Phase 2 study of tefinostat in chronic myelomonocytic leukaemia (CMML)
| ISRCTN | ISRCTN17394489 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17394489 |
| EudraCT/CTIS number | 2015-002281-23 |
| Secondary identifying numbers | SPON 1345-14 |
- 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
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Contact information
Dr Steven Knapper
Scientific
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
| Study design | Single-arm phase 2 trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| 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 hypothesis | 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 |
| Condition | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Tefinostat |
| Primary outcome measure | 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 outcome measures | 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. |
| Overall study start date | 01/03/2015 |
| Overall study end date | 26/07/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 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) |
| Total final enrolment | 21 |
| Participant 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 |
| Participant 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 |
| Recruitment start date | 01/09/2015 |
| Recruitment end date | 21/09/2017 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Cardiff University
Department of Haematology
Cardiff University
Heath Park
Cardiff
CF14 4XN
United Kingdom
Cardiff University
Heath Park
Cardiff
CF14 4XN
United Kingdom
University Hospital of Wales
Heath Park Way
Cardiff
CF14 4XW
United Kingdom
Cardiff
CF14 4XW
United Kingdom
St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Leeds
LS9 7TF
United Kingdom
The Christie Hospital
Wilmslow Road
Manchester
M20 4BX
United Kingdom
Manchester
M20 4BX
United Kingdom
Aberdeen Royal Infirmary
Foresterhill Health Campus
Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom
Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom
Churchill Hospital
Old Road
Oxford
OX3 7LE
United Kingdom
Oxford
OX3 7LE
United Kingdom
Guy's Hospital
Great Maze Pond
London
SE1 9RT
United Kingdom
London
SE1 9RT
United Kingdom
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
Glasgow
G12 0YN
United Kingdom
Ysbyty Gwynedd
Bangor
LL57 2PW
United Kingdom
LL57 2PW
United Kingdom
Bristol Haematology and Oncology Centre
Horfield Road
Avon
Bristol
BS2 8ED
United Kingdom
Avon
Bristol
BS2 8ED
United Kingdom
Nottingham City Hospital
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Castle Hill Hospital
Castle Road
Cottingham
HU16 5JQ
United Kingdom
Cottingham
HU16 5JQ
United Kingdom
Kent and Canterbury Hospital
Ethelbert Road
Canterbury
CT1 3NG
United Kingdom
Canterbury
CT1 3NG
United Kingdom
Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Sponsor information
Cardiff University (UK)
University/education
University/education
7th Floor
30-36 Newport Road
Cardiff
CF24 0DE
Wales
United Kingdom
"ROR" |
https://ror.org/03kk7td41 |
|---|
Funders
Funder type
Charity
Leukaemia and Lymphoma Research
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/09/2020 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Precise publication plans will be confirmed at a later date. Following completion of study treatment and follow-up it is our intention to initially present the findings from this study at a high profile international haematology meeting (American Society of Hematology or European Haematology Association) prior to publication in high impact peer-reviewed journal. |
| IPD sharing plan | Not provided at time of registration |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | 23/10/2018 | 23/10/2018 | No | Yes | |
| Plain English results | 23/06/2020 | No | Yes | ||
| Abstract results | results presented at ASH | 29/11/2018 | 21/07/2020 | No | No |
| Protocol file | version 3.0 | 28/03/2017 | 18/10/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN17394489_PIS_23Oct2018.pdf
- Uploaded 23/10/2018
- 31184 Monocle Protocol V3.0 28MAR2017.pdf
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.
