Repurposed Drugs to Improve Haematological Responses in Myelodysplastic Syndromes

Overview

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

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