Phase I 5-Azacytidine Plus VPA Plus ATRA

Myelodysplastic Syndrome Clinical Trial

Official title:

Phase I 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01575691
• Other study ID #: 2004-0799 Phase I
• Status: Completed
• Phase: Phase 1
• First received: April 9, 2012
• Last updated: April 10, 2012
• Start date: July 2005
• Est. completion date: December 2007

Study information

• Verified date: April 2012
• Source: M.D. Anderson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical 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. 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.

Description:

Participants receive 5-aza as an injection under the skin once a day for 7 days. This will be repeated every 3-8 weeks depending on blood counts and how well bone marrow is recovering. This is defined as 1 treatment cycle. Also during each cycle, participant will take VPA by mouth for 7 days and ATRA by mouth for 5 days. VPA will be given on the same days as 5-aza. ATRA will start on Day 3.

In the Phase I portion of the study, the dose of VPA will be increased in each new group of participants until the highest safe dose is found. A minimum of 3 participants and a maximum of 10 will be treated at each dose level.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: December 2007
• Est. primary completion date: July 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years and older

Eligibility

Inclusion Criteria:

• 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.

• Adequate liver function (bilirubin of < 2mg/dL, SGPT < 3 * Upper Limits of Normal (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.

Exclusion Criteria:

• 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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• 5-Azacytidine (5-aza)
Start at 75 mg/m^2 subcutaneously daily for 7 days.
• Valproic Acid
50 mg/kg daily by mouth for 7 days, same days as 5-aza.
• All-Trans Retinoic Acid (ATRA)
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.

Locations

Country	Name	City	State
United States	The University of Texas M.D. Anderson Cancer Center	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center	Celgene Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximal tolerated dose (MTD) of valproic acid (VPA) in combination with 5-azacytidine (5-aza) and all-trans retinoic acid (ATRA)	MTD defined as the dose level below where either 0 dose limiting toxicities (DLTs) out of the first 3 participants, or 1 DLT in the first 3 participants, and 0 DLTs in following additional 3 participants of a cohort. The MTD designation will apply to cycle 1 (28 day cycle). Routine blood tests (about 1-2 teaspoons each time) 2-3 times a week.	28 day cycle	Yes

External Links

•   M.D. Anderson's internet website