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Decitabine With or Without Valproic Acid in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

Primary Purpose

Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Mantle Cell Lymphoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
decitabine
valproic acid
pharmacological study
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Adult Burkitt Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Histologically or cytologically confirmed aggressive B-cell non-Hodgkin's lymphoma (NHL), including any of the following subtypes: Mantle cell lymphoma Diffuse large cell lymphoma Burkitt's lymphoma Transformed NHL* arising from a previously diagnosed low-grade lymphoma, including any of the following: Follicular lymphoma Small lymphocytic lymphoma Chronic lymphocytic leukemia Relapsed or refractory disease Relapsed or refractory disease must have occurred during the most recent prior therapy Has accessible tissue for biopsy OR evidence of ≥ 50% bone marrow involvement AND willing to undergo serial biopsy Not eligible for OR refused curative stem cell transplantation No active or untreated CNS lymphoma Performance status - ECOG 0-2 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 75,000/mm^3 AST and ALT ≤ 2.5 times upper limit of normal Bilirubin ≤ 1.5 mg/dL Creatinine ≤ 2.0 mg/dL No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No known HIV positivity No ongoing or active infection No other uncontrolled illness No psychiatric illness or social situation that would preclude study compliance Prior stem cell transplantation allowed Recovered from all prior biologic therapy-related toxicity Recovered from all prior chemotherapy-related toxicity No other concurrent chemotherapy unless it is used in the chronic daily setting for other medical conditions, including pulmonary, rheumatologic, or adrenal disorders No concurrent corticosteroids unless they are used in the chronic daily setting for other medical conditions, including pulmonary, rheumatologic, or adrenal disorders Recovered from all prior radiotherapy-related toxicity No concurrent palliative radiotherapy Recovered from all prior therapy-related toxicity No concurrent anticonvulsants, including valproic acid (except as used in this study)

Sites / Locations

  • Ohio State University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I

Arm II

Arm Description

Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Patients receive decitabine as in stage 1 and valproic acid PO TID on days 5-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

MEPD of single agent decitabine defined as the dose where an 80% decrease in DNMT1 protein level and a 100% increase in re-expression of the methylated target genes are noted in 5 of 6 patients, with DLT in less than or equal to 1 patient
MTD of valproic acid in combination with the MEPD of decitabine defined as the dose level below that dose at which greater than or equal to 2 DLT are observed and that results in less than or equal to 1 DLT in 6 patients using CTCAE v3.0
MEPD of valproic acid and decitabine defined as the dose where an 80% decrease in DNMT1 protein level and a 100% increase in re-expression of the methylated target genes are noted in 5 of 6 patients, with DLT in less than or equal to 1 patient
Toxicities of single agent decitabine alone and in combination with valproic acid assessed using CTCAE v3.0

Secondary Outcome Measures

Full Information

First Posted
May 3, 2005
Last Updated
June 3, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00109824
Brief Title
Decitabine With or Without Valproic Acid in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma
Official Title
A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Completed
Study Start Date
March 2006 (undefined)
Primary Completion Date
March 2009 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Valproic acid may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving decitabine together with valproic acid may be an effective treatment for non-Hodgkin's lymphoma. This phase I trial is studying the side effects and best dose of decitabine and valproic acid in treating patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the minimally effective pharmacological dose (MEPD) of single-agent decitabine in patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. II. Determine the maximum tolerated dose of valproic acid when administered with the MEPD of decitabine in these patients. III. Determine the MEPD of valproic acid when administered with decitabine in these patients. IV. Determine the toxic effects of decitabine alone and in combination with valproic acid in these patients. SECONDARY OBJECTIVES: I. Determine the response rate in patients treated with these drugs. II. Determine the pharmacokinetics of these drugs in these patients. OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 treatment stages. STAGE 1: Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. STAGE 2: Patients receive decitabine as in stage 1 and valproic acid orally (PO) thrice daily (TID) on days 5-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. For both stages, patients who achieve an objective response (complete response [CR], unconfirmed CR, or partial response) may discontinue study treatment and undergo stem cell transplantation, if eligible. PROJECTED ACCRUAL: Approximately 18-42 patients (18 for stage 1 and 24 for stage 2) will be accrued for this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Mantle Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Arm Title
Arm II
Arm Type
Experimental
Arm Description
Patients receive decitabine as in stage 1 and valproic acid PO TID on days 5-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
decitabine
Other Intervention Name(s)
5-aza-dCyd, 5AZA, DAC
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
valproic acid
Other Intervention Name(s)
Alti-Valproic, Depakene, Novo-Valproic, VA
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
MEPD of single agent decitabine defined as the dose where an 80% decrease in DNMT1 protein level and a 100% increase in re-expression of the methylated target genes are noted in 5 of 6 patients, with DLT in less than or equal to 1 patient
Time Frame
28 days
Title
MTD of valproic acid in combination with the MEPD of decitabine defined as the dose level below that dose at which greater than or equal to 2 DLT are observed and that results in less than or equal to 1 DLT in 6 patients using CTCAE v3.0
Time Frame
28 days
Title
MEPD of valproic acid and decitabine defined as the dose where an 80% decrease in DNMT1 protein level and a 100% increase in re-expression of the methylated target genes are noted in 5 of 6 patients, with DLT in less than or equal to 1 patient
Time Frame
28 days
Title
Toxicities of single agent decitabine alone and in combination with valproic acid assessed using CTCAE v3.0
Time Frame
Up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically or cytologically confirmed aggressive B-cell non-Hodgkin's lymphoma (NHL), including any of the following subtypes: Mantle cell lymphoma Diffuse large cell lymphoma Burkitt's lymphoma Transformed NHL* arising from a previously diagnosed low-grade lymphoma, including any of the following: Follicular lymphoma Small lymphocytic lymphoma Chronic lymphocytic leukemia Relapsed or refractory disease Relapsed or refractory disease must have occurred during the most recent prior therapy Has accessible tissue for biopsy OR evidence of ≥ 50% bone marrow involvement AND willing to undergo serial biopsy Not eligible for OR refused curative stem cell transplantation No active or untreated CNS lymphoma Performance status - ECOG 0-2 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 75,000/mm^3 AST and ALT ≤ 2.5 times upper limit of normal Bilirubin ≤ 1.5 mg/dL Creatinine ≤ 2.0 mg/dL No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No known HIV positivity No ongoing or active infection No other uncontrolled illness No psychiatric illness or social situation that would preclude study compliance Prior stem cell transplantation allowed Recovered from all prior biologic therapy-related toxicity Recovered from all prior chemotherapy-related toxicity No other concurrent chemotherapy unless it is used in the chronic daily setting for other medical conditions, including pulmonary, rheumatologic, or adrenal disorders No concurrent corticosteroids unless they are used in the chronic daily setting for other medical conditions, including pulmonary, rheumatologic, or adrenal disorders Recovered from all prior radiotherapy-related toxicity No concurrent palliative radiotherapy Recovered from all prior therapy-related toxicity No concurrent anticonvulsants, including valproic acid (except as used in this study)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kristie Blum
Organizational Affiliation
Ohio State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

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Decitabine With or Without Valproic Acid in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

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