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

Purpose

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.

Condition	Intervention	Phase
Recurrent Adult Burkitt Lymphoma Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Mantle Cell Lymphoma	Drug: decitabine Drug: valproic acid Other: pharmacological study Other: laboratory biomarker analysis	Phase 1


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment
Official Title:	A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma

Resource links provided by NLM:

MedlinePlus related topics: Lymphoma

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

Genetic and Rare Diseases Information Center resources: Burkitt Lymphoma Lymphosarcoma Diffuse Large B-Cell Lymphoma Mantle Cell Lymphoma Lymphoma, Large-cell B-cell Lymphoma

U.S. FDA Resources

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

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 [ Time Frame: 28 days ]
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 ]
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 ]
Toxicities of single agent decitabine alone and in combination with valproic acid assessed using CTCAE v3.0 [ Time Frame: Up to 3 years ]


Enrollment:	42
Study Start Date:	March 2006
Primary Completion Date:	March 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm I 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.	Other: pharmacological study Correlative studies Other Name: pharmacological studies Other: laboratory biomarker analysis Correlative studies
Experimental: Arm II 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.	Drug: decitabine Given IV Other Names: 5-aza-dCyd 5AZA DAC Drug: valproic acid Given PO Other Names: Alti-Valproic Depakene Novo-Valproic VA Other: pharmacological study Correlative studies Other Name: pharmacological studies Other: laboratory biomarker analysis Correlative studies

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.

Eligibility


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

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)

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: NCT00109824

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


Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00109824 History of Changes
Other Study ID Numbers:	NCI-2012-01465 0475 CDR0000426523 OSU-0475 NCI-6997 OSU-2004C0119 U01CA076576 ( U.S. NIH Grant/Contract )
Study First Received:	May 3, 2005
Last Updated:	June 3, 2013

Additional relevant MeSH terms:


Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Mantle-Cell Lymphoma, Large B-Cell, Diffuse Burkitt Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, B-Cell Epstein-Barr Virus Infections Herpesviridae Infections DNA Virus Infections	Virus Diseases Tumor Virus Infections 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

ClinicalTrials.gov processed this record on September 21, 2017