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

This study is currently recruiting participants.
Verified November 2012 by Assistance Publique - Hôpitaux de Paris
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01342692
First received: April 21, 2011
Last updated: November 19, 2012
Last verified: November 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
MDS
 Drug: Azacitidine
Drug: Azacitidine associated with Valproic acid
Drug: Azacitidine associated with Lenalidomide
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial Seeking the Most Promising Drug Association With Azacitidine- in Higher Risk Myelodysplastic Syndromes

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Remission, complete, partial or medullary after 6 cycles [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Achievement of remission, complete, partial or medullary, according to the IWG 2006 criteria39 (see section 10 below) after 6 cycles


Secondary Outcome Measures:
  • Stable disease with hematological improvement [ Time Frame: 3 and 6 months ] [ Designated as safety issue: No ]
    Achievement of stable disease with hematological improvement (HI), according to IWG 2006 criteria after 3 and 6 cycles

  • Duration of response [ Time Frame: within 3 years ] [ Designated as safety issue: No ]
    Duration of response

  • Progression to acute myeloid leukemia [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Number of adverse events [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
    Number of adverse events


Estimated Enrollment: 240
Study Start Date: June 2011
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Other Name: Azacitidine
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)

Other Name: Azacitidine associated with Valproic acid
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)

Other Name: Azacitidine associated with Lenalidomide

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01342692

Contacts
Contact: Pierre Fenaux, MD, PhD 33(1)48957050 pierre.fenaux@avc.aphp.fr

Locations
France
Avicenne hospital Recruiting
Bobigny, France, 93009
Contact: Pierre Fenaux, MD, PhD     33(1)48957050     pierre.fenaux@avc.aphp.fr    
Principal Investigator: Pierre Fenaux, MD, PhD            
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Pierre Fenaux, MD, PhD Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01342692     History of Changes
Other Study ID Numbers: P081225
Study First Received: April 21, 2011
Last Updated: November 19, 2012
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Valproic Acid
Lenalidomide
Thalidomide
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
 Therapeutic Uses
Enzyme Inhibitors
Anticonvulsants
Central Nervous System Agents
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Immunosuppressive Agents
Immunologic Factors
Leprostatic Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on June 18, 2013