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 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.

• Authors: 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
• Journal: BMC cancer (BMC Cancer) Vol. 21 Issue 1 Pg. 851 (Jul 23 2021) ISSN: 1471-2407 [Electronic] England
• PMID: 34301221 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Biomarkers, Tumor
• DNA-Binding Proteins
• Histone Deacetylase Inhibitors
• RAD23B protein, human
• DNA Repair Enzymes

Topics

• Adult
• Aged
• Biomarkers, Tumor
• DNA Repair Enzymes (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Gene Expression
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Humans
• Immunohistochemistry (methods)
• Lymphoma (diagnosis, drug therapy, genetics)
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (diagnosis, drug therapy, genetics)
• Treatment Outcome