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

This study is currently recruiting participants.
Verified June 2017 by Assistance Publique - Hôpitaux de Paris
Sponsor:
ClinicalTrials.gov Identifier:
NCT01342692
First Posted: April 27, 2011
Last Update Posted: June 15, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
  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 Drug: Azacitidine associated with Idarubicine Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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:


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 ]
    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 ]
    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 ]
    Duration of response

  • Progression to acute myeloid leukemia [ Time Frame: 3 years ]
  • Overall survival [ Time Frame: 3 years ]
  • Number of adverse events [ Time Frame: 3 years ]
    Number of adverse events


Estimated Enrollment: 320
Study Start Date: June 2011
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: January 2018 (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
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)

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01342692     History of Changes
Other Study ID Numbers: P081225
First Submitted: April 21, 2011
First Posted: April 27, 2011
Last Update Posted: June 15, 2017
Last Verified: June 2017

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Lenalidomide
Thalidomide
Azacitidine
Idarubicin
Valproic Acid
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Immunosuppressive Agents
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Anticonvulsants
GABA Agents
Neurotransmitter Agents
Antimanic Agents