Chronic myelomonocytic leukaemia is a myelodysplastic / myeloproliferative neoplasm with a high median age of presentation (>70yrs) and poor prognosis
Conditions
Interventions
All patients will receive tefinostat (CHR-2845) which is a novel monocyte/macrophage-targeted HDAC inhibitor that is cleaved to an active acid (CHR-2847) by an intracellular esterase (hCE-1) that is f
Sponsors
Cardiff University (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. All CMML-2 patients are eligible 2. For patients classified as CMML-1, the following must be present: 2.1. Symptomatic bone marrow failure / myeloproliferation defined as one or more of: red cell transfusion dependence with pre-transfusion Hb 50 x 109/l and/or 2.2. CMML-specific Prognostic Score (CPSS) of intermediate-2 or high risk (16) (details of derivation of CPSS score given below) and/or 2.3. Systemic symptoms including weight loss with no alternative explanation (10% of baseline weight within previous 6 months) 2.4. Symptomatic splenomegaly 2.5. Symptomatic extrameduallary involvement, eg. skin infiltration, serous effusions 3. Subject is able and willing to sign the informed consent form 4. Age greater than or equal to 18 years at the time of signing the informed consent form 5. Willingness to undergo scheduled assessments as per the study protocol including bone marrow assessments 6. ECOG performance status of 0-2 at study entry 7. Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to starting study drug 8. Women of childbearing potential must use at least two effective contraceptive methods throughout the study and for three months following the date of the last dose of study drug 9. Men whose partner is a woman of childbearing potential must use at least two effective contraceptive
Exclusion criteria
Exclusion criteria: 1. CMML with eosinophillia and 5q33 abnormality 2. Previous chemotherapy for CMML except Hydroxycarbamide and 5-azacitidine 3. Creatinine concentration > 2x the institutional upper limit of normal range 4. Liver transaminases (AST / ALT) > 3x the institutional upper limit of normal range or serum bilirubin > 4x the institutional upper limit of normal range 5. Pregnant or lactating females 6. Use of experimental drug or therapy within 28 days of registration 7. Other malignancy within the last 3 years other than curatively-treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with negative prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma 8. Known seropositivity for HIV infection or infectious hepatitis (type B or C) 9. Uncontrolled inter-current illness including, but not limited to, ongoing infection, psychiatric illness or social situation that the treating physician judges would limit compliance with study requirements
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Safety and tolerability of tefinostat defined as the proportion of patients experiencing CTC grade 3-4 non-haematological toxicity or death thought to be at least possibly related to tefinostat 2. Overall clinical response rate (according to Wattel and modified IWG criteria) Patients will receive tefinostat continuously for 6 continuous 4-week cycles (24 weeks). Primary outcome measures will be assessed continuously over this period, including fortnightly peripheral blood assessment (full blood count, blood film/differential) and bone marrow assessments performed after 12 and 24 weeks of therapy. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Incidence and duration of CR/PR/haematological improvement 2. Achievement of red blood cell and platelet transfusion independence 3. Overall survival 4. Progression-free survival 5. Incidence of transformation of CMML to acute myeloid leukaemia (AML), and the time to AML transformation 6. Duration of tefinostat therapy 7. BIological correlates including hCE-1 expression, changes in protein acetylation Patients will receive tefinostat continuously for 6 continuous 4-week cycles (24 weeks). Secondary outcome measures will be assessed continuously over this period, including fortnightly peripheral blood assessment (full blood count, blood film/differential) and bone marrow assessments performed after 12 and 24 weeks of therapy. | — |
Countries
England, Scotland, United Kingdom, Wales
Outcome results
None listed