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Richard Piekarz - One of the best experts on this subject based on the ideXlab platform.

  • a phase i pharmacokinetic study of Belinostat in patients with advanced cancers and varying degrees of liver dysfunction
    British Journal of Clinical Pharmacology, 2019
    Co-Authors: Naoko Takebe, Richard Piekarz, Jan H Beumer, Brian F Kiesel, Shivaani Kummar, Afshin Dowlati, Geraldine Osullivan Coyne, Larry Rubinstein, Laura K Fogli, Ulka N Vaishampayan
    Abstract:

    Aims The histone deacetylase inhibitor Belinostat has activity in various cancers. Because Belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. Methods We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of Belinostat in patients with advanced cancer and varying degrees of liver dysfunction. Results Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of Belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. Conclusion While a statistically significant difference in clearance indicates increased Belinostat exposure with worsening liver function, no relationship was observed between Belinostat exposure and toxicity. An assessment of Belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.

  • phase i trial of Belinostat in combination with 13 cis retinoic acid in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Cancer Chemotherapy and Pharmacology, 2019
    Co-Authors: Thehang Luu, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, Heinz Joseph Lenz, David R Gandara, Brian F Kiesel, Richard Piekarz
    Abstract:

    The reported maximum tolerated dose (MTD) of single-agent Belinostat is 1000 mg/m2 given days 1–5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of Belinostat combined with 50–100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. Belinostat was administered days 1–5 and 13-cRA days 1–14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to Belinostat. Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of Belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. The combination of Belinostat 2000 mg/m2 days 1–5 and 13-cRA 100 mg/m2 days 1–14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of Belinostat.

  • effects of ugt1a1 genotype on the pharmacokinetics pharmacodynamics and toxicities of Belinostat administered by 48 hour continuous infusion in patients with cancer
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Andrew K L Goey, Tristan M Sissung, Cody J Peer, Jane B Trepel, Minjung Lee, Yusuke Tomita, Sheryl Ehrlich, Christine Bryla, Sanjeeve Balasubramaniam, Richard Piekarz
    Abstract:

    The histone deacetylase inhibitor Belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased Belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter Belinostat exposure and toxicity. In a phase 1 trial (Belinostat over 48 hours in combination with cisplatin and etoposide), Belinostat (400, 500, 600, or 800 mg/m(2) /24 h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n = 25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and Belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P = .003), and t1/2 increased (P = .0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400 mg/m(2) /24 h. The incidence of grades 3-4 thrombocytopenia (P = .0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of Belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic Belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses > 400 mg/m(2) /24 h.

  • ugt1a1 genotype dependent dose adjustment of Belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Cody J Peer, Andrew K L Goey, Tristan M Sissung, Jane B Trepel, Minjung Lee, Yusuke Tomita, Sanjeeve Balasubramaniam, Richard Piekarz, Sheryl Erlich, Susan E Bates
    Abstract:

    Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in Belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize Belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible Belinostat exposure/response relationship, consistent with previous reports.

  • abstract ct207 pharmacokinetic analysis of the hdac inhibitor Belinostat pxd 101 and metabolites in patients with hepatic dysfunction
    Cancer Research, 2014
    Co-Authors: Brian F Kiesel, Guru Reddy, Richard Piekarz, Robert A Parise, Yan Lin, Deborah Allen, S P Chawla, Percy Ivy, Shivaani Kumar, Jan H Beumer
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Histone deacetylases (HDAC) are frequently deregulated in human cancers and their inhibition allows re-expression of silenced genes. Belinostat is an HDAC inhibitor with in vitro and in vivo activity in multiple malignancies, currently in phase II trials. We report the pharmacokinetics of Belinostat and metabolites in patients enrolled in a phase I liver dysfunction trial currently being conducted and led by the NCI. Methods: Patients enrolled into the study were assigned to varying cohorts depending on their level of hepatic dysfunction (normal=N, mild=H1, moderate=H2, and severe=H3). All patients were given a 30 minute infusion at 400 mg/m2 on cycle 1 day -7. Heparinized plasma samples were collected prior to infusion, 15 and 25 min after start, and 5, 10, 15, 30, 60, 90, 120, 240, 360, 480 and 1440 minutes after infusion. Patients from the NCIDTC had samples collected and these were quantitated by a previously validated assay for Belinostat, Belinostat-glucuronide, methyl-Belinostat, M21, M24, and M26. Pharmacokinetic parameters were derived non-compartmentally with PK Solutions. Metabolic ratios were calculated as a measure of metabolic fate. Results: 15 patients (N=2, H1=10, H2=2, H3=1) had useable pharmacokinetic data. Observed Belinostat Cmax (N=21.1±4.9, H1=55.8±78.0, H2=23.0±7.2, H3=23.1 µg/mL) and Belinostat AUC0-inf (N=806±294, H1=1308±996, H2=702±82, H3=780 µg/mL•min) did not reveal any trends with dysfunction cohort. Metabolic AUC0-inf ratios of Belinostat to the various metabolites also did not appear to change with dysfunction cohort. Conclusion: Liver function does not appear to affect the pharmacokinetics or metabolic fate of Belinostat. Analysis of additional subjects is ongoing. The results of this study will facilitate optimal dosing for patients with liver dysfunction. Citation Format: Brian Kiesel, Robert Parise, Yan Lin, Deborah Allen, Guru Reddy, Shanta Chawla, Richard Piekarz, Percy Ivy, Shivaani Kumar, Jan H. Beumer. Pharmacokinetic analysis of the HDAC inhibitor Belinostat (PXD-101) and metabolites in patients with hepatic dysfunction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT207. doi:10.1158/1538-7445.AM2014-CT207

Jan H Beumer - One of the best experts on this subject based on the ideXlab platform.

  • a phase i pharmacokinetic study of Belinostat in patients with advanced cancers and varying degrees of liver dysfunction
    British Journal of Clinical Pharmacology, 2019
    Co-Authors: Naoko Takebe, Richard Piekarz, Jan H Beumer, Brian F Kiesel, Shivaani Kummar, Afshin Dowlati, Geraldine Osullivan Coyne, Larry Rubinstein, Laura K Fogli, Ulka N Vaishampayan
    Abstract:

    Aims The histone deacetylase inhibitor Belinostat has activity in various cancers. Because Belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. Methods We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of Belinostat in patients with advanced cancer and varying degrees of liver dysfunction. Results Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of Belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. Conclusion While a statistically significant difference in clearance indicates increased Belinostat exposure with worsening liver function, no relationship was observed between Belinostat exposure and toxicity. An assessment of Belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.

  • phase i trial of Belinostat in combination with 13 cis retinoic acid in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Cancer Chemotherapy and Pharmacology, 2019
    Co-Authors: Thehang Luu, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, Heinz Joseph Lenz, David R Gandara, Brian F Kiesel, Richard Piekarz
    Abstract:

    The reported maximum tolerated dose (MTD) of single-agent Belinostat is 1000 mg/m2 given days 1–5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of Belinostat combined with 50–100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. Belinostat was administered days 1–5 and 13-cRA days 1–14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to Belinostat. Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of Belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. The combination of Belinostat 2000 mg/m2 days 1–5 and 13-cRA 100 mg/m2 days 1–14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of Belinostat.

  • abstract ct207 pharmacokinetic analysis of the hdac inhibitor Belinostat pxd 101 and metabolites in patients with hepatic dysfunction
    Cancer Research, 2014
    Co-Authors: Brian F Kiesel, Guru Reddy, Richard Piekarz, Robert A Parise, Yan Lin, Deborah Allen, S P Chawla, Percy Ivy, Shivaani Kumar, Jan H Beumer
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Histone deacetylases (HDAC) are frequently deregulated in human cancers and their inhibition allows re-expression of silenced genes. Belinostat is an HDAC inhibitor with in vitro and in vivo activity in multiple malignancies, currently in phase II trials. We report the pharmacokinetics of Belinostat and metabolites in patients enrolled in a phase I liver dysfunction trial currently being conducted and led by the NCI. Methods: Patients enrolled into the study were assigned to varying cohorts depending on their level of hepatic dysfunction (normal=N, mild=H1, moderate=H2, and severe=H3). All patients were given a 30 minute infusion at 400 mg/m2 on cycle 1 day -7. Heparinized plasma samples were collected prior to infusion, 15 and 25 min after start, and 5, 10, 15, 30, 60, 90, 120, 240, 360, 480 and 1440 minutes after infusion. Patients from the NCIDTC had samples collected and these were quantitated by a previously validated assay for Belinostat, Belinostat-glucuronide, methyl-Belinostat, M21, M24, and M26. Pharmacokinetic parameters were derived non-compartmentally with PK Solutions. Metabolic ratios were calculated as a measure of metabolic fate. Results: 15 patients (N=2, H1=10, H2=2, H3=1) had useable pharmacokinetic data. Observed Belinostat Cmax (N=21.1±4.9, H1=55.8±78.0, H2=23.0±7.2, H3=23.1 µg/mL) and Belinostat AUC0-inf (N=806±294, H1=1308±996, H2=702±82, H3=780 µg/mL•min) did not reveal any trends with dysfunction cohort. Metabolic AUC0-inf ratios of Belinostat to the various metabolites also did not appear to change with dysfunction cohort. Conclusion: Liver function does not appear to affect the pharmacokinetics or metabolic fate of Belinostat. Analysis of additional subjects is ongoing. The results of this study will facilitate optimal dosing for patients with liver dysfunction. Citation Format: Brian Kiesel, Robert Parise, Yan Lin, Deborah Allen, Guru Reddy, Shanta Chawla, Richard Piekarz, Percy Ivy, Shivaani Kumar, Jan H. Beumer. Pharmacokinetic analysis of the HDAC inhibitor Belinostat (PXD-101) and metabolites in patients with hepatic dysfunction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT207. doi:10.1158/1538-7445.AM2014-CT207

  • lc ms ms assay for the quantitation of the hdac inhibitor Belinostat and five major metabolites in human plasma
    Journal of Pharmaceutical and Biomedical Analysis, 2013
    Co-Authors: Brian F Kiesel, Jette Tjornelund, Shivaani Kummar, Robert A Parise, Mette Knak Christensen, Einars Loza, Hussein Tawbi, Edward Chu, Jan H Beumer
    Abstract:

    The histone deacetylase inhibitor Belinostat is being evaluated clinically as a single agent in the treatment of peripheral T-cell lymphomas and in combination with other anticancer agents to treat a wide range of human cancers including acute leukemias and solid tumors. To determine the pharmacokinetics of Belinostat in the NCI ODWG liver dysfunction study, we developed and validated an LC-MS/MS assay for the quantitation of Belinostat and five major metabolites in 0.05 mL human plasma. After protein precipitation, chromatographic separation was achieved with a Waters Acquity BEH C18 column and a linear gradient of 0.1% formic acid in acetonitrile and water. Detection with an ABI 4000Q mass spectrometer utilized both electrospray positive and negative mode ionization. The assay was linear from 30 to 5000 ng/mL for all six analytes and proved to be accurate (92.0-104.4%) and precise (CV <13.7%), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring parent drug and five major metabolites in plasma from a patient who was administered Belinostat IV at a dose of 400 mg/m(2). The LC-MS/MS assay that has been developed will be an essential tool to further define the metabolism and pharmacology of Belinostat in the ongoing liver organ dysfunction as well as other studies that investigate Belinostat with other anticancer agents.

  • phi 53 nci 7251 phase i trial of Belinostat pxd101 in combination with 13 cis retinoic acid 13c ra in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Journal of Clinical Oncology, 2013
    Co-Authors: Thehang Luu, Richard Piekarz, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, David R Gandara, Heinzjosef Lenz, Edward M Newman
    Abstract:

    2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma Belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of Belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to toxicity: ≥grade 3. We sought the MTD of Belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose ...

David R Gandara - One of the best experts on this subject based on the ideXlab platform.

  • phase i trial of Belinostat in combination with 13 cis retinoic acid in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Cancer Chemotherapy and Pharmacology, 2019
    Co-Authors: Thehang Luu, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, Heinz Joseph Lenz, David R Gandara, Brian F Kiesel, Richard Piekarz
    Abstract:

    The reported maximum tolerated dose (MTD) of single-agent Belinostat is 1000 mg/m2 given days 1–5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of Belinostat combined with 50–100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. Belinostat was administered days 1–5 and 13-cRA days 1–14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to Belinostat. Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of Belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. The combination of Belinostat 2000 mg/m2 days 1–5 and 13-cRA 100 mg/m2 days 1–14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of Belinostat.

  • phi 53 nci 7251 phase i trial of Belinostat pxd101 in combination with 13 cis retinoic acid 13c ra in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Journal of Clinical Oncology, 2013
    Co-Authors: Thehang Luu, Richard Piekarz, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, David R Gandara, Heinzjosef Lenz, Edward M Newman
    Abstract:

    2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma Belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of Belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to toxicity: ≥grade 3. We sought the MTD of Belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose ...

  • phase ii study of Belinostat pxd101 a histone deacetylase inhibitor for second line therapy of advanced malignant pleural mesothelioma
    Journal of Thoracic Oncology, 2009
    Co-Authors: Suresh S Ramalingam, Paul Frankel, David R Gandara, Christopher Ruel, Chandra P Belani, Barbara J Gitlitz, Marianna Koczywas, Igor Espinozadelgado
    Abstract:

    Background: Belinostat (PXD 101) is a novel inhibitor of class I and II histone deacetylases. This class of compounds has demonstrated anticancer activity in malignant mesothelioma. We conducted a phase II study of Belinostat in patients with relapsed malignant pleural mesothelioma. Methods: Patients with advanced mesothelioma, progression with one prior chemotherapy regimen and Eastern Cooperative Oncology Group performance status 0–2 were eligible. Belinostat was administered at 1000 mg/m 2 intravenously over 30 minutes on days 1–5 of every 3 week cycle. The primary end point was response rate. The Simon two-stage design was used. Disease assessments were performed every two cycles. Results: Thirteen patients were enrolled. Baseline characteristics were: median age of 73 years; Eastern Cooperative Oncology Group performance status 0 ( n = 4), 1 (8) and 2 (1). A median of two cycles of therapy were administered. Disease stabilization was seen in two patients. No objective responses were noted and the study did not meet criteria to proceed to the second stage of accrual. Median survival was 5 months with a median progression-free survival of 1 month. Salient toxicities included nausea, emesis, fatigue, and constipation. One patient died as a consequence of cardiac arrhythmia which was deemed ‘possibly' related to therapy. Conclusions: Belinostat is not active as monotherapy against recurrent malignant pleural mesothelioma. Evaluation of combination strategies or alternate dosing schedules may be necessary for further development of this novel agent in mesothelioma.

Edward M Newman - One of the best experts on this subject based on the ideXlab platform.

  • a phase 2 study of Belinostat pxd101 in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia a california cancer consortium study
    Leukemia & Lymphoma, 2014
    Co-Authors: Mark Kirschbaum, Joseph Tuscano, Paul Frankel, Kenneth A Foon, Christopher Ruel, Bernadette Pulone, Edward M Newman
    Abstract:

    We performed a phase II study of Belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m(2) daily on days 1-5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.

  • phi 53 nci 7251 phase i trial of Belinostat pxd101 in combination with 13 cis retinoic acid 13c ra in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Journal of Clinical Oncology, 2013
    Co-Authors: Thehang Luu, Richard Piekarz, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, David R Gandara, Heinzjosef Lenz, Edward M Newman
    Abstract:

    2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma Belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of Belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to toxicity: ≥grade 3. We sought the MTD of Belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose ...

Paul Frankel - One of the best experts on this subject based on the ideXlab platform.

  • phase i trial of Belinostat in combination with 13 cis retinoic acid in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Cancer Chemotherapy and Pharmacology, 2019
    Co-Authors: Thehang Luu, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, Heinz Joseph Lenz, David R Gandara, Brian F Kiesel, Richard Piekarz
    Abstract:

    The reported maximum tolerated dose (MTD) of single-agent Belinostat is 1000 mg/m2 given days 1–5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of Belinostat combined with 50–100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. Belinostat was administered days 1–5 and 13-cRA days 1–14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to Belinostat. Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day Belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of Belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. The combination of Belinostat 2000 mg/m2 days 1–5 and 13-cRA 100 mg/m2 days 1–14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of Belinostat.

  • a phase 2 study of Belinostat pxd101 in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia a california cancer consortium study
    Leukemia & Lymphoma, 2014
    Co-Authors: Mark Kirschbaum, Joseph Tuscano, Paul Frankel, Kenneth A Foon, Christopher Ruel, Bernadette Pulone, Edward M Newman
    Abstract:

    We performed a phase II study of Belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m(2) daily on days 1-5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.

  • phi 53 nci 7251 phase i trial of Belinostat pxd101 in combination with 13 cis retinoic acid 13c ra in advanced solid tumor malignancies a california cancer consortium nci ctep sponsored trial
    Journal of Clinical Oncology, 2013
    Co-Authors: Thehang Luu, Richard Piekarz, Paul Frankel, Jan H Beumer, Dean Lim, Mihaela C Cristea, Leonard Joseph Appleman, David R Gandara, Heinzjosef Lenz, Edward M Newman
    Abstract:

    2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma Belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of Belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to toxicity: ≥grade 3. We sought the MTD of Belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose ...

  • phase ii study of Belinostat pxd101 a histone deacetylase inhibitor for second line therapy of advanced malignant pleural mesothelioma
    Journal of Thoracic Oncology, 2009
    Co-Authors: Suresh S Ramalingam, Paul Frankel, David R Gandara, Christopher Ruel, Chandra P Belani, Barbara J Gitlitz, Marianna Koczywas, Igor Espinozadelgado
    Abstract:

    Background: Belinostat (PXD 101) is a novel inhibitor of class I and II histone deacetylases. This class of compounds has demonstrated anticancer activity in malignant mesothelioma. We conducted a phase II study of Belinostat in patients with relapsed malignant pleural mesothelioma. Methods: Patients with advanced mesothelioma, progression with one prior chemotherapy regimen and Eastern Cooperative Oncology Group performance status 0–2 were eligible. Belinostat was administered at 1000 mg/m 2 intravenously over 30 minutes on days 1–5 of every 3 week cycle. The primary end point was response rate. The Simon two-stage design was used. Disease assessments were performed every two cycles. Results: Thirteen patients were enrolled. Baseline characteristics were: median age of 73 years; Eastern Cooperative Oncology Group performance status 0 ( n = 4), 1 (8) and 2 (1). A median of two cycles of therapy were administered. Disease stabilization was seen in two patients. No objective responses were noted and the study did not meet criteria to proceed to the second stage of accrual. Median survival was 5 months with a median progression-free survival of 1 month. Salient toxicities included nausea, emesis, fatigue, and constipation. One patient died as a consequence of cardiac arrhythmia which was deemed ‘possibly' related to therapy. Conclusions: Belinostat is not active as monotherapy against recurrent malignant pleural mesothelioma. Evaluation of combination strategies or alternate dosing schedules may be necessary for further development of this novel agent in mesothelioma.