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

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Brief 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

Official Title

A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Selected Hematologic Malignancies

Brief Summary

      This phase I trial is studying the side effects and best dose of decitabine and valproic acid
      in treating patients with refractory or relapsed acute myeloid leukemia or previously treated
      chronic lymphocytic leukemia or small lymphocytic leukemia. 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.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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.

      II. Determine the maximum tolerated dose (MTD) of valproic acid in combination with the MEPD
      of decitabine in these patients.

      III. Determine the MEPD of valproic acid in combination with decitabine in these patients.

      IV. 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 OBJECTIVES:

      I. Determine the therapeutic response in patients treated with decitabine alone and in
      combination with valproic acid.

      II. Determine the pharmacokinetics of this regimen in these patients. III. Determine kinetics
      of methyltransferase activity and re-expression of select target genes in AML [p15, estrogen
      receptor (ER), WT-1, calcitonin, MYOD1] and in CLL/SLL [DERMO-1, DAPK, and ID4] known to be
      methylated in primary tumor cells.

      IV. 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.

      V. Determine kinetics of HDAC enzyme inhibition and changes in the acetylation status of
      histones H3 or H4 following treatment with the combination. These parameters will be used to
      define the MEPD of the combination.

      VI. Examine baseline and post-therapy changes in the "histone code' in both AML and CLL cells
      by assessment of the acetylation and methylation status of histones H3 and H4 lysine residues
      using both Western Blot and Mass Spectrometry techniques.

      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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

MEPD of single agent decitabine


Condition

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Intervention

decitabine

Study Arms / Comparison Groups

 Treatment (decitabine, valproic acid)
Description:  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 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 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 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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

84

Start Date

February 2004


Primary Completion Date

May 2011

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with AML (Stratum I) or CLL/SLL (Stratum II) will be enrolled

          -  Patients in stratum I will have one of the following:

               -  Primary refractory or relapsed (in 1 year or less) disease and not a candidate
                  for potentially curative therapy

               -  Untreated AML patients who are not candidates for chemotherapy

               -  Patients in stratum I must have a normal WBC (=< 10 x 10^9/L) or a WBC =< 40 x
                  10^9/L that is stable for 1 week (this may be sustained with hydroxyurea prior to
                  starting therapy and during the first 4 days of therapy if clinically indicated)

          -  Patients in stratum II will have received at least one prior therapy for CLL/SLL that
             has included a purine analog; patients in stratum II with a history of severe
             autoimmune disease or requiring therapy with chronic corticosteroids or who have any
             other specific relative contraindications to receive a purine analog and, therefore,
             have received another form of therapy that include alkylating agents will be eligible
             to participate

          -  Performance status - ECOG 0-2

          -  At least 12 weeks life expectancy

          -  Stratum II:

               -  No uncontrolled autoimmune hemolytic anemia

               -  No idiopathic thrombocytopenia purpura

          -  Bilirubin =< 1.5 mg/dL

          -  ALT and AST =< 2 times upper limit of normal

          -  Creatinine =< 2.0 mg/dL

          -  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

          -  More than 14 days since prior chemotherapy (except hydroxyurea)

          -  No prior FR901228 (depsipeptide) for step 2 of this study

          -  No other concurrent chemotherapy

          -  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

          -  More than 14 days since prior radiotherapy

          -  No concurrent palliative radiotherapy

          -  No concurrent anticonvulsant medication, including valproic acid
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Kristie Blum, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00079378

Organization ID

NCI-2012-01447

Secondary IDs

NCI-2012-01447

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Kristie Blum, Principal Investigator, Ohio State University


Verification Date

September 2013