Condition category
Cancer
Date applied
24/09/2015
Date assigned
25/09/2015
Last edited
24/11/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Scientific

Primary contact

Dr Steven Knapper

ORCID ID

http://orcid.org/0000-0002-6405-4441

Contact details

Institute of Cancer & Genetics
Cardiff University
Heath Park
Cardiff
CF14 4XN
United Kingdom
+44 (0)292 074 5379
knappers@cardiff.ac.uk

Additional identifiers

EudraCT number

2015-002281-23

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

A phase 2 study of the monocyte-targeted histone deacetylase inhibitor tefinostat (CHR-2845) in chronic myelomonocytic leukaemia (CMML)

Acronym

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

Wales REC 3, 15/01/2016, REC ref: 15/WA/0391

Study design

Single-arm phase 2 trial

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not yet available

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

Phase

Phase II

Drug names

Tefinostat

Primary outcome measures

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 trial start date

01/03/2015

Overall trial end date

28/02/2018

Reason abandoned

Eligibility

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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

40

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

01/03/2017

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Cardiff University
Department of Haematology Cardiff University Heath Park
Cardiff
CF14 4XN
United Kingdom

Sponsor information

Organisation

Cardiff University (UK)

Sponsor details

7th Floor
30-36 Newport Road
Cardiff
CF24 0DE
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

Leukaemia and Lymphoma Research

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

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.

Intention to publish date

01/03/2018

Participant level data

Not expected to be available

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

24/11/2016: Internal review. 24/03/2016: Ethics approval information added.