Abstract
BackgroundThis 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.MethodsPatients 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.ResultsFifty-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.ConclusionsCXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted.Trial registrationClinicalTrials.gov identifier NCT01977638. Registered 07 November 2013.
Highlights
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 UV excision repair protein RAD23 (HR23B) protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity
HDAC inhibitors have been studied across numerous cancer types and have gained regulatory approval in the United States in relapsed / refractory (R/R) cutaneousand peripheral- T-cell lymphoma and in combination with proteasome inhibitors in myeloma
The pivotal Phase 2 studies of Romidepsin [8] and Belinostat [9] demonstrated a small number of patients with peripheral T-cell lymphoma had remarkably durable responses, but there are as yet no established biomarkers to predict response to HDAC inhibitors and potentially guide therapy [5]
Summary
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. HDACs have been described to have non-histone targets, for example deacetylation of the tumour suppressor p53 increases its activity, and other targets include heat shock protein 90 (HSP90) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [4, 5]. HDAC inhibitors have been studied across numerous cancer types and have gained regulatory approval in the United States in relapsed / refractory (R/R) cutaneousand peripheral- T-cell lymphoma and in combination with proteasome inhibitors in myeloma. There are, numerous ongoing studies evaluating HDAC inhibitors in combination with other agents [5]
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