Ignite Creation Date:
2024-05-05 @ 11:32 AM
Last Modification Date:
2024-10-26 @ 9:10 AM
Study NCT ID:
NCT00079378
Status:
COMPLETED
Last Update Posted:
2013-09-30
First Post:
2004-03-08
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
Sponsor:
National Cancer Institute NCI
Organization:
National Cancer Institute NCI
Study Overview
Official Title:
A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Selected Hematologic Malignancies
Status:
COMPLETED
Status Verified Date:
2013-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 CLLSLL 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
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 CLLSLL 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| U01CA076576 | NIH | CTEP | httpsreporternihgovquickSearchU01CA076576 |
| NCI-2012-01447 | REGISTRY | None | None |
| NCI-6236 | None | None | None |
| OSU-2003C0094 | None | None | None |
| CDR0000355412 | None | None | None |
| 0336 | OTHER | None | None |
| 6236 | OTHER | None | None |
| R21CA110496 | NIH | None | None |