative and 47 HIV-positive patients without PML as well as bone marrow and urine or kidney samples from 8 HIV-negative and 15 HIV-positive patients with PML. Samples were tested for JCV DNA by quantitative polymerase chain reaction and for JCV protein expression by immunohistochemical analysis. JCV regulatory regions (RRs) were characterized by sequencing. Results JCV DNA was detected in bone marrow samples from 10 (13%) of 75 and 22 (47%) of 47 of the HIV-negative and HIV-positive patients without PML, respectively, compared with 3 (38%) of 8 and 4 (27%) of 15 of the HIV-negative and HIV-positive patients with PML. JCV DNA (range, 2-1081 copies/microg of cellular DNA) was detected in multiple leukocyte subpopulations of blood and bone marrow samples. JCV large T antigen, but not VP1 capsid protein, was expressed in bone marrow plasma cells. Bone marrow JCV RR sequences were similar to those usually found in the brains of patients with PML. Conclusions Bone marrow is an important reservoir and a possible site of neurotropic transformation for JCV.
- Published
- 2009
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