Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes (AZA-PLUS)

Randomized Phase II Trial Seeking the Most Promising Drug Association With Azacitidine- in Higher Risk Myelodysplastic Syndromes

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.

Study Overview

• Status: Unknown
• Conditions: MDS
• Intervention / Treatment: Drug: Azacitidine; Drug: Azacitidine associated with Valproic acid; Drug: Azacitidine associated with Lenalidomide; Drug: Azacitidine associated with Idarubicine

Detailed Description

The main objective of this phase II randomized trial is to identify, among 3 combinations of Azacitidine and another drug evaluated simultaneously, the most promising combination(s) for the treatment of higher risk MDS (IPSS Int-2 and High) compared to Azacitidine alone. The 3 tested drugs in combination with Azacitidine are: Valproic Acid, Lenalidomide and Idarubicin.

The aim of this trial is to identify, in a situation where several potentially interesting drugs tested in combination with AZA exist, the most promising combination(s) based on efficacy compared to azacitidine alone, based on a two-stage design that allows a formal efficacy comparison between the K=3 investigational treatment groups and the control group.

• Study Type: Interventional
• Enrollment (Anticipated): 320
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bobigny, France, 93009
    • Avicenne Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azacitidine alone	Drug: Azacitidine; 6 cycles of Azacitidine 75 mg/m2 subcutaneously daily for 7 days, every 4 weeks The first course will be started on day 1 regardless of the blood count. Subsequent courses will be scheduled every 4 weeks
Experimental: Azacitidine +Valproic acid	Drug: Azacitidine associated with Valproic acid; 6 cycles of Azacitidine 75 mg/m2 subcutaneously daily for 7 days, every 4 weeks Valproic Acid (Depakine-Chrono®) (VPA) will be administered concomitantly for a minimum of 6 cycles. - In patients aged 60 years or less: VPA (25 mg/kg twice a day i.e. 50 mg/kg/d) administered orally, daily for 7 days (days 1-7) - In patients older than 60 years: VPA (17.5 mg/kg twice a day i.e. 35 mg/Kg/d) administered orally daily for 7 days (days 1-7)
Experimental: Azacitidine +Lenalidomide	Drug: Azacitidine associated with Lenalidomide; 6 cycles of Azacitidine 75 mg/m2 subcutaneously daily for 7 days, every 4 weeks Lenalidomide (Revlimid®) will be administered once daily orally as continuous schedule started on day 1 of Azacitidine. Patients will receive Lenalidomide 10 mg/d, during 14 days (D1 to D14)
Experimental: Azacitidine + Idarubicine	Drug: Azacitidine associated with Idarubicine; Azacitidine (Vidaza®) will be administered similarly to group 1 exposed above. Idarubicin (Zavedos®) as the reconstituted solution, will be administered slowly by the intravenous route over 60 minutes at 10 mg/m²of body-surface area on day 8 of Azacitidine or day 10 if azacitidine was administered according to (5-2-2 regimen)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission, complete, partial or medullary after 6 cycles	Achievement of remission, complete, partial or medullary, according to the IWG 2006 criteria39 (see section 10 below) after 6 cycles	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		3 years
Stable disease with hematological improvement	Achievement of stable disease with hematological improvement (HI), according to IWG 2006 criteria after 3 and 6 cycles	3 and 6 months
Duration of response	Duration of response	within 3 years
Progression to acute myeloid leukemia		3 years
Number of adverse events	Number of adverse events	3 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Pierre Fenaux, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Jacob L, Uvarova M, Boulet S, Begaj I, Chevret S. Evaluation of a multi-arm multi-stage Bayesian design for phase II drug selection trials - an example in hemato-oncology. BMC Med Res Methodol. 2016 Jun 2;16:67. doi: 10.1186/s12874-016-0166-7.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2011
• Primary Completion (Actual): July 1, 2018
• Study Completion (Anticipated): June 1, 2019

Study Registration Dates

• First Submitted: April 21, 2011
• First Submitted That Met QC Criteria: April 26, 2011
• First Posted (Estimate): April 27, 2011

Study Record Updates

• Last Update Posted (Actual): February 19, 2019
• Last Update Submitted That Met QC Criteria: February 18, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Preleukemia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Antibiotics, Antineoplastic; Lenalidomide; Valproic Acid; Azacitidine; Idarubicin
• Other Study ID Numbers: P081225