Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes

NCT01342692 | Unknown Phase 2 DMC

• 1 other identifier: P081225
• Study Type: interventional
• Target: 320
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

MDS

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Stable disease with hematological improvement

  3 and 6 months

• Duration of response

  within 3 years

• Progression to acute myeloid leukemia

  3 years

• Overall survival

  3 years

• Number of adverse events

  3 years

Study Arms (4)

Azacitidine alone

ACTIVE COMPARATOR

Drug: Azacitidine

Azacitidine +Valproic acid

EXPERIMENTAL

Drug: Azacitidine associated with Valproic acid

Azacitidine +Lenalidomide

EXPERIMENTAL

Drug: Azacitidine associated with Lenalidomide

Azacitidine + Idarubicine

EXPERIMENTAL

Drug: Azacitidine associated with Idarubicine

Interventions

Azacitidine DRUG

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

Azacitidine alone

Azacitidine associated with Valproic acid DRUG

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)

Azacitidine +Valproic acid

Azacitidine associated with Lenalidomide DRUG

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)

Azacitidine +Lenalidomide

Azacitidine associated with Idarubicine DRUG

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)

Azacitidine + Idarubicine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Treatment with AZA or Decitabine in the previous 6 months
• 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.
• Ongoing treatment with corticosteroids exceeding 30mg of prednisone per day. A wash out period of at least 7 days is required.
• HIV infection
• Creatinine \> 1.5 ULN
• Serum AST or ALT \> 3.0 x upper limit of normal (ULN)
• Serum total bilirubin \> 1.5 mg/dl (except for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS).
• ≥ grade-2 neuropathy
• Previous history of Acute myeloblastic leukemia (with marrow blasts\>30%)
• Previous history of allogeneic stem cell transplantation
• Contra-indication to Anthracyclines: Myocardiopathy, uncontrolled infection, serious renal or hepatic impairment; associated with yellow fever vaccine
• 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
• Patients with a history of severe congestive heart failure, clinically unstable cardiac or pulmonary disease
• All hepatitis or known personal or familial severe hepatitis, particularly due to drugs
• Depression with suicidal tendency

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Avicenne hospital

Bobigny, 93009, France

Location

Related Publications (1)

• 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.

  PMID: 27250349 DERIVED

MeSH Terms

Interventions

Azacitidine; Valproic Acid; Lenalidomide; Idarubicin

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Fatty Acids, Volatile; Fatty Acids; Lipids; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Pierre Fenaux, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2011
• First Posted: April 27, 2011
• Study Start: June 1, 2011
• Primary Completion: July 1, 2018
• Study Completion: June 1, 2019
• Last Updated: February 19, 2019

Record last verified: 2019-02

Locations

FR (1)