Repurposed drugs to improve blood counts and reduce transfusions in myelodysplastic syndromes

Multi-centre open label randomised phase II trial, to evaluate haematological improvement in patients with low-risk MDS by comparing VBaP versus danazol in patients who have either received ESAs and lost response, not responded to ESAs or are deemed unlikely to respond to ESAs.

The study will test two new experimental treatment options, taking already existing drugs currently used for other purposes or conditions, and now using them to treat MDS. Treatment Group 1 receive sodium valproate (V), bezafibrate (Ba), and medroxyprogesterone (P). This treatment is called ‘VBaP’. Bezafibrate and medroxyprogesterone were used in an earlier trial in acute myeloid leukaemia patients. Several people responded with improved blood cell production. The research team's laboratory has shown that the addition of valproate at low doses could make BaP work better. Treatment Group 2 receive danazol. This drug has been used for many years in patients with low blood counts, but newer studies suggest it may work particularly well in MDS. The study is trying to find out if these ‘repurposed’ drugs can be used to treat MDS patients and to improve their blood counts, reduce their need for transfusions, improve their quality of life, and prolong their survival.

Patients aged 18 years and over diagnosed with lower-risk MDS, who have either not been suitable for erythropoietin injections (EPO), have not responded or stopped responding to EPO, or they have a low neutrophil and/or platelet cell count.

Haematological improvement (HI) in each arm and in the trial overall, with 25% or more of the participants having HI in each arm and overall. HI will be assessed in each participant by comparing post-randomisation FBC parameters (haemoglobin, platelet and neutrophil counts) and transfusion requirements, with their individual baseline as determined by the International Working Group (IWG) 2018 haematology response criteria in patients with MDS. Baseline assessment will be determined by the mean FBC parameters (haemoglobin, platelet and neutrophil counts) and transfusion burden (non-transfused [NTD], low transfusion burden [LTB], high transfusion burden [HTB]) during a 16-week lead-in to randomisation to either VBaP or danazol treatment; Timepoint(s): 12 months.

1. Burden of red cell and/or platelet transfusions measured by comparing mean haemoglobin, platelet and neutrophil counts in addition to transfusion requirements collected during the 16-week evaluation lead-in period to data collected 8 weeks from the start of trial treatment
2. Duration of haematological improvement (i.e. clinically meaningful response as per the IWG 2018 criteria) will be assessed in each participant by comparing post-randomisation full blood counts parameters (haemoglobin, platelet and neutrophil counts) and transfusion requirements, with their individual baseline as determined by the IWG 2018 haematology response criteria in patients with MDS. Baseline assessment will be determined by the mean full blood counts parameters (haemoglobin, platelet and neutrophil counts) and transfusion burden (NTD, LTB, HTB) during a 16-week lead-in to randomisation to either treatment arm.
3. Quality of life measured using patient-reported health-related quality of life (QoL) scores (EQ5D-5L, EORTC-QlQ-C30, HM-PRO and QOL-E) at time of randomisation (baseline), 12 weeks post-randomisation, 24 weeks post-randomisation & 12 months post-randomisation
4. Overall survival assessed using Kaplan Meier curves at 12 months post-randomisation
5. Health resource use measured utilising data collected via the Clinical Report Forms in respect to clinic attendances, admissions, blood transfusion episodes and trial drug and through the use of patient diaries collected at randomisation, 12 weeks, 24 weeks and 12 months post-randomisation

120 participants