High-risk Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukaemia (CMML-2) and Acute Myeloid Leukaemia (AML) with less than 30% blasts. MedDRA version: 18.0 Level: PT Classification code 10000880 Term: Acute myeloid leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 18.0 Level: PT Classification code 10009018 Term: Chronic myelomonocytic leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and u
Conditions
Interventions
Trade Name: Revolade (eltrombopag)
Product Name: Eltrombopag
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Eltrombopag
CAS Number: 496775-61-2
Concentration unit: mg milligram(s)
Concen
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Age =16 years of age • Platelet count at baseline =65 years) yes F.1.3.1 Number of subjects for this age range 30
Exclusion criteria
Exclusion criteria: • AML with >30% blasts • Patients who have received allogeneic bone marrow transplant • Known HIV positive • Known liver cirrhosis • Uncontrolled infection (grade 4 CTCAE v4) • Previous exposure to azacitidine • Previous exposure to thrombomimetic agents • Use of prior investigational agents within 4 weeks • Other severe, concurrent diseases or mental disorders that in the opinion of the investigator make the patients unsuitable for the trial • 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 • Grade 4 bone marrow fibrosis according to the European consensus[3] • Clinical evidence of splenomegaly • Known hypersensitivity to study drugs or any of their excipients • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry) • Females of childbearing potential (i.e. not post-menopausal 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. • 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 • 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of eltrombopag (an oral thrombopoietin receptor agonist) in combination with azacitidine (the standard therapy) in patients with advanced myelodysplastic syndromes and related diseases by establishing the Maximum Tolerated Dose (MTD) and Optimum Biological Dose (OBD). ;Secondary Objective: To investigate the effect of eltrombopag with azacitidine on MDS/AML stem cells. The feasibility of Leukaemic Stem Cell (LSC) tracking as a marker of response and predictor of treatment failure will also be explored for future Phase II/III studies.;Primary end point(s): Safety and tolerability (including establishing the Maximum Tolerated Dose) of eltrombopag in combination with azacitidine when administered to patients with MDS who are suitable for azacitidine treatment.;Timepoint(s) of evaluation of this end point: Within 5 weeks of eltrombopag treatment (i.e. one azacitidine cycle). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • To establish the Optimal Biological dose (OBD) of eltrombopag in combination with azacitidine where this is not limited by MTD. • To evaluate the effect of eltrombopag on platelet counts • To evaluate the effect of eltrombopag on the need for platelet transfusions • To evaluate the effect of eltrombopag on azacitidine treatment delays and dose reductions • To evaluate the effect of eltrombopag on bleeding complications • To evaluate evidence for a dose response effect of eltrombopag on bone marrow blast percentage • To evaluate the activity of eltrombopag plus azacitidine per modified IWG 2006 haematological improvement criteria for MDS response criteria for MDS (Appendix 1 [1]) • To evaluate the activity of eltrombopag plus azacitidine per modified IWG 2006 response criteria for MDS (Appendix 8 [1]) • To evaluate the dosage effect of eltrombopag on stem/progenitor subset numbers and fate ;Timepoint(s) of evaluation of this end point: The OBD will be established via post hoc statistical modelling. The effect of eltrombopag on platelet counts, need for platelet transfusions, azacitidine treatment delays and dose reductions and bleeding will be assessed during combination treatment (3 or 6 azacitidine cycles). The dose response effect of eltrombopag on bone marrow blast percentage will be measured at day 8, week 13 and after 6 cycles of azacitidine (for those patients continuing up to 6 cycles). Activity of eltrombopag according to IWG 2006 will be measured weekly until week 13 and every 4 weeks during weeks 14-25 for patients continuing treatment with azacitidine. | — |
Countries
United Kingdom
Contacts
Public ContactSonia Fox
University of Birmingham
Outcome results
None listed