A Phase Ib study of eltrombopag and azacitidine in patients with high risk myelodysplastic syndromes and related disorders

ISRCTN	ISRCTN05858391
DOI	https://doi.org/10.1186/ISRCTN05858391
EudraCT/CTIS number	2013-000341-39
Secondary identifying numbers	14761

Submission date: 05/07/2013
Registration date: 05/07/2013
Last edited: 21/07/2022

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 of protocol

http://www.cancerresearchuk.org/about-cancer/trials/trials-search/a-trial-eltrombopag-azacitidine-myelodysplastic-syndrome-elastic

Contact information

Mrs Becky Bishop
Scientific

Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom

Phone	+44 (0) 121 371 7868
Email	elastic@trials.bham.ac.uk

Study information

Study design	Non-randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	A Phase Ib study of eltrombopag and azacitidine in patients with high risk myelodysplastic syndromes and related disorders
Study acronym	ELASTIC
Study objectives	ELASTIC is a 3+3 cohort trial designed to evaluate the Maximum Tolerated Dose (MTD) and Optimal Biological Dose (OBD) of eltrombopag in combination with azacitidine. This trial will recruit patients with IPSS INT-2/high-risk Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukaemia (CMML-2) and Acute Myeloid Leukaemia (AML) with less than 30% blasts. The objectives of the trial are to evaluate the safety and tolerability of the oral thrombopoietin receptor agonist eltrombopag in combination with azacitidine in patients with advanced MDS and establish the Maximum Tolerated Dose (MTD) and Optimum Biological Dose (OBD). The trial will also aim to investigate the effect of eltrombopag with azacitidine on the fate of MDS/AML stem cell progenitors from patients so treated. The feasibility of Leukaemic Stem Cell (LSC) tracking as a marker of response and predictor of treatment failure in future Phase II/III studies will be explored. A maximum of 27 patients will be recruited to the 3+3 dose finding component of the study and a minimum of 3. The number of patients recruited is determined by the maximum dose of 300mg. An additional 10 patients will then be recruited at the MTD to allow a preliminary estimate of activity. A maximum of 37 patients in total will be recruited to this study.
Ethics approval(s)	13/SC/0309; First MREC approval date 28/06/2013
Health condition(s) or problem(s) studied	Topic: National Cancer Research Network; Subtopic: Haematological Oncology; Disease: Miscellaneous
Intervention	Azacitidine, Hypomethylating agent used within its licensed indication; Eltrombopag, Thrombopoietin receptor (TpoR) agonist; Follow Up Length: 7 month(s); Study Entry : Registration only
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase I
Drug / device / biological / vaccine name(s)	Eltrombopag, azacitidine
Primary outcome measure	Safety and tolerability of eltrombopag in combination with azacitidine; Timepoint(s): Within 5 weeks (1 cycle) of azacitidine treatment
Secondary outcome measures	1. To establish the Optimal Biological dose (OBD) of eltrombopag in combination with azacitidine; Timepoint(s): Within 5 weeks (1 cycle) of azacitidine treatment 2. To evaluate evidence for a dose response effect of eltrombopag on bone marrow blast percentage; Timepoint(s): During 3 cycles of azacitidine treatment 3. To evaluate the activity of eltrombopag plus azacitidine per IWG 2006 response criteria for MDS; Timepoint(s): During 3 cycles of azacitidine treatment 4. To evaluate the dosage effect of eltrombopag on stem/progenitor subset numbers and fate; Timepoint(s): During 3 cycles of azacitidine treatment 5. To evaluate the effect of eltrombopag on azacitidine treatment delays and dose reductions; Timepoint(s): During 3 cycles of azacitidine treatment 6. To evaluate the effect of eltrombopag on bleeding complications; Timepoint(s): During 3 cycles of azacitidine treatment 7. To evaluate the effect of eltrombopag on platelet counts; Timepoint(s): During 3 cycles of azacitidine treatment 8. To evaluate the effect of eltrombopag on the need for platelet transfusions; Timepoint(s): During 3 cycles of azacitidine treatment
Overall study start date	02/09/2013
Completion date	31/08/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	Planned Sample Size: 37; UK Sample Size: 37; Description: As this is a 3+3 design, no formal power calculation has been carried out and analysis will be descriptive only.
Total final enrolment	31
Key inclusion criteria	1. Age >=16 years of age 2. Platelet count at baseline <150 x 109/l 3. Myelodysplastic Syndromes (MDS) classified as Intermediate 2 risk or high risk according to the International Prognostic Scoring System (IPSS) at registration or Chronic Myelomonocytic Leukaemia (CMML) with 10-29% bone marrow blasts without proliferation (peripheral white blood cell count <13 x 109/l) or Acute Myeloid Leukaemia (AML) with 20-30% bone marrow blast 4. Subjects must have platelet count and platelet transfusion data available over a period of 4 weeks prior to registration 5. A baseline bone marrow examination to evaluate blast percentage, karyotype and assessment of fibrotic change within 8 weeks of registraton 6. Alanine Aminotransferase ALT/Aspartate Aminotransferase (AST) < 3 x upper limit of normal ECOG = 2 7. Valid informed consent Target Gender: Male & Female ; Lower Age Limit 16 years
Key exclusion criteria	1. AML with >30% blasts 2. Known HIV positive 3. Known liver cirrhosis 4. Uncontrolled infection (grade 4 CTCAE v4) 5. Previous exposure to azacitidine 6. Previous exposure to thrombomimetic agents 7. Use of prior investigational agents within 6 weeks 8. Other severe, concurrent diseases or mental disorders 9. Concurrent active or previous malignancy within the last 3 years except controlled, localised prostate cancer on hormone therapy or non-melanoma skin malignancy or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ 10. Bone marrow fibrosis 11. Clinical evidence of splenomegaly 12. Known hypersensitivity to study drugs or any of their excipients 13. Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry) 14. Females of childbearing potential (i.e. not postmenopausal or surgically sterilised) who are not willing to use adequate methods of contraception to prevent pregnancy or abstain from heterosexual activity for the duration of the trial and for at least 3 months following treatment discontinuation. 15. Male patients who are not willing to use an adequate method of contraception for the duration of the trial treatment if engaged in sexual activity with a female of childbearing potential and for at least 3 months following treatment discontinuation 16. Patients of east Asian ancestry* * Patients will be excluded if either parent is East Asian (such as Chinese, Japanese, Taiwanese or Korean). In previous studies, the pharmacokinetics of eltrombopag in patients of East Asian ancestry differs significantly from the non-East Asian patients. The SPC for eltrombopag recommends patients receive 50% of the recommended dose. As this is a dose finding study, inclusion of these patients may impair an accurate finding of MTD and OBD that could be applied to the UK population.
Date of first enrolment	02/09/2013
Date of final enrolment	05/10/2015

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

University of Birmingham

Birmingham
B15 2TT
United Kingdom

Sponsor information

University of Birmingham
University/education

Edgbaston
Birmingham
B15 2TT
England
United Kingdom

"ROR"	https://ror.org/03angcq70

Funders

Funder type

Charity

Leukaemia and Lymphoma Research
Private sector organisation / Other non-profit organizations

Location: United Kingdom

Results and Publications

Intention to publish date	01/08/2022
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a peer-reviewed journal. Currently under review.
IPD sharing plan	The Cancer Research UK Clinical Trials Unit (CRCTU) is committed to responsible and controlled sharing of anonymised clinical trial data with the wider research community to maximise potential patient benefit while protecting the privacy and confidentiality of study participants. A summary of the clinical trial results is already available. Participant data and the associated supporting documentation will typically be available for all CRCTU clinical trials within 6 months after the publication of the outcome measures. Only scientifically sound proposals from appropriately qualified research groups will be considered for data sharing. Data Sharing Requests will be reviewed independently by the CRCTU Directors in discussion with the Chief Investigator and relevant Trial Management Group and due diligence checks will be performed.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results		23/09/2021	20/05/2022	No	No
Plain English results	Cancer Research UK summary of results		21/07/2022	No	Yes
HRA research summary			28/06/2023	No	No

Editorial Notes

21/07/2022: The following changes have been made:
1. The Cancer Research UK lay results summary has been added.
2. The total final enrolment number has been added.
23/06/2022: The following changes have been made:
1. The intention to publish date has been changed from 31/01/2021 to 01/08/2022.
2. The publication and dissemination plan has been added.
3. The individual participant data (IPD) sharing statement has been added and the IPD sharing summary has been changed from to.
20/05/2022: EU Clinical Trials Register results added.
10/07/2020: The overall trial end date has been changed from 30/05/2020 to 31/08/2020.
18/03/2020: The following changes have been made:
1. The overall trial end date has been changed from 29/03/2019 to 30/05/2020.
2. The intention to publish date has been changed from 31/12/2019 to 30/01/2021.
10/04/2019: The scientific contact has been changed from Sonia Fox (s.fox.2@bham.ac.uk) to Becky Bishop (elastic@trials.bham.ac.uk).
09/04/2019: The following changes were made to the trial record:
1. The overall end date was changed from 05/10/2015 to 29/03/2019
2. The intention to publish date was added
14/11/2017: No publications found, verifying study status with principal investigator.