A randomised phase 2 study of ASTX727 versus best supportive care in MDS/MPN Overlap Syndromes

Study ID: 52390
Short Title: AMMO
Trust Name: UHS
Recruitment Site: Southampton General Hospital
Disease Area: Haematology
Phase: II
Expected End Date: 31/05/2024
Postcode: SO16 6YD
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

• ≥18 years of age at the time of trial entry • Morphologically confirmed diagnosis of MDS/MPN (excluding JMML),in accordance with WHO 2016 diagnostic criteria (Appendix 4),with any of the following characteristics:  CMML-2 disease stage [CMML only]  CPSS [Such et al Blood 2013] or CPSS-Mol [Elena et al Blood 2016] score of intermediate-2 or high risk [CMML only]  Other patients with one or more of the following: o Bone Marrow blasts > 10% (including promonocytes) o Adverse risk cytogenetics (as defined by CPSS or MDS R-IPSS) o WCC ≥50 (or ≥30 with symptoms attributable to myeloproliferation) o RBC transfusion dependence with pre-transfusion Hb < 90 g/L o Symptomatic anaemia (with Hb ≤100 g/L) o Thrombocytopenia (Plt ≤50 x 109/L) o Symptomatic splenomegaly o Systemic symptoms with no alternative explanation (including weight loss ≥10% of baseline over previous 6 months) o Symptomatic extramedullary involvement (e.g. skin infiltration,serous effusions) • Treatment-naïve for prior hypomethylating agent,intensive chemotherapy or other disease-modifying anti-neoplastic therapy (e.g. lenalidomide); patients may have received prior hydroxycarbamide,recombinant erythropoietin,danazol,interferon or anagrelide. • ECOG performance status of 0,1 or 2 at trial entry (Appendix 3). • Life expectancy of ≥3 months at trial entry,as assessed by the treating physician. • Must have adequate hepatic,renal and endocrine function during screening as demonstrated by the following:  ALT and/or AST ≤3x upper limit of normal (ULN);  Total bilirubin ≤1.5x ULN or ≤2x ULN if upon judgement of the treating investigator the hyperbilirubinaemia is due to extramedullary haematopoiesis related to the underlying MDS/MPN or to Gilbert’s disease;  Serum creatinine ≤1.5x ULN or estimated creatinine clearance >/= 30ml/min/1.73m2. • Patient willing and able to comply with scheduled visits,treatment plan and other study procedures. • Patient able to provide written informed consent for the trial

• Patients eligible for intensive chemotherapy and/or allogeneic haematopoietic stem cell transplantation (HSCT). • CMML with eosinophilia and 5q33 abnormality. • Previous cytotoxic chemotherapy for MDS/MPN,except hydroxycarbamide. • Prior hypomethylating agent exposure. • Transformation to AML (≥20% myeloid blasts in bone marrow or peripheral blood at screening). • Prior organ transplantation,including allogeneic haematopoietic stem cell transplant (HSCT). • Known or suspected central nervous system disease involvement. • Known history of clinically significant or uncontrolled cardiac disease,including recent history (within 6 months) of unstable angina,acute myocardial infarction,NYHA class III or IV congestive cardiac failure,or clinically significant arrhythmia. • Other active malignancy,not including localized non-melanoma skin cancer,cervical carcinoma in situ,breast ductal carcinoma in situ of the breast,or localized prostate cancer controlled with hormone therapy. Patients with history of other cancers should be free of disease without ongoing anti-neoplastic therapy for at least 2 years. • Receipt of wide-field radiotherapy (including therapeutic radioisotopes) ≤28 days or limited field radiation for palliation ≤14 days prior to starting any study medications (or has not recovered from side effects of such therapy). • Active,uncontrolled infection. Patients with infection under control with active treatment are eligible. • Pregnant and lactating patients (patients of childbearing potential (see Section 7.7) must have a negative pregnancy test prior to study entry). • Females of childbearing potential,and their partners,not willing to use adequate contraception during and for up to 6 months after treatment (see Section 7.7). • Any other concurrent serious or unstable medical,psychiatric,familial,geographic or sociological condition that in the investigator’s opinion would jeopardise the patient’s ability to comply with the protocol.

A multicentre,phase II,randomised (2:1) clinical trial of ASTX727 compared to best supportive care (BSC) +/- hydroxycarbamide in adult patients with MDS/Overlap syndromes including CMML. A total of 75 patients will be recruited over a 2 year period from across the network of UK TAP sites. Randomisation will be stratified by (i) presence or absence of proliferative disease (defined by WHO criteria as a white cell count ≥ or < 13 x109/L); and (ii) time from diagnosis,to extend eligibility to both newly diagnosed and longer established patients. At screening treating physicians will declare in advance a proposed BSC approach for that patient,to be employed in the event of randomisation to the BSC arm. The main aim of the study is to compare the overall response rate of ASTX727 vs best supportive care +/- hydroxycarbamide.

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