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

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, 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

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.

Keywords: Biomarker; HR23B; Histone deacetylase (HDAC); Lymphoma.

Conflict of interest statement

Graham P. Collins has received personal fees from Celleron Therapeutics for work performed as part of the current study. John Whittaker, Nick La Thangue, and David Kerr are directors of Celleron Therapeutics. Celleron Therapeutics was involved in the design of the study. The Oxford Centre for Experimental Cancer Medicine was involved in design of the study, data collection, analysis, and interpretation.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Swimmer plot of treatment duration by CXD101 dose and tumour histology * Recommended Phase 2 dose
Fig. 2
Fig. 2
Best tumour responses in patients with lymphoma evaluable for response. Best tumour responses as assessed by sum of product diameters of target lesions in evaluable patients with lymphoma (in percentage) for CXD101 doses of ≥16 mg twice daily in patients shown according to baseline tumour HR23B status by immunohistochemistry and best disease response by Cheson et al. [21]. Two patients (1 FL and 1cHL) were not evaluable for objective response but clinically had a best response of progressive disease. * denotes patients with reduction in target lesions but clear progression of non-target lesions and / or new lesions. cHL classic Hodgkin lymphoma; GZL grey zone lymphoma; AITL angioimmunoblastic T-cell lymphoma; PTCL Peripheral T-cell lymphoma NOS; FL follicular lymphoma

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