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Anas Younes - One of the best experts on this subject based on the ideXlab platform.

  • a phase 2 study of Mocetinostat a histone deacetylase inhibitor in relapsed or refractory lymphoma
    British Journal of Haematology, 2017
    Co-Authors: Connie Lee Batlevi, Michael Crump, Charalambos Andreadis, David A Rizzieri, Sarit Assouline, Richard Van Der Jagt, Amanda R Copeland, Diane Potvin, Richard Chao, Anas Younes
    Abstract:

    Summary Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated Mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received Mocetinostat (starting doses: 70–110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clinical benefit (response or stable disease) from Mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1·8 to 22·8 months and 11·8 to 26·3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhoea (61·1%). Although Mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

  • a phase ii study of single agent Mocetinostat an oral isotype selective histone deacetylase hdac inhibitor in patients with diffuse large cell b cell dlbcl and follicular fl lymphomas
    Journal of Clinical Oncology, 2013
    Co-Authors: Michael Crump, Charalambos Andreadis, David A Rizzieri, Sarit Assouline, Richard Van Der Jagt, Gregory K Reid, Robert E Martell, Amanda Copeland, Jeffrey M. Besterman, Anas Younes
    Abstract:

    8535 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received Mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achi...

  • Mocetinostat for relapsed classical hodgkin s lymphoma an open label single arm phase 2 trial
    Lancet Oncology, 2011
    Co-Authors: Anas Younes, Amanda Copeland, Gregory R Bociek, John Kuruvilla, Michelle A Fanale, Sattva S Neelapu, Daniela Buglio, Ahmed Galal, J M Besterman, Zuomei Li
    Abstract:

    Summary Background The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of Mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Methods Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with Mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982. Findings 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Interpretation Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. Funding MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.

  • Mocetinostat mgcd0103 a review of an isotype specific histone deacetylase inhibitor
    Expert Opinion on Investigational Drugs, 2011
    Co-Authors: Yanis Boumber, Anas Younes, Guillermo Garciamanero
    Abstract:

    Introduction: HDAC inhibitors (HDACIs) have the potential to restore gene expression and display antitumor effects in vitro. As single agents, HDACIs have clinical activity in lymphoma. In myeloid leukemias, combinations of DNA methylation inhibitors and HDACIs are promising. Other combinations are being studied in solid tumors. Areas covered: This article covers basic information and an update on preclinical and clinical experience with the oral isotype-selective HDACI MGCD0103 (Mocetinostat) in hematological malignancies and solid tumors. It also examines data concerning MGCD0103 from recent conferences and articles through to November 2010, including new data regarding responses in lymphoma and toxicities. Expert opinion: MGCD0103 is well-tolerated and exhibits favorable pharmacokinetic and pharmacodynamic profiles, demonstrating target inhibition and clinical responses. It induces cell death and autophagy, synergizes with proteasomal inhibitors and affects non-histone targets, such as microtubules. In...

  • Mocetinostat mgcd0103 an isotype selective histone deacetylase hdac inhibitor produces clinical responses in relapsed refractory hodgkin lymphoma hl update from a phase ii clinical study
    Blood, 2010
    Co-Authors: Anas Younes, Jeffrey M. Besterman, Gregory R Bociek, John Kuruvilla, Pierre Laneuville, Henry C Fung, Michel Drouin, Tracy Patterson, Robert E Martell
    Abstract:

    Abstract 1763 Background: HL patients with relapsed or refractory disease are incurable with standard therapies and new options are needed. Deregulation of HDAC activity can cause malignant diseases in humans. Mocetinostat inhibits Class I and IV HDACs and was shown to have preclinical and clinical activity. Methods: This was an open-label, Phase II trial in adults (≥18 years old) with relapsed/refractory HL. Patients initially received MGCD0103 at a starting dose of 110 mg (110 mg cohort) or 85 mg (85 mg cohort) 3x per week in 4-week cycles. Eligibility criteria included ≥1 target lesion (≥2 cm), no limit of prior therapies, ECOG status of 0–1, and platelet counts ≥25,000/μL. Tumor responses were determined every 8 weeks. The primary objective of this study was to estimate the treatment success rate defined as complete response (CR) + partial response (PR) + durable stable disease (SD for at least 6 cycles). Results: A total of 51 patients (23 patients in the 110 mg cohort and 28 patients in the 85 mg cohort) were enrolled (median age: 33 years old, range: 19–68 years old; gender: 29 male, 22 female; 84% caucasians; ECOG: 0: 49%, 1: 51%). Two patients experienced CR (110 mg cohort), 12 patients experienced PR (6 patients in each cohort) and 1 patient experienced durable SD (in the 85 mg cohort). The success rate was found to be 35% in the efficacy evaluable population (n=43) and 29% in the intent-to-treat population (n=51). Treatment-related adverse events of grade 3 or higher in ≥ 5% of patients included: thrombocytopenia (22%), fatigue (16%), neutropenia (14%), pneumonia (12%), anemia (10%), pericardial effusion (6%) and abnormal liver function tests (6%). Conclusions: Mocetinostat demonstrated single agent activity in heavily pretreated relapsed/refractory HL patients. The response rate reported in this study is among the best single agent activity described in HL with HDAC inhibitors, especially in the context of the minimal hematological toxicity observed. Despite the modest increased incidence of non-fatal pericardial effusions, the benefits of Mocetinostat outweigh the risks in this heavily pretreated patient population for which no curative options are available. Further development of Mocetinostat in HL is warranted, especially in less heavily treated patients and with prospective cardiac evaluations. Disclosures: Younes:Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Kuruvilla:Hoffman Laroche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria. Drouin:Methylgene: Employment. Patterson:Methylgene: Employment. Besterman:Methylgene: Employment, Equity Ownership. Martell:Methylgene: Equity Ownership.

Robert E Martell - One of the best experts on this subject based on the ideXlab platform.

  • a phase ii study of Mocetinostat an oral isotype selective histone deacetylase hdac inhibitor in combination with 5 azacitidine in patients with myelodysplastic syndrome mds
    Journal of Clinical Oncology, 2013
    Co-Authors: Selina M Luger, Casey Oconnell, Virginia M Klimek, Maureen Cooper, Emmanuel C Besa, James M Rossetti, Gregory K Reid, Rachel Humphrey, Robert E Martell, Guillermo Garciamanero
    Abstract:

    7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of Mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and Mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + ...

  • A phase II study of single agent Mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas.
    Journal of Clinical Oncology, 2013
    Co-Authors: Michael Crump, Charalambos Andreadis, David A Rizzieri, Sarit Assouline, Richard Van Der Jagt, Gregory K Reid, Amanda Copeland, Jeffrey M. Besterman, Robert E Martell
    Abstract:

    8535 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received Mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range:

  • a phase ii study of single agent Mocetinostat an oral isotype selective histone deacetylase hdac inhibitor in patients with diffuse large cell b cell dlbcl and follicular fl lymphomas
    Journal of Clinical Oncology, 2013
    Co-Authors: Michael Crump, Charalambos Andreadis, David A Rizzieri, Sarit Assouline, Richard Van Der Jagt, Gregory K Reid, Robert E Martell, Amanda Copeland, Jeffrey M. Besterman, Anas Younes
    Abstract:

    8535 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received Mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achi...

  • Mocetinostat mgcd0103 an isotype selective histone deacetylase hdac inhibitor produces clinical responses in relapsed refractory hodgkin lymphoma hl update from a phase ii clinical study
    Blood, 2010
    Co-Authors: Anas Younes, Jeffrey M. Besterman, Gregory R Bociek, John Kuruvilla, Pierre Laneuville, Henry C Fung, Michel Drouin, Tracy Patterson, Robert E Martell
    Abstract:

    Abstract 1763 Background: HL patients with relapsed or refractory disease are incurable with standard therapies and new options are needed. Deregulation of HDAC activity can cause malignant diseases in humans. Mocetinostat inhibits Class I and IV HDACs and was shown to have preclinical and clinical activity. Methods: This was an open-label, Phase II trial in adults (≥18 years old) with relapsed/refractory HL. Patients initially received MGCD0103 at a starting dose of 110 mg (110 mg cohort) or 85 mg (85 mg cohort) 3x per week in 4-week cycles. Eligibility criteria included ≥1 target lesion (≥2 cm), no limit of prior therapies, ECOG status of 0–1, and platelet counts ≥25,000/μL. Tumor responses were determined every 8 weeks. The primary objective of this study was to estimate the treatment success rate defined as complete response (CR) + partial response (PR) + durable stable disease (SD for at least 6 cycles). Results: A total of 51 patients (23 patients in the 110 mg cohort and 28 patients in the 85 mg cohort) were enrolled (median age: 33 years old, range: 19–68 years old; gender: 29 male, 22 female; 84% caucasians; ECOG: 0: 49%, 1: 51%). Two patients experienced CR (110 mg cohort), 12 patients experienced PR (6 patients in each cohort) and 1 patient experienced durable SD (in the 85 mg cohort). The success rate was found to be 35% in the efficacy evaluable population (n=43) and 29% in the intent-to-treat population (n=51). Treatment-related adverse events of grade 3 or higher in ≥ 5% of patients included: thrombocytopenia (22%), fatigue (16%), neutropenia (14%), pneumonia (12%), anemia (10%), pericardial effusion (6%) and abnormal liver function tests (6%). Conclusions: Mocetinostat demonstrated single agent activity in heavily pretreated relapsed/refractory HL patients. The response rate reported in this study is among the best single agent activity described in HL with HDAC inhibitors, especially in the context of the minimal hematological toxicity observed. Despite the modest increased incidence of non-fatal pericardial effusions, the benefits of Mocetinostat outweigh the risks in this heavily pretreated patient population for which no curative options are available. Further development of Mocetinostat in HL is warranted, especially in less heavily treated patients and with prospective cardiac evaluations. Disclosures: Younes:Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Kuruvilla:Hoffman Laroche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria. Drouin:Methylgene: Employment. Patterson:Methylgene: Employment. Besterman:Methylgene: Employment, Equity Ownership. Martell:Methylgene: Equity Ownership.

  • Mocetinostat (MGCD0103), An Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, Produces Clinical Responses In Relapsed/Refractory Hodgkin Lymphoma (HL): Update From a Phase II Clinical Study
    Blood, 2010
    Co-Authors: Anas Younes, Jeffrey M. Besterman, John Kuruvilla, Pierre Laneuville, Henry C Fung, Michel Drouin, Tracy Patterson, R. Gregory Bociek, Robert E Martell
    Abstract:

    Abstract 1763 Background: HL patients with relapsed or refractory disease are incurable with standard therapies and new options are needed. Deregulation of HDAC activity can cause malignant diseases in humans. Mocetinostat inhibits Class I and IV HDACs and was shown to have preclinical and clinical activity. Methods: This was an open-label, Phase II trial in adults (≥18 years old) with relapsed/refractory HL. Patients initially received MGCD0103 at a starting dose of 110 mg (110 mg cohort) or 85 mg (85 mg cohort) 3x per week in 4-week cycles. Eligibility criteria included ≥1 target lesion (≥2 cm), no limit of prior therapies, ECOG status of 0–1, and platelet counts ≥25,000/μL. Tumor responses were determined every 8 weeks. The primary objective of this study was to estimate the treatment success rate defined as complete response (CR) + partial response (PR) + durable stable disease (SD for at least 6 cycles). Results: A total of 51 patients (23 patients in the 110 mg cohort and 28 patients in the 85 mg cohort) were enrolled (median age: 33 years old, range: 19–68 years old; gender: 29 male, 22 female; 84% caucasians; ECOG: 0: 49%, 1: 51%). Two patients experienced CR (110 mg cohort), 12 patients experienced PR (6 patients in each cohort) and 1 patient experienced durable SD (in the 85 mg cohort). The success rate was found to be 35% in the efficacy evaluable population (n=43) and 29% in the intent-to-treat population (n=51). Treatment-related adverse events of grade 3 or higher in ≥ 5% of patients included: thrombocytopenia (22%), fatigue (16%), neutropenia (14%), pneumonia (12%), anemia (10%), pericardial effusion (6%) and abnormal liver function tests (6%). Conclusions: Mocetinostat demonstrated single agent activity in heavily pretreated relapsed/refractory HL patients. The response rate reported in this study is among the best single agent activity described in HL with HDAC inhibitors, especially in the context of the minimal hematological toxicity observed. Despite the modest increased incidence of non-fatal pericardial effusions, the benefits of Mocetinostat outweigh the risks in this heavily pretreated patient population for which no curative options are available. Further development of Mocetinostat in HL is warranted, especially in less heavily treated patients and with prospective cardiac evaluations. Disclosures: Younes:Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Kuruvilla:Hoffman Laroche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria. Drouin:Methylgene: Employment. Patterson:Methylgene: Employment. Besterman:Methylgene: Employment, Equity Ownership. Martell:Methylgene: Equity Ownership.

Guillermo Garciamanero - One of the best experts on this subject based on the ideXlab platform.

  • a phase ii study of Mocetinostat an oral isotype selective histone deacetylase hdac inhibitor in combination with 5 azacitidine in patients with myelodysplastic syndrome mds
    Journal of Clinical Oncology, 2013
    Co-Authors: Selina M Luger, Casey Oconnell, Virginia M Klimek, Maureen Cooper, Emmanuel C Besa, James M Rossetti, Gregory K Reid, Rachel Humphrey, Robert E Martell, Guillermo Garciamanero
    Abstract:

    7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of Mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and Mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + ...

  • Mocetinostat mgcd0103 a review of an isotype specific histone deacetylase inhibitor
    Expert Opinion on Investigational Drugs, 2011
    Co-Authors: Yanis Boumber, Anas Younes, Guillermo Garciamanero
    Abstract:

    Introduction: HDAC inhibitors (HDACIs) have the potential to restore gene expression and display antitumor effects in vitro. As single agents, HDACIs have clinical activity in lymphoma. In myeloid leukemias, combinations of DNA methylation inhibitors and HDACIs are promising. Other combinations are being studied in solid tumors. Areas covered: This article covers basic information and an update on preclinical and clinical experience with the oral isotype-selective HDACI MGCD0103 (Mocetinostat) in hematological malignancies and solid tumors. It also examines data concerning MGCD0103 from recent conferences and articles through to November 2010, including new data regarding responses in lymphoma and toxicities. Expert opinion: MGCD0103 is well-tolerated and exhibits favorable pharmacokinetic and pharmacodynamic profiles, demonstrating target inhibition and clinical responses. It induces cell death and autophagy, synergizes with proteasomal inhibitors and affects non-histone targets, such as microtubules. In...

John Kuruvilla - One of the best experts on this subject based on the ideXlab platform.

  • Mocetinostat for relapsed classical hodgkin s lymphoma an open label single arm phase 2 trial
    Lancet Oncology, 2011
    Co-Authors: Anas Younes, Amanda Copeland, Gregory R Bociek, John Kuruvilla, Michelle A Fanale, Sattva S Neelapu, Daniela Buglio, Ahmed Galal, J M Besterman, Zuomei Li
    Abstract:

    Summary Background The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of Mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Methods Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with Mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982. Findings 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Interpretation Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. Funding MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.

  • Mocetinostat mgcd0103 an isotype selective histone deacetylase hdac inhibitor produces clinical responses in relapsed refractory hodgkin lymphoma hl update from a phase ii clinical study
    Blood, 2010
    Co-Authors: Anas Younes, Jeffrey M. Besterman, Gregory R Bociek, John Kuruvilla, Pierre Laneuville, Henry C Fung, Michel Drouin, Tracy Patterson, Robert E Martell
    Abstract:

    Abstract 1763 Background: HL patients with relapsed or refractory disease are incurable with standard therapies and new options are needed. Deregulation of HDAC activity can cause malignant diseases in humans. Mocetinostat inhibits Class I and IV HDACs and was shown to have preclinical and clinical activity. Methods: This was an open-label, Phase II trial in adults (≥18 years old) with relapsed/refractory HL. Patients initially received MGCD0103 at a starting dose of 110 mg (110 mg cohort) or 85 mg (85 mg cohort) 3x per week in 4-week cycles. Eligibility criteria included ≥1 target lesion (≥2 cm), no limit of prior therapies, ECOG status of 0–1, and platelet counts ≥25,000/μL. Tumor responses were determined every 8 weeks. The primary objective of this study was to estimate the treatment success rate defined as complete response (CR) + partial response (PR) + durable stable disease (SD for at least 6 cycles). Results: A total of 51 patients (23 patients in the 110 mg cohort and 28 patients in the 85 mg cohort) were enrolled (median age: 33 years old, range: 19–68 years old; gender: 29 male, 22 female; 84% caucasians; ECOG: 0: 49%, 1: 51%). Two patients experienced CR (110 mg cohort), 12 patients experienced PR (6 patients in each cohort) and 1 patient experienced durable SD (in the 85 mg cohort). The success rate was found to be 35% in the efficacy evaluable population (n=43) and 29% in the intent-to-treat population (n=51). Treatment-related adverse events of grade 3 or higher in ≥ 5% of patients included: thrombocytopenia (22%), fatigue (16%), neutropenia (14%), pneumonia (12%), anemia (10%), pericardial effusion (6%) and abnormal liver function tests (6%). Conclusions: Mocetinostat demonstrated single agent activity in heavily pretreated relapsed/refractory HL patients. The response rate reported in this study is among the best single agent activity described in HL with HDAC inhibitors, especially in the context of the minimal hematological toxicity observed. Despite the modest increased incidence of non-fatal pericardial effusions, the benefits of Mocetinostat outweigh the risks in this heavily pretreated patient population for which no curative options are available. Further development of Mocetinostat in HL is warranted, especially in less heavily treated patients and with prospective cardiac evaluations. Disclosures: Younes:Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Kuruvilla:Hoffman Laroche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria. Drouin:Methylgene: Employment. Patterson:Methylgene: Employment. Besterman:Methylgene: Employment, Equity Ownership. Martell:Methylgene: Equity Ownership.

  • Mocetinostat (MGCD0103), An Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, Produces Clinical Responses In Relapsed/Refractory Hodgkin Lymphoma (HL): Update From a Phase II Clinical Study
    Blood, 2010
    Co-Authors: Anas Younes, Jeffrey M. Besterman, John Kuruvilla, Pierre Laneuville, Henry C Fung, Michel Drouin, Tracy Patterson, R. Gregory Bociek, Robert E Martell
    Abstract:

    Abstract 1763 Background: HL patients with relapsed or refractory disease are incurable with standard therapies and new options are needed. Deregulation of HDAC activity can cause malignant diseases in humans. Mocetinostat inhibits Class I and IV HDACs and was shown to have preclinical and clinical activity. Methods: This was an open-label, Phase II trial in adults (≥18 years old) with relapsed/refractory HL. Patients initially received MGCD0103 at a starting dose of 110 mg (110 mg cohort) or 85 mg (85 mg cohort) 3x per week in 4-week cycles. Eligibility criteria included ≥1 target lesion (≥2 cm), no limit of prior therapies, ECOG status of 0–1, and platelet counts ≥25,000/μL. Tumor responses were determined every 8 weeks. The primary objective of this study was to estimate the treatment success rate defined as complete response (CR) + partial response (PR) + durable stable disease (SD for at least 6 cycles). Results: A total of 51 patients (23 patients in the 110 mg cohort and 28 patients in the 85 mg cohort) were enrolled (median age: 33 years old, range: 19–68 years old; gender: 29 male, 22 female; 84% caucasians; ECOG: 0: 49%, 1: 51%). Two patients experienced CR (110 mg cohort), 12 patients experienced PR (6 patients in each cohort) and 1 patient experienced durable SD (in the 85 mg cohort). The success rate was found to be 35% in the efficacy evaluable population (n=43) and 29% in the intent-to-treat population (n=51). Treatment-related adverse events of grade 3 or higher in ≥ 5% of patients included: thrombocytopenia (22%), fatigue (16%), neutropenia (14%), pneumonia (12%), anemia (10%), pericardial effusion (6%) and abnormal liver function tests (6%). Conclusions: Mocetinostat demonstrated single agent activity in heavily pretreated relapsed/refractory HL patients. The response rate reported in this study is among the best single agent activity described in HL with HDAC inhibitors, especially in the context of the minimal hematological toxicity observed. Despite the modest increased incidence of non-fatal pericardial effusions, the benefits of Mocetinostat outweigh the risks in this heavily pretreated patient population for which no curative options are available. Further development of Mocetinostat in HL is warranted, especially in less heavily treated patients and with prospective cardiac evaluations. Disclosures: Younes:Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Kuruvilla:Hoffman Laroche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria. Drouin:Methylgene: Employment. Patterson:Methylgene: Employment. Besterman:Methylgene: Employment, Equity Ownership. Martell:Methylgene: Equity Ownership.

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

  • Phase I/II study of Mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors
    Cancer Chemotherapy and Pharmacology, 2018
    Co-Authors: Emily Chan, Diane Potvin, Richard Chao, E. Gabriela Chiorean, Peter J. O’dwyer, Nashat Y. Gabrail, Thierry Alcindor, Herbert Hurwitz
    Abstract:

    Purpose To evaluate the safety and efficacy of Mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer. Methods In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m^2, day 1 of three consecutive weeks, 4-week cycles) and oral Mocetinostat [50–110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR). Results Forty-eight patients were enrolled into the Phase I ( n  = 25) and Phase II ( n  = 23) studies. In the Phase I study, the MTD/RP2D was Mocetinostat 90 mg TIW + gemcitabine 1000 mg/m^2. Grade ≥ 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study ( n  = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated. Conclusions Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting.

  • a phase 2 study of Mocetinostat a histone deacetylase inhibitor in relapsed or refractory lymphoma
    British Journal of Haematology, 2017
    Co-Authors: Connie Lee Batlevi, Michael Crump, Charalambos Andreadis, David A Rizzieri, Sarit Assouline, Richard Van Der Jagt, Amanda R Copeland, Diane Potvin, Richard Chao, Anas Younes
    Abstract:

    Summary Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated Mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received Mocetinostat (starting doses: 70–110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clinical benefit (response or stable disease) from Mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1·8 to 22·8 months and 11·8 to 26·3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhoea (61·1%). Although Mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

  • combination therapy with Mocetinostat an oral spectrum selective histone deacetylase hdac inhibitor and 5 azaciditine indication of clinical activity in mds
    Blood, 2013
    Co-Authors: Luger Selina, Richard Chao, Emmanuel C Besa, James M Rossetti, Rachel Humphrey, Klimek Virginia, Cooper Maureen, Lewis R Silverman
    Abstract:

    ![Graphic][1] Background Mocetinostat (MGCD0103) is an orally available, spectrum-selective, non-hydroxamate histone deacetylase (HDAC) inhibitor targeting HDACs 1, 2, 3 and 11. Single-agent activity has been observed in Myelodysplastic Syndromes (MDS), Acute Myelogenous Leukemia (AML), Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. Preclinical studies demonstrating potential synergy between hypomethylating agents and HDAC inhibitors in relieving transcriptional repression support the evaluation of Mocetinostat in combination with 5-azacitidine (AZA) in MDS and AML. Methods The objectives of this open-label, Phase I/II trial of patients with MDS or AML were to determine the MTD of Mocetinostat when combined with AZA (75 mg/m2 SC; days 1-7 every 28 days) and to estimate the overall response rate of this combination. In addition, we conducted an ad hoc, independent response assessment for all patients in this study (ASCO 2013) and performed a retrospective, subset analysis on those patients entering this study with 5-20% bone marrow blasts at screening to represent a population with RAEB-1 and RAEB-2. Results A total of 66 subjects with AML and intermediate and high-risk MDS were enrolled in this phase I/II trial. In the Phase I component, 24 patients were treated at 5 dose levels of Mocetinostat that ranged from 35 to 135 mg administered 3x/wk starting on Day 5 of treatment with AZA, and in the Phase II component, 42 patients were treated at 90 mg or 110 mg of Mocetinostat 3x/wk with AZA. We were interested in analyzing the responses of MDS patients enrolled in this study to gauge the potential for improved activity compared to AZA monotherapy. Therefore, the subset of interest for the current analysis included 22 with baseline bone marrow blast counts of 5-20%, including 8 with 5-9% and 14 with 10-20% bone marrow blasts. The median age was 73 (range 41-82) with 13M and 9F. Thirteen pts received no prior treatment with chemotherapy or other agents for MDS, and 9 were previously treated. Cytogenetic analyses were available for 7 patients: diploid, 2; monosomy 7, 3 (all with other anomalies); complex, 1; and trisomy 8, 1. Chromosome 5 abnormalities occurred in the presence of other abnormalities (2 with monosomy 7). Eighteen patients initiated dosing at 90 mg, 3 at 110 mg, and 1 at 135 mg. The most common ≥ Grade 3 drug-related adverse events were diarrhea (23%), fatigue (18%), thrombocytopenia (18%), and anemia (14%). The CR+CRi rate was 13/22 (59%), with 1 additional patient demonstrating hematologic improvement. The CR+CRi rate appeared similar regardless of line of therapy and the percentage of blasts at baseline (5-9% vs. 10-20%). Most patients (68%) demonstrated decreases in bone marrow blast counts on at least one post-treatment assessment. Of 17 patients who were either RBC or platelet transfusion dependent at baseline, 6 patients (35%) became transfusion-free of both red cells and platelets. Conclusions The combination of Mocetinostat and AZA is active in patients with MDS, including some patients who were previously treated and is associated with a 59% rate of CR+CRi in a subset of patients with 5-20% bone marrow blasts at screening, and with 35% of transfusion-dependent patients becoming transfusion independent. A randomized study is planned to further evaluate the clinical activity of Mocetinostat plus AZA in MDS. Disclosures: Chao: Mirati Therapeutics: Employment. Humphrey: Mirati Therapeutics Inc.: Employment. [1]: /embed/inline-graphic-2.gif