MDSPhase 2AZA-PLUSNCT01342692
Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes
A Phase 2 study testing Azacitidine, Azacitidine associated with Valproic acid and Azacitidine associated with Lenalidomide in people with MDS, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- MDS
- What is being tested?
- Azacitidine, Azacitidine associated with Valproic acid and Azacitidine associated with Lenalidomide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 320 participants
- Where
- 1 siteFrance
- Study dates
- Jun 2011to Jun 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 21Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- MDS
- Being tested
- Azacitidine, Azacitidine associated with Valproic acid, Azacitidine associated with Lenalidomide, Azacitidine associated with Idarubicine
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
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 associated with Valproic acidDrug
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 associated with LenalidomideDrug
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 associated with IdarubicineDrug
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)
| Study group | Role | What they receive |
|---|---|---|
| Azacitidine alone | Active comparator | Not described Receives: Drug: Azacitidine |
| Azacitidine +Valproic acid | Experimental | Not described Receives: Drug: Azacitidine associated with Valproic acid |
| Azacitidine +Lenalidomide | Experimental | Not described Receives: Drug: Azacitidine associated with Lenalidomide |
| Azacitidine + Idarubicine | Experimental | Not described Receives: Drug: Azacitidine associated with Idarubicine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 6 months
Secondary outcomes (5)
Stable disease with hematological improvement
Achievement of stable disease with hematological improvement (HI), according to IWG 2006 criteria after 3 and 6 cycles
Measured: 3 and 6 months
Duration of response
Duration of response
Measured: within 3 years
Progression to acute myeloid leukemia
Measured: 3 years
Overall survival
Measured: 3 years
Number of adverse events
Number of adverse events
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Apr 2011 (estimated)
- Study startJun 2011
- Primary completionJul 2018
- Study completionJun 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MDSStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 320 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Pierre Fenaux, MD, PhD, Principal investigator, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01342692
- Sponsor's protocol ID
- P081225
- Acronym
- AZA-PLUS
- Status last verified
- Feb 2019
- First submitted
- 21 Apr 2011
- Last updated
- 19 Feb 2019
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 27250349
Study at a glance
From the registry record, last updated by the sponsor on 19 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Phase II Trial Seeking the Most Promising Drug Association With Azacitidine- in Higher Risk Myelodysplastic Syndromes
- ClinicalTrials.gov ID
- NCT01342692
- Acronym / sponsor ID
- AZA-PLUS / P081225
- Conditions
- MDS
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 320 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Jun 2011 (actual)
- Primary completion
- Jul 2018 (actual)
- Study completion
- Jun 2019 (estimated)
- First posted
- 27 Apr 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (21 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Azacitidine6 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 | Drug | Azacitidine alone |
| Azacitidine associated with Valproic acid6 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) | Drug | Azacitidine +Valproic acid |
| Azacitidine associated with Lenalidomide6 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) | Drug | Azacitidine +Lenalidomide |
| Azacitidine associated with IdarubicineAzacitidine (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) | Drug | Azacitidine + Idarubicine |
Primary outcome
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
5 secondary outcomes
Stable disease with hematological improvement
Time frame: 3 and 6 months
Duration of response
Time frame: within 3 years
Progression to acute myeloid leukemia
Time frame: 3 years
Overall survival
Time frame: 3 years
Number of adverse events
Time frame: 3 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Feb 2019.
- Derived from this study: PubMed 27250349Jacob 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.
Related trials for MDS
RecruitingPhase 2
Testing New Therapies for Patients With Acute Myeloid Leukemia Who Are Newly Diagnosed and Have Not Yet Started Treatment (A MyeloMATCH Treatment Trial)
Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm
Active, not recruitingPhase 1/2
Omacetaxine + Azacitidine in Untreated Patients With High Grade MDS
High Grade Myelodysplastic Syndromes
RecruitingPhase 1/2
Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms
Myelodysplastic Syndromes
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Not yet recruitingPhase 1
ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS
Acute Myeloid Leukemia, High-risk Myelodysplastic Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pierre Fenaux, MD, PhD principal investigator
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Azacitidine, Azacitidine associated with Valproic acid and Azacitidine associated with Lenalidomide in people with MDS, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Remission, complete, partial or medullary after 6 cycles (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01342692, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2019.