Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Decitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Closed	18 and over	NCI	OSU-0336 NCI-6236, OSU-2003C0094, 6236, NCT00079378

Objectives

Primary

1. 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.
2. Determine the maximum tolerated dose (MTD) of valproic acid in combination with the MEPD of decitabine in these patients.
3. Determine the MEPD of valproic acid in combination with decitabine in these patients.
4. Determine the qualitative and quantitative toxic effects of decitabine alone and in combination with valproic acid, in terms of organ specificity, time course, predictability, and reversibility in these patients.

Secondary

1. Determine the therapeutic response in patients treated with decitabine alone and in combination with valproic acid.
2. Determine the pharmacokinetics of this regimen in these patients.
3. 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.

Entry 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 who have any other specific relative contraindication to receive a purine analog may have received another form of therapy that included alkylating agents]




• No granulocytic sarcoma

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 for 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

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Stratum I:
  • WBC ≤ 10,000/mm³ (40,000/mm³ if stable for the past week)*
• Stratum II:
  • No uncontrolled autoimmune hemolytic anemia
  • No idiopathic thrombocytopenia purpura

 [Note: *May be sustained with hydroxyurea before starting therapy and during the first 4 days of therapy]

Hepatic

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

Renal

• Creatinine ≤ 2.0 mg/dL

Other

• No active infection 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

Expected Enrollment

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

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 1-5 or 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.

Blum W, Klisovic RB, Hackanson B, et al.: Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25 (25): 3884-91, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

Guido Marcucci, MD, Protocol chair		Ph: 614-293-9868

Registry Information
Official Title		A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Selected Hematologic Malignancies
Trial Start Date		2004-03-05
Trial Completion Date		2005-11-25 (estimated)
Registered in ClinicalTrials.gov		NCT00079378 1
Date Submitted to PDQ		2004-02-04
Information Last Verified		2007-04-05
NCI Grant/Contract Number		CA16058

Table of Links

1	http://clinicaltrials.gov/ct/show/NCT00079378