Phase 2 study of tefinostat in chronic myelomonocytic leukaemia (CMML)
| ISRCTN | ISRCTN17394489 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17394489 |
| Clinical Trials Information System (CTIS) | 2015-002281-23 |
| Protocol serial number | SPON 1345-14 |
| Sponsor | Cardiff University (UK) |
| Funder | Leukaemia and Lymphoma Research |
- Submission date
- 24/09/2015
- Registration date
- 25/09/2015
- Last edited
- 18/10/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English summary of protocol
Contact information
Scientific
Institute of Cancer & Genetics
Cardiff University
Heath Park
Cardiff
CF14 4XN
United Kingdom
 ORCID ID |
0000-0002-6405-4441 |
|---|---|
| Phone | +44 (0)292 074 5379 |
| knappers@cardiff.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Single-arm phase 2 trial |
| Secondary study design | Non randomised study |
| Participant information sheet | ISRCTN17394489_PIS_23Oct2018.pdf |
| Scientific title | A phase 2 study of the monocyte-targeted histone deacetylase inhibitor tefinostat (CHR-2845) in chronic myelomonocytic leukaemia (CMML) |
| Study acronym | MONOCLE |
| Study objectives | The dual primary objectives of the study are: 1. To evaluate the safety and tolerability of tefinostat (CHR-2845) in chronic myelomonocytic leukaemia 2. To evaluate the overall clinical response rate to tefinostat in patients with chronic myelomonocytic leukaemia (according to Wattel and modified IWG criteria) |
| Ethics approval(s) | Wales REC 3, 15/01/2016, REC ref: 15/WA/0391 |
| Health condition(s) or problem(s) studied | Chronic myelomonocytic leukaemia is a myelodysplastic / myeloproliferative neoplasm with a high median age of presentation (>70yrs) and poor prognosis; the median survival from diagnosis remains only 11-17 months and very few clinical studies have addressed the disease in isolation. |
| Intervention | 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 found only in cells of monocytoid lineage. CHR-2847 selectively accumulates within hCE-1 expressing cells resulting in a 20 to 100-fold increase in potency of tefinostat for monocytic tumour cells, which make up the majority of the disease cells in CMML. In a previous first-in-man study of tefinostat in patients with refractory haematological malignancies treated with continuous doses of 20 to 640mg, tefinostat was well-tolerated with no 'maximum tolerated dose' being defined. Selective targeted increases in protein acetylation in monocytoid cells were demonstrated between 40 and 320mg. Of 2 CMML patients treated in that study, one achieved a bone marrow complete response at relatively small doses (20-80mg). |
| Intervention type | Drug |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Tefinostat |
| Primary outcome measure(s) |
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 |
| Key secondary outcome measure(s) |
1. Incidence and duration of CR/PR/haematological improvement |
| Completion date | 26/07/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | All |
| Target sample size at registration | 40 |
| Total final enrolment | 21 |
| Key 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 <90g/l symptomatic anaemia (Hb <115g/l) thrombocytopenia (platelets <50 x 109/l) symptomatic bleeding due to platelet function defect or DIC/fibrinolysis white blood cell count >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 |
| Key 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 |
| Date of first enrolment | 01/09/2015 |
| Date of final enrolment | 21/09/2017 |
Locations
Countries of recruitment
- United Kingdom
- England
- Scotland
- Wales
Study participating centres
Cardiff University
Heath Park
Cardiff
CF14 4XN
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Leeds
LS9 7TF
United Kingdom
Manchester
M20 4BX
United Kingdom
Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom
Oxford
OX3 7LE
United Kingdom
London
SE1 9RT
United Kingdom
Glasgow
G12 0YN
United Kingdom
LL57 2PW
United Kingdom
Avon
Bristol
BS2 8ED
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Cottingham
HU16 5JQ
United Kingdom
Canterbury
CT1 3NG
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Results and Publications
| Individual participant data (IPD) Intention to share | No |
|---|---|
| IPD sharing plan summary | Not expected to be made available |
| IPD sharing plan | Not provided at time of registration |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Abstract results | results presented at ASH | 29/11/2018 | 21/07/2020 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Participant information sheet | 23/10/2018 | 23/10/2018 | No | Yes | |
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
| Plain English results | 23/06/2020 | No | Yes | ||
| Protocol file | version 3.0 | 28/03/2017 | 18/10/2022 | No | No |
Additional files
- ISRCTN17394489_PIS_23Oct2018.pdf
- Uploaded 23/10/2018
- 31184 Monocle Protocol V3.0 28MAR2017.pdf
- Protocol file
Editorial Notes
18/10/2022: The following changes were made to the trial record:
1. Uploaded protocol (not peer-reviewed) as an additional file.
2. The acronym was added.
21/07/2020: The following changes have been made:
1. Publication reference added.
2. The final enrolment number has been updated from the reference.
23/06/2020: The following changes were made to the trial record:
1. The total final enrolment was added.
2. Link to results (plain English) added.
10/06/2020: The following changes were made to the trial record:
1. The acronym was added.
2. The recruitment end date was changed from 01/03/2017 to 21/09/2017.
3. The intention to publish date was changed from 31/12/2019 to 01/09/2020.
23/10/2018: The following changes have been made to the trial record:
1. The protocol/serial number was added
2. The overall trial end date has been changed from 28/02/2018 to 26/07/2019
3. The participant information sheet has been uploaded
4. The target number of participants has been changed from "40" to "20 (previously 40; however, there were an insufficient number of objective clinical responses seen in part 1 of the study to reach the threshold required to trigger the opening of part 2. Therefore the trial never opened to the second stage and did not fulfil the overall study recruitment target of 40 patients)"
5. University Hospital of Wales, St James's Hospital, The Christie Hospital, Aberdeen Royal Infirmary, Churchill Hospital, Guys Hospital, Beatson West of Scotland Cancer Centre, Ysbyty Gwynedd, Bristol Haematology and Oncology Centre, Nottingham City Hospital, Castle Hill Hospital, Kent and Canterbury Hospital and Freeman Hospital were added as trial participating centres
6. The intention to publish date was changed from 01/03/2018 to 31/12/2019
24/05/2017: Cancer Help UK lay summary link added to plain English summary field
10/04/2017: Internal review.
24/03/2016: Ethics approval information added.
