Clinical trial NCT04997811: Repurposed Drugs to Improve Haematological Responses in Myelodysplastic Syndromes
Official title: Evaluation of Haematological Improvement in Patients With Low-risk MDS by Comparing VBaP With Danazol in Patients Who Have Either Received Erythropoiesis Stimulating Agents (ESA) and Lost Response, Not Responded to ESA or Are Deemed Unlikely to Respond to ESA
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Myelodysplastic Syndromes (MDS)
Lead sponsor: University of Warwick
Sponsor class: OTHER
Collaborators: name: Blood Cancer UK
name: Dudley Group NHS Foundation Trust
name: University of Birmingham
name: University of Manchester
name: King's College Hospital NHS Trust
First posted: 2021-08-10
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Over 7,000 people in the UK are living with Myelodysplastic Syndromes (MDS). Approximately 1,600 of these individuals (23%) die each year from their disease. MDS affects the production of blood cells by the bone marrow, causing chronic fatigue, bleeding, and recurrent infections. Many patients die because their disease transforms into acute myeloid leukaemia (AML) an even more aggressive blood cancer. The general outlook for AML is poor, but when AML arises from MDS it is worse.

REPAIR-MDS seeks to repurpose existing drugs in order to dramatically improve the outlook, health and quality of life of people with MDS. The trial treatments aim to improve the production of healthy functioning blood and immune cells that will fight against infections and boost the immune system's action against the MDS clone.

REPAIR-MDS design is a is a multicentre open label phase 2 randomised controlled trial which will compare VBaP (sodium valproate, bezafibrate, medroxyprogesterone) with danazol in patients who have received either Erythropoiesis Stimulating Agents (ESAs) and lost response, not responded to ESAs or are deemed unlikely to respond to ESAs.


Eligibility criteria: Inclusion Criteria (for Randomisation):

1. Provision of written informed consent
2. Age ≥ 18 years and able to give informed consent
3. Diagnosis of Myelodysplastic Syndrome with an IPSS-R score of less than or equal to 3.51
4. Haematological parameters:

   1. Mean haemoglobin \< 100 g/l over 16 weeks (pre transfusion) OR
   2. Mean platelets \< 100 x 109/l over 16 weeks + evidence of bleeding (assessed using the ISTH Bleeding Assessment Tool) OR
   3. Mean neutrophils \< 1.0 x 109/l over 16 weeks + history of infection (the requirement for antimicrobial therapy and hospital admissions associated with infection)
5. No response to Erythroid Stimulating Agents (ESAs) OR Have Ceased to respond to ESAs OR are predicated not to respond to ESAs by current UK guidelines2,3￼ (NB Patients with thrombocytopenia and/or neutropenia, without anaemia, are eligible as they are predicated not to respond to ESAs).
6. ECOG performance status 0-3
7. Expected survival \> 12months

Exclusion Criteria (For Randomisation):

Abnormal liver function (if patient has Gilbert's syndrome, then abnormal direct Bilirubin is an exclusion) 2. Cockcroft Gault CrCl \< 20ml/min 3. Current systemic treatment for low risk MDS 4. History of Allogeneic Bone Marrow Transplant 5. History of having received ESAs and/or G-CSF in the past 16 weeks 6. Currently receiving statin medication for Secondary Prophylaxis of Cardiovascular Disease, Cerebrovascular Disease or Peripheral Vascular Disease (Please note patients receiving statin medication for Primary Prophylaxis of Cardiovascular Disease - i.e. the patient has no prior history of Ischaemic Heart Disease nor Cerebrovascular Disease - can still be entered, please see section 1.4 Statin use) 7. Currently receiving fibrate medications 8. Currently receiving sodium valproate, carbamazepine or phenytoin for treatment of epilepsy 9. Prior cytotoxic chemotherapy or hypomethylating agents for AML/MDS (eg Azacitidine) 10. Concurrent active malignancy requiring treatment 11. History of any Androgen Dependent Tumour (patients with Prostate Cancer are Excluded when a biopsy proven diagnosis of Prostate Cancer has been made OR their PSA is known to be elevated OR they are on active treatment for Prostate Cancer, including hormonal therapy).

12. Currently receiving Vitamin K-Antagonist Anticoagulation (though patients receiving DOACs (direct oral anticoagulants) can be included) 13. History of Venous Thrombo-Embolism (VTE) 14. Cardiac Failure NYHA Class III or IV 15. Women of childbearing potential, pregnant or lactating 16. The physician or patient consider VBaP or danazol to be inappropriate for the patient 17. Known HIV 18. Abnormally high CK level 19. Presence of isolated del 5q 20. Acute Porphyria 21. Contraindications to any of the trial medications or known hypersensitivity to any of the investigational products (see Appendix C for contraindications) 22. Previous randomisation in the REPAIR-MDS trial 23. Participation in a clinical trial of an investigational medicinal product in the last 16 weeks

Primary outcomes:
measure: 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.
timeFrame: 12 months
Secondary outcomes:
measure: Reduced burden of red cell and/or platelet transfusion in each arm and in the trial overall, as per the IWG 2018 response criteria.
timeFrame: 12 months
measure: Duration of haematological response
timeFrame: 12 months
measure: Reported improved Health Related Quality of Life scores in each arm and in the trial overall.
timeFrame: 12 months
measure: Overall survival
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: Heartlands Hospital
state: Bordesley Green East
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital NHS Trust
state: Cornwall
city: Poole
country: United Kingdom
facility: University Hospitals Dorset NHS Foundation Trust
state: Dorset
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
state: England
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: England
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
state: Essex
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
state: Essex
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital,
state: Hampshire
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust
state: Hampshire
city: Canterbury
country: United Kingdom
facility: East Kent Hospitals University Foundation Trust
state: Kent
city: Gorleston-on-Sea
country: United Kingdom
facility: James Paget University Hospitals NHS Foundation Trust
state: Norfolk
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Hucknall Road
state: Nottinghamshire
city: Aberdeen
country: United Kingdom
facility: Grampian Health Board
state: Scotland
city: Birmingham
country: United Kingdom
facility: Good Hope Hospital
state: Sutton Coldfield
city: Hull
country: United Kingdom
facility: Hull University Teaching Hospitals
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital, South Tees Hospitals NHS Foundation Trust
city: Newport
country: United Kingdom
facility: Royal Gwent Hospital, Aneurin Bevan University Health Board
Study officials:
References: