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Myelodysplastic SyndromePhase 2NCT00326170

Phase II 5-Azacytidine Plus VPA Plus ATRA

A Phase 2 study testing 5-Azacytidine (5-aza), Valproic Acid and All-Trans Retinoic Acid (ATRA) in people with Myelodysplastic Syndrome and Acute Myelogenous Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

5-aza is a chemotherapy drug with activity in leukemia and myelodysplastic syndromes (MDS). Researchers hope that valproic acid (VPA) and all-trans retinoic acid (ATRA)will increase the effects of 5-aza. Read more about this study

Who is it for?
Ages 3 years and older
What is being tested?
5-Azacytidine (5-aza), Valproic Acid and All-Trans Retinoic Acid (ATRA)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
1 siteUnited States
Study dates
Jul 2005to Dec 2007
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 3 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Patients with refractory or relapsed: acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS) (bone marrow blasts > or = 10%) are eligible.
  • Untreated patients older than 60 years of age with AML or MDS (bone marrow blasts > or = 10%) who refuse or are not eligible for front-line chemotherapy, are eligible.
  • Performance status of < or = 2 by the Eastern Cooperative Oncology Group (ECOG) scale.
  • Signed informed consent indicating that patients are aware of the investigational nature of this study in keeping with the policies of University of Texas M D Anderson Cancer Center (UTMDACC).
  • Age > 2 years. Valproic acid has been associated with a higher rate of severe liver toxicity in children younger than 2 years.
  • Patients must have been off chemotherapy for 2 weeks prior to entering this study and recovered from the toxic effects of that therapy, unless there is evidence of rapidly progressive disease. Use of hydroxyurea for patients with rapidly proliferative disease is allowed for the first two weeks on therapy.
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  • Adequate liver function (bilirubin of < 2mg/dL, SGPT < 3 * ULN) and renal function (creatinine < 2mg/dL).
  • Women of childbearing potential must practice contraception. Men and women must continue birth control for the duration of the trial.
  • Patients with relapsed /refractory disease with inv16, t(8;21) or t(15;17) are eligible.

Who cannot join

  • Nursing and pregnant females are excluded.
  • Patients with active and uncontrolled infections are excluded.
  • Patients already receiving valproic acid or receiving other anticonvulsants will be excluded.
  • Untreated patients younger than 60 years will not be candidates for this study.
  • Patients with untreated disease inv16, t(8;21) or t(15;17) will be excluded.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • The University of Texas M.D. Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Phase II Study of the Combination of 5-azacytidine With Valproic Acid and All-trans Retinoic Acid in Patients With High Risk Myelodysplastic Syndrome and Acute Myelogenous Leukemia

5-aza is a chemotherapy drug with activity in leukemia and myelodysplastic syndromes (MDS). Researchers hope that valproic acid (VPA) and all-trans retinoic acid (ATRA)will increase the effects of 5-aza. The goal of this clinical research study is to find the highest safe dose of valproic acid (VPA) that can be given in combination with 5-azacytidine (5-aza) and all-trans retinoic acid (ATRA) in the treatment of AML and MDS. The safety and effectiveness of this combination therapy will also be studied.

Additional blood and bone marrow samples will be requested. These samples will be used to evaluate the effect of the treatment on leukemic cells. In addition, any leftover blood and bone marrow samples that are collected at the start of the study and during the regularly scheduled evaluations to be sent for research studies. The research studies will examine changes in the blood and bone marrow cells that might help explain the causes of leukemia and MDS and how the combination of 5-aza, VPA, and ATRA works.

Read the detailed description

Recent studies have shown synergy between demethylating agents and histone deacetylase inhibitors. In my laboratory, we have developed in vitro models using HL-60 and MOLT4 leukemic cells to study the effects of the combination of decitabine (a 5-azacytidine analogue) and valproic acid. Valproic acid is an antiepileptic agent with histone deacetylase inhibitory capacity. These results indicate that the addition of valproic acid to decitabine has an additive effect on growth inhibition, induction of apoptosis, induction of p57KIP2 and p21CIP1 expression independent of cell cycle arrest. These results were dependent on the dose and duration of treatment but not on the sequence used. Based on this data, we developed a phase I/II study of the combination of decitabine and valproic acid (2003-0314) in patients with leukemia that has shown that valproic acid can be safely administered up to doses of 50 mg/kg orally for 10 days in combination with decitabine, and that this combination has significant activity in patients with relapsed/refractory AML and MDS. All-trans retinoic acid (ATRA) is a biological agent that has been shown to induce cell differentiation in leukemia cell lines and has significant clinical activity in acute promyelocytic leukemia with minimal toxicity. In vitro, the combination of ATRA with either a hypomethylating agent or a histone deacetylase inhibitor has been shown to restore ATRA sensitivity in resistant cells. More recently, a German group has reported that the combination of valproic acid and ATRA has activity in patients with MDS and an excellent toxicity profile. 5-azacytidine is a nucleoside analogue with hypomethylating activity that has been shown in a randomized study to benefit patients with MDS, including an improvement in quality of life. Based on this data, this agent was recently approved by the FDA for its use in patients with MDS, and has become the first line agent for patients with MDS that required therapy.

The objectives of the clinical trial are the following:

  • To determine the maximal tolerated dose of valproic acid (VPA) in combination with 5-azacytidine (5-aza) and all-trans retinoic acid.
  • To determine the clinical activity of the combination of 5-azacytidine, valproic acid and all-trans retinoic acid in patients with AML and MDS.
  • To determine the in vivo molecular and biological effects of this combination. These will include analysis of changes in Deoxyribonucleic acid (DNA) methylation, histone modifications, and gene expression.
Being tested
5-Azacytidine (5-aza), Valproic Acid, All-Trans Retinoic Acid (ATRA)
Keywords
Combination Chemotherapy, MDS, High-Risk Myelodysplastic Syndrome, AML, Acute myelogenous leukemia, valproic acid, VPA, Depakene, 5-azacytidine, 5-aza, Azacitidine, 5-AZC, Vidaza, AZA-CR, Ladakamycin, NSC-102816, All-trans retinoic acid, ATRA, Tretinoin, Vesanoid
Medical subject headings
Myelodysplastic Syndromes, Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 5-Azacytidine (5-aza)Drug

    Also called Azacitidine, 5-azacytidine, 5-AZC, Vidaza

    Start at 75 mg/m^2 subcutaneously daily for 7 days.

  • Valproic AcidDrug

    Also called Depakene

    50 mg/kg daily by mouth for 7 days, same days as 5-aza.

  • All-Trans Retinoic Acid (ATRA)Drug

    Also called Tretinoin (oral), Vesanoid

    45 mg/m^2 orally daily (in two divided doses) for 5 days starting on day 3 of the administration of 5-aza and VPA.

Study groups in NCT00326170
Study groupRoleWhat they receive
VPA + 5-aza + ATRAExperimentalDaily for 7 days, Valproic acid (VPA) starting dose 75 mg/m^2 subcutaneously in combination with 5-azacytidine (5-aza) 50 mg/kg orally; and all-trans retinoic acid (ATRA) 45 mg/m^2 orally daily (in two divided doses) for 5 days starting on day 3.
Receives: Drug: 5-Azacytidine (5-aza); Drug: Valproic Acid; Drug: All-Trans Retinoic Acid (ATRA)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Response

    Clinical activity of combination defined as: Complete Response (CR), bone marrow with 5% or fewer blasts and peripheral blood count with an absolute neutrophil count of 10^9/L or more and platelet count of 100x10^9 or more; Complete response without platelets (CRp), a complete response except for a platelet count less than 100x10^9 and transfusion independent; and Bone Marrow (BM) Response, bone marrow blast of 5% or less but without meeting the peripheral blood count criteria for (CR) or (CRp).

    Measured: Up to 12 cycles of treatment (28 day cycles)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 May 2006 (estimated)
  2. Study startJul 2005
  3. Primary completionJul 2007
  4. Study completionDec 2007

Resources

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
34 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00326170
Sponsor's protocol ID
2004-0799
Status last verified
Jun 2012
First submitted
12 May 2006
Last updated
15 Jun 2012
Data monitoring committee
No

Publications

  • Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007 Oct 1;110(7):2302-8. doi: 10.1182/blood-2007-03-078576. Epub 2007 Jun 27.

    PubMed 17596541

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing 5-Azacytidine (5-aza), Valproic Acid and All-Trans Retinoic Acid (ATRA) in people with Myelodysplastic Syndrome and Acute Myelogenous Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

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 9 inclusion and 5 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: finished, as of the sponsor's last update on 15 Jun 2012. 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 United States. 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?

Yes. Results are posted in the registry (first posted 11 Jul 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Number of Participants With Response (time frame: Up to 12 cycles of treatment (28 day cycles)). 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 NCT00326170, 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 15 Jun 2012.

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