RATIONALE: Drugs used in chemotherapy, such as decitabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Valproic acid may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Combining decitabine with valproic acid may kill more cancer cells.

PURPOSE: Phase I trial to study the effectiveness of combining decitabine with valproic acid in treating patients who have refractory or relapsed acute myeloid leukemia or previously-treated chronic lymphocytic leukemia or small lymphocytic leukemia.

Condition	Treatment or Intervention	Phase
adult acute myeloid leukemia refractory chronic lymphocytic leukemia Small Lymphocytic Lymphoma	Drug: decitabine  Drug: valproic acid  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy	Phase I

OBJECTIVES: Primary

• Determine the minimally effective pharmacological dose (MEPD) of decitabine in patients with refractory or relapsed acute myeloid leukemia or with previously treated chronic lymphocytic lymphoma or small lymphocytic lymphoma.
• Determine the maximum tolerated dose (MTD) of valproic acid in combination with the MEPD of decitabine in these patients.
• Determine the MEPD of valproic acid in combination with decitabine in these patients.
• Determine the qualitative and quantitative toxic effects of decitabine alone and in combination with valproic acid, in regard to organ specificity, time course, predictability, and reversibility in these patients.

Secondary

• Determine the therapeutic response of patients treated with decitabine alone and in combination with valproic acid.
• Determine the pharmacokinetics of this regimen in these patients.
• Correlate baseline and post-treatment changes in DNA methyltransferases (MT1, MT3a, and MT3b) expression with achievement of decitabine MEPD, toxicity, treatment resistance, and disease response in these patients.

OUTLINE: This is a dose-escalation study. Patients are stratified according to disease (refractory or relapsed acute myeloid leukemia vs chronic lymphocytic leukemia or small lymphocytic lymphoma).

Patients receive decitabine IV over 1 hour on days 1-10. Treatment repeats every 28 days.

Cohorts of 6 patients receive escalating doses of decitabine until the minimally effective pharmacological dose (MEPD) is determined. The MEPD is defined as the dose at which at least 5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences dose limiting toxicity (DLT).

Once the MEPD is determined, patients receive decitabine at that dose level administered as above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days.

Cohorts of 3-6 patients receive escalating doses of valproic acid until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. The MEPD of valproic acid is then determined using established gene methylation and toxicity criteria.

Treatment continues for up to 24 months in the absence of disease progression or unacceptable toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 84 patients (42 per stratum) will accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following as defined by the WHO classification:
• Acute myeloid leukemia (AML) (Stratum I) meeting one of the following criteria:
• Primary refractory or relapsed (in 1 year or less) disease and not a candidate for potentially curative therapy
• Untreated (or previously treated but fulfilling criteria for poor prognosis) with poor-risk leukemia defined by any of the following criteria:
• More than 65 years old
• Poor-risk cytogenetics, defined as patients with karyotype abnormalities other than t(8;21), inv(16), t(15;17)
• Poor candidate for aggressive chemotherapy
• Chronic lymphocytic leukemia or small lymphocytic lymphoma (Stratum II) meeting the following criteria:
• Received at least one prior therapy that included a purine analog* NOTE: *Patients with a history of severe autoimmune disease or requiring therapy with chronic corticosteroids or have any other specific relative contraindications to receive a purine analog may have received another form of therapy that includes alkylating agents
• No granulocytic sarcoma

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Stratum I:
• WBC ≤ 10,000/mm
• (40,000/mm
• if stable for the past week)* NOTE: *May be sustained with hydroxyurea before starting therapy and during the first 4 days of therapy
• Stratum II:
• No uncontrolled autoimmune hemolytic anemia
• No idiopathic thrombocytopenia purpura

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• ALT and AST ≤ 2 times upper limit of normal

Renal

• Creatinine ≤ 2.0 mg/dL

Other

• No active infections requiring IV antibiotics
• HIV negative
• No other severe medical condition that would preclude study participation
• No psychiatric condition that would preclude study compliance
• No history of seizures
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics
• More than 14 days since prior chemotherapy (except hydroxyurea)
• No prior FR901228 (depsipeptide) for step 2 of this study
• No other concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics
• No concurrent corticosteroids for antiemetic therapy
• No concurrent hormonal therapy except the following:
• Steroids for treatment of adrenal failure or septic shock
• Insulin for diabetes
• Tamoxifen or equivalent for breast cancer prevention or adjuvant therapy
• Estrogens or progestins for gynecologic indications

Radiotherapy

• More than 14 days since prior radiotherapy
• No concurrent palliative radiotherapy

Surgery

• Not specified

Other

• No concurrent anticonvulsant medication, including valproic acid

Ohio
      Arthur G. James Cancer Hospital at Ohio State University, Columbus,  Ohio,  43210-1240,  United States; Recruiting

Study chairs or principal investigators

Guido Marcucci, MD,  Study Chair,  Arthur G. James Cancer Hospital & Richard J. Solove Research Institute   

Study ID Numbers:  CDR0000355412; OSU-0336; NCI-6236; OSU-2003C0094
Record last reviewed:  March 2004
Record first received:  March 8, 2004
ClinicalTrials.gov Identifier:  NCT00079378
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-18