Abstract
Background
Chronic myelomonocytic leukemia (CMML) is a highly heterogeneous myeloid neoplasm with poor prognosis and limited therapeutic options. Tefinostat (CHR-2845) is a cell permeant ester that is converted to an active acid histone deacetylase (HDAC) inhibitor (CHR-2847) by human carboxylesterase 1 (hCE-1), an enzyme predominantly found in cells of monocyte lineage. Pre-clinical studies confirmed selective activity of tefinostat, correlating with hCE-1 expression and acetylation induction, in monocyte derived cell lines, primary CMML and AML (M4/M5) cells (1). A phase 1 study in refractory haematological malignancies showed tefinostat to be well tolerated, with complete remission reported in 1/2 CMML patients (2). Given the compelling rationale for selective activity in monocytoid malignancies, we conducted a phase 2 study to assess safety and efficacy of tefinostat in CMML.
Methods
MONOCLE was a single arm phase 2 trial conducted to a Bryant and Day 2-stage design with dual primary endpoints of safety and clinical efficacy. CMML-2 patients were included; additionally CMML-1 patients with symptomatic bone marrow failure or proliferative disease, symptomatic splenomegaly, extramedullary involvement, systemic symptoms or CMML-specific Prognostic Score (CPSS) int-2/high. Tefinostat was administered orally in continuous 28-day cycles starting at 360mg once daily, increasing to 480mg after 4 weeks if well tolerated. Concomitant hydroxycarbamide was permitted only with cycles 1-3. Clinical response was assessed according to International Consortium MDS/MPN Response Criteria (3); responding patients at cycle 6 were permitted to continue therapy. Toxicity was assessed according to CTCAE v4.0.
Results
In stage 1, 21 patients were enrolled at 9 centers (Jan-Sep 2017). 20 patients received tefinostat (median age 75 years [64-88], M/F 14/6) including 16 with CMML-1 (80%) and 4 CMML-2 (20%), 8 (40%) with myelodysplastic and 12 (60%) myeloproliferative CMML; respective proportions in CPSS low/int-1/int-2/high risk groups were 5/50/40/5%. Myeloid NGS analysis confirmed a molecularly relatively high risk population: 70% ASXL1 mutation frequency and median 4 (2-7) mutations per patient; other most commonly observed mutations being TET2 (65%), SRSF2 (50%), EZH2 (35%) and NRAS (35%). Prior therapy included azacitidine (3 patients) and hydroxycarbamide (7). 17/20 patients had high hCE-1 levels, assessed flow cytometrically at trial entry in monocytoid cells (vs bulk myeloid population). Median number of cycles of tefinostat received was 4 (1-15). Of 13 patients completing ≥3 cycles of tefinostat, 1 patient achieved clinical benefit (partial bone marrow response at cycle 6 with red cell transfusion independence sustained over 15 cycles of treatment), 9 had stable disease (of whom 1 had transient clinical benefit [MPN-SAF symptom reduction] which was not sustained to cycle 6) and 3 had progressive disease. Most frequent non-hematologic adverse events of any grade were raised creatinine (55% patients), fatigue (40%) and nausea/vomiting (30%). Grade ≥3 AEs judged potentially related to tefinostat included thrombocytopenia (3 patients), fatigue (2), raised creatinine (2), anorexia, AV block, nausea and neutropenia (1 each). Creatinine rises were in all cases reversible following tefinostat dose reduction/cessation. Induction of intracellular lysine acetylation in monocytes (a marker of HDAC inhibition) was observed in 50% of patients (including clinical responders), peaking between days 15-28 of cycle 1. While no clear relationship between baseline hCE-1 expression and clinical response was evident, reductions in marrow monocyte and myeloid blast fractions were seen in both clinical responders.
Conclusion
Following failure to achieve a pre-defined minimum number of clinical responses to tefinostat, patient recruitment was not continued into stage 2 of this phase 2 study. Drug tolerability was encouraging although observed renal effects will likely preclude dose escalation in this challenging, often frail patient group. Despite compelling scientific rationale and pre-clinical data favoring this monocyte targeted treatment approach we were unable to demonstrate a clinically significant single agent disease modifying effect in CMML.
(1) Zabkiewicz J. Oncotarget 2016; 7: 16650-62
(2) Ossenkoppele G. Br J Haem 2013; 162: 191-201
(3) Savona M. Blood 2015; 125: 1857-65
Disclosures
Knapper: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Meeting and travel support; Jazz: Other: Meeting and travel support; Daiichi Sankyo: Other: Meeting and travel support; Chroma Therapeutics: Research Funding. Hills:Daiichi Sankyo: Consultancy, Honoraria. Dillon:Teva Pharmaceuticals UK: Consultancy, Honoraria; AbbVie UK: Consultancy, Honoraria. Pocock:Kent & Canterbury Hospital: Employment. Culligan:Pfizer: Honoraria; Takeda: Honoraria, Other: Support to attend conferences; JAZZ: Honoraria; Merck Sharp & Dohme (MSD): Honoraria; Abbvie: Other: Support to attend conferences; Celgene: Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences.
Results of a Phase 2 Trial of the Monocyte-Targeted Histone Deacetylase Inhibitor Tefinostat (CHR-2845) in Chronic Myelomonocytic Leukemia (CMML) — the UK Monocle Study