Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes

• Status: Unknown status
• Trial end date: 2019-06-01
• Target enrollment: 0
• Participant gender: All

Summary

In order to improve the overall survival benefit observed with AZA in higher risk MDS, its combination with other active drugs in MDS must be tested.

Among drugs that have demonstrated to be active as a single agent in MDS and have preclinical potential additive or synergistic activity with AZA are Histone deacetylase (HDAC) inhibitors including Valproic acid, Lenalidomide and idarubicin. Phase I studies have already been conducted or are being conducted combining those agents to demethylating agents, showing a low toxicity profile and significant responses in high risk MDS. In this phase II randomized trial, we want to identify the most promising combination of Azacitidine and another drug (among 3 drugs: Valproic acid, Lenalidomide and Idarubicin) in higher risk MDS, by comparison to Azacitidine alone. Of note, based on efficacy and toxicity, one or several combinations may be stopped, and others, previously tested in phase I trials, included after protocol amendment.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Assistance Publique - Hôpitaux de Paris
• Treatments: Azacitidine; Idarubicin; Lenalidomide; Thalidomide; Valproic Acid

Criteria

Inclusion Criteria:

• age>=18 years

• Must be able to adhere to the study visit schedule and other protocol requirements

• Documented diagnosis of MDS, including AREB-t according to FAB classification or CMML (with WBC < 13,000/mm3) that meets IPSS criteria for intermediate-2 or high-risk.

• Patients should be willing to use adequate contraceptive methods during all the duration of the study

Exclusion Criteria:

1. Treatment with AZA or Decitabine in the previous 6 months

2. Previous treatment with any HDAC inhibitor (Sodium valproate, Vorinostat, depsipeptide ou NSC-630176, MS 275, LAQ-824, PXD-101, LBH589, MGCD0103, CRA024781, etc). If Sodium Valproate (Depakine®) was used for seizure, a wash-out period of at least 30 days is required and an appropriate treatment replacement should be performed.

3. Ongoing treatment with corticosteroids exceeding 30mg of prednisone per day. A wash out period of at least 7 days is required.

4. HIV infection

5. Creatinine > 1.5 ULN

6. Serum AST or ALT > 3.0 x upper limit of normal (ULN)

7. Serum total bilirubin > 1.5 mg/dl (except for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS).

8. ≥ grade-2 neuropathy

9. Previous history of Acute myeloblastic leukemia (with marrow blasts>30%)

10. Previous history of allogeneic stem cell transplantation

11. Contra-indication to Anthracyclines: Myocardiopathy, uncontrolled infection, serious renal or hepatic impairment; associated with yellow fever vaccine

12. Known hypersensitivity to the active substance or to any of the excipients of Vidaza®, of valproate, of divalproate, of valpromide, of Lenalidomide, of thalidomide, of idarubicin and/or anthracyclines

13. Patients with a history of severe congestive heart failure, clinically unstable cardiac or pulmonary disease

14. All hepatitis or known personal or familial severe hepatitis, particularly due to drugs

15. Depression with suicidal tendency

16. Use of MILLEPERTUIS, mefloquine

17. No medical insurance in the French Health system

18. Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years.

19. Pregnant or lactating females

20. Eligibility for allogeneic stem cell transplantation

21. very altered general condition , with WHO performance status of 4, or life expectancy of less than 6 months