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

Purpose

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.

Condition	Intervention	Phase
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Recurrent Adult Acute Myeloid Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Untreated Adult Acute Myeloid Leukemia	Drug: decitabine Drug: valproic acid Other: pharmacological study Other: laboratory biomarker analysis	Phase 1


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment
Official Title:	A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Selected Hematologic Malignancies

Resource links provided by NLM:

Genetics Home Reference related topics: core binding factor acute myeloid leukemia cytogenetically normal acute myeloid leukemia familial acute myeloid leukemia with mutated CEBPA

Drug Information available for: Valproic acid Valproate sodium Decitabine Divalproex sodium

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Lymphosarcoma Chronic Lymphocytic Leukemia Leukemia, B-cell, Chronic

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

MEPD of single agent decitabine [ Time Frame: 10 days ]
MTD of the combination of valproic acid with the MEPD of decitabine [ Time Frame: Up to 21 days ]
MEPD of valproic acid in combination with decitabine [ Time Frame: Up to 29 days ]
Qualitative and quantitative toxicities of single agent decitabine alone and in combination with valproic acid in regard to organ specificity, time course, predictability, and reversibility [ Time Frame: Up to 24 months ]


Enrollment:	84
Study Start Date:	February 2004
Primary Completion Date:	May 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Treatment (decitabine, valproic acid) 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.	Drug: decitabine Given IV Other Names: 5-aza-dCyd 5AZA DAC Drug: valproic acid Given orally Other Names: Alti-Valproic Depakene Novo-Valproic VA Other: pharmacological study Correlative studies Other Name: pharmacological studies Other: laboratory biomarker analysis Correlative studies

Arms

Assigned Interventions

Experimental: Treatment (decitabine, valproic acid)

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.

Drug: decitabine

Given IV

Other Names:

5-aza-dCyd
5AZA
DAC

Drug: valproic acid

Given orally

Other Names:

Alti-Valproic
Depakene
Novo-Valproic
VA

Other: pharmacological study

Correlative studies

Other Name: pharmacological studies

Other: laboratory biomarker analysis

Correlative studies

Show Detailed Description

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00079378

Locations


United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators


Principal Investigator:	Kristie Blum	Ohio State University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007 Sep 1;25(25):3884-91. Epub 2007 Aug 6.


Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00079378 History of Changes
Other Study ID Numbers:	NCI-2012-01447 NCI-2012-01447 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) NCI-6236 OSU-2003C0094 CDR0000355412 0336 ( Other Identifier: Ohio State University Medical Center ) 6236 ( Other Identifier: CTEP ) R21CA110496 ( U.S. NIH Grant/Contract ) U01CA076576 ( U.S. NIH Grant/Contract )
Study First Received:	March 8, 2004
Last Updated:	September 27, 2013

Additional relevant MeSH terms:


Lymphoma Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Leukemia, B-Cell Decitabine Azacitidine	Valproic Acid Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Enzyme Inhibitors Anticonvulsants GABA Agents Neurotransmitter Agents Physiological Effects of Drugs Antimanic Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs

ClinicalTrials.gov processed this record on September 21, 2017