Phase I 5-Azacytidine Plus VPA Plus ATRA

Condition(s) targeted: Myelodysplastic Syndrome; Acute Myelogenous Leukemia

Intervention: 5-Azacytidine (5-aza) (Drug); Valproic Acid (Drug); All-Trans Retinoic Acid (ATRA) (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Guillermo Garcia-Manero, MD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center

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.

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

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

Primary outcome: Maximal tolerated dose (MTD) of valproic acid (VPA) in combination with 5-azacytidine (5-aza) and all-trans retinoic acid (ATRA)

Detailed 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.

Minimum age: 3 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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.

The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States

M.D. Anderson's internet website

Starting date: July 2005
Last updated: April 10, 2012