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

Primary Purpose

MDS

Status

Unknown status

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

Azacitidine

Azacitidine associated with Valproic acid

Azacitidine associated with Lenalidomide

Azacitidine associated with Idarubicine

About this trial

This is an interventional treatment trial for MDS

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

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
Use of MILLEPERTUIS, mefloquine
No medical insurance in the French Health system
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.
Pregnant or lactating females
Eligibility for allogeneic stem cell transplantation
very altered general condition , with WHO performance status of 4, or life expectancy of less than 6 months

Sites / Locations

Avicenne hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Arm Label

Azacitidine alone

Azacitidine +Valproic acid

Azacitidine +Lenalidomide

Azacitidine + Idarubicine

Arm Description

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Stable disease with hematological improvement

Achievement of stable disease with hematological improvement (HI), according to IWG 2006 criteria after 3 and 6 cycles

Duration of response

Progression to acute myeloid leukemia

Overall survival

Number of adverse events

Full Information

NCT ID

NCT01342692

First Posted

April 21, 2011

Last Updated

February 18, 2019

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT01342692

Brief Title

Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes

Acronym

AZA-PLUS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2019

Overall Recruitment Status

Unknown status

Study Start Date

June 2011 (Actual)

Primary Completion Date

July 2018 (Actual)

Study Completion Date

June 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

MDS

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

320 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Azacitidine alone

Arm Type

Active Comparator

Arm Title

Azacitidine +Valproic acid

Arm Type

Experimental

Arm Title

Azacitidine +Lenalidomide

Arm Type

Experimental

Arm Title

Azacitidine + Idarubicine

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Azacitidine associated with Valproic acid

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

Azacitidine associated with Lenalidomide

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

Azacitidine associated with Idarubicine

Intervention Description

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)

Primary Outcome Measure Information:

Title

Remission, complete, partial or medullary after 6 cycles

Description

Achievement of remission, complete, partial or medullary, according to the IWG 2006 criteria39 (see section 10 below) after 6 cycles

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Stable disease with hematological improvement

Description

Achievement of stable disease with hematological improvement (HI), according to IWG 2006 criteria after 3 and 6 cycles

Time Frame

3 and 6 months

Title

Duration of response

Description

Duration of response

Time Frame

within 3 years

Title

Progression to acute myeloid leukemia

Time Frame

3 years

Title

Overall survival

Time Frame

3 years

Title

Number of adverse events

Description

Number of adverse events

Time Frame

3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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: 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 Use of MILLEPERTUIS, mefloquine No medical insurance in the French Health system 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. Pregnant or lactating females Eligibility for allogeneic stem cell transplantation very altered general condition , with WHO performance status of 4, or life expectancy of less than 6 months

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pierre Fenaux, MD, PhD

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Principal Investigator

Facility Information:

Facility Name

Avicenne hospital

City

Bobigny

ZIP/Postal Code

93009

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

27250349

Citation

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.

Results Reference

derived

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Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes

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