A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma
Abstract Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and...
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doaj-ed0569a0654b401a969430ba23e234a62021-07-25T11:34:01ZengBMCBMC Cancer1471-24072021-07-0121111010.1186/s12885-021-08595-wA Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphomaStephen W. Booth0Toby A. Eyre1John Whittaker2Leticia Campo3Lai Mun Wang4Elizabeth Soilleux5Daniel Royston6Gabrielle Rees7Murali Kesavan8Catherine Hildyard9Farasat Kazmi10Nick La Thangue11David Kerr12Mark R. Middleton13Graham P. Collins14Department of Haematology, NIHR Oxford Biomedical Research Centre, Oxford University HospitalsDepartment of Haematology, NIHR Oxford Biomedical Research Centre, Oxford University HospitalsCelleron Therapeutics LtdDepartment of Oncology, University of OxfordDepartment of Cellular Pathology, Oxford University HospitalsDepartment of Pathology, University of CambridgeDepartment of Cellular Pathology, Oxford University HospitalsDepartment of Cellular Pathology, Oxford University HospitalsDepartment of Haematology, NIHR Oxford Biomedical Research Centre, Oxford University HospitalsDepartment of Haematology, Milton Keynes University HospitalDepartment of Oncology, University of OxfordCelleron Therapeutics LtdCelleron Therapeutics LtdDepartment of Oncology, University of OxfordDepartment of Haematology, NIHR Oxford Biomedical Research Centre, Oxford University HospitalsAbstract Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.https://doi.org/10.1186/s12885-021-08595-wHistone deacetylase (HDAC)HR23BBiomarkerLymphoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stephen W. Booth Toby A. Eyre John Whittaker Leticia Campo Lai Mun Wang Elizabeth Soilleux Daniel Royston Gabrielle Rees Murali Kesavan Catherine Hildyard Farasat Kazmi Nick La Thangue David Kerr Mark R. Middleton Graham P. Collins |
spellingShingle |
Stephen W. Booth Toby A. Eyre John Whittaker Leticia Campo Lai Mun Wang Elizabeth Soilleux Daniel Royston Gabrielle Rees Murali Kesavan Catherine Hildyard Farasat Kazmi Nick La Thangue David Kerr Mark R. Middleton Graham P. Collins A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma BMC Cancer Histone deacetylase (HDAC) HR23B Biomarker Lymphoma |
author_facet |
Stephen W. Booth Toby A. Eyre John Whittaker Leticia Campo Lai Mun Wang Elizabeth Soilleux Daniel Royston Gabrielle Rees Murali Kesavan Catherine Hildyard Farasat Kazmi Nick La Thangue David Kerr Mark R. Middleton Graham P. Collins |
author_sort |
Stephen W. Booth |
title |
A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma |
title_short |
A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma |
title_full |
A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma |
title_fullStr |
A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma |
title_full_unstemmed |
A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma |
title_sort |
phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of cxd101 in patients with advanced solid-organ cancer expressing hr23b or lymphoma |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2021-07-01 |
description |
Abstract Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013. |
topic |
Histone deacetylase (HDAC) HR23B Biomarker Lymphoma |
url |
https://doi.org/10.1186/s12885-021-08595-w |
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