CHR-2845, a Monocyte/Macrophage Targeted Histone Deacetylase Inhibitor In a First In Man Clinical Trial In Subjects with Advanced Haematological Malignancies

Abstract 3279 CHR-2845 is a novel type of histone deacetylase inhibitor (HDACi) for use in cancer, which is targeted specifically to cells of the monocyte-macrophage lineage. CHR-2845 is a cell-permeant ester that is cleaved to an active acid, CHR-2847, by an intracellular esterase (human carboxylesterase-1, hCE-1) that is primarily found in cells of the monocyte lineage including macrophages, monocytes and Kupffer cells, and also hepatocytes. CHR-2847, being a charged molecule, cannot readily leave cells and, hence, selectively accumulates and is active within hCE-1-expressing cells, resulting in a 20–100 fold increase in anti-proliferative potency of CHR-2845 for monocytic over non-monocytic tumour cells. This selectivity should lead to an increased therapeutic window in haematological malignancies involving cells of the monocyte lineage (AML-M4, AML-M5 and CMML). In addition, there is increasing evidence that macrophages associated with progressive, solid tumours (tumour-associated macrophages (TAMs)) and lymphomas are involved in supporting the growth and spread of the tumour. Circulating monocytes differentiate into resident tissue macrophages and, depending on the local microenvironment, acquire specialised phenotypic characteristics and diverse functions. In tumours, macrophages are reprogrammed by neighbouring tumour cells to induce immune suppression of host defences, facilitating progressive tumour growth and tumour cell dissemination. Targeting TAMs with CHR-2845 could, therefore, also have a beneficial effect in non-monocyte derived tumours. The CHR-2845-001 trial recruited patients with advanced haematological malignancies, who are either refractory to standard therapy or for whom no standard therapy exists. This study is a first in man, open label, dose escalating, multi-centre, phase I study of oral CHR-2845 given once a day over a 28 day course of treatment, with the next cycle started at day 29. Cohorts of 3 to 6 patients were treated at increasing dose levels to establish the MTD. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were taken from all patients in all cohorts. The PD evaluation consisted of a FACS-based assay to compare histone acetylation in monocytes, granulocytes and lymphocytes. 18 patients, 7 F:11 M, median age 73 yrs (51 - 80) were enrolled at doses of 20 (n=3), 40 (n=3), 80 (n=3), 160 (n=3), 320 (n=3) and 640 mg (n=3). Intra-subject dose escalations were allowed, with 2 patients receiving 3 dose levels, and 3 patients receiving 2 different dose levels. The median number of cycles administered was 3 (1 – 9). One patient with AML M2 was treated for 7 cycles, a patient with NHL is ongoing at 7 cycles, and a patient with CMML was on treatment for 9 cycles and achieved a bone marrow response and symptomatic relief, although no impact on peripheral monocytes was seen. Dose limiting toxicities (DLT) have not been observed at any dose, possibly due to the targeted nature of CHR-2845. Dose escalation has been halted at 640 mg. Of 197 AEs reported to date, 54 were considered at least possibly related to CHR-2845. Most were grade 1/2, with only 3 grade 3 (anorexia, asthenia, acute confused state). The most frequent drug-related AEs were nausea (11), anorexia (6) and fatigue (5). No liver enzyme disturbances have been noted. PK analysis of CHR-2845 distribution revealed rapid absorption (Tmax 0.9 – 2.1h) and mean elimination plasma half-life of 2.5 hrs. Cmax and AUC(0-t) increased dose proportionally, although there was high variability between patients. There was no substantial accumulation of CHR-2845 observed on Day 28. Preliminary analysis of histone acetylation in PBMCs shows a pattern of monocyte-specific increases in histone acetylation, with no increase in histone acetylation in granulocytes and lymphocytes. Evaluation of PD samples is continuing and an updated analysis will be presented at the meeting. Conclusions: CHR-2845 is well tolerated, with very few of the drug-related adverse events (like nausea, fatigue, diarrhea) commonly seen with HDACi. Plasma concentrations of CHR-2845 achieved in this trial exceed those required for in vitro anti-proliferative activity in the absence of significant toxicity. Updated results will be presented at the meeting, including an assessment of histone acetylation as a pharmacodynamic biomarker in a FACS based assay which can distinguish between targeted acetylation in monocytes versus granulocytes and lymphocytes. Disclosures: Debnam:Chroma Therapeutics: Employment, Equity Ownership. Needham:Chroma Therapeutics: Employment, Equity Ownership. Bawden:Chroma Therapeutics: Employment, Equity Ownership. Hooftman:Chroma Therapeutics: Employment, Equity Ownership.