RATIONALE: 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.

PURPOSE: 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	Treatment or Intervention	Phase
recurrent adult Burkitt's lymphoma recurrent adult diffuse large cell lymphoma recurrent mantle cell lymphoma	Drug: decitabine  Drug: valproic acid  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy	Phase I

Further Study Details: 

OBJECTIVES: Primary

• Determine the minimally effective pharmacological dose (MEPD) of single-agent decitabine in patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma.
• Determine the maximum tolerated dose of valproic acid when administered with the MEPD of decitabine in these patients.
• Determine the MEPD of valproic acid when administered with decitabine in these patients.
• Determine the toxic effects of decitabine alone and in combination with valproic acid in these patients.

Secondary

• Determine the response rate in patients treated with these drugs.
• 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.

• : Patients receive decitabine IV over 1 hour on days 1-10. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. 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 an 80% decrease in DNMT1 protein level AND a 100% increase in re-expression of the methylated target genes (DAP-kinase, p15^INK4b, or p16^INK4a) occurs in 5 of 6 patients AND ≤ 1 of 6 patients experiences dose-limiting toxicity (DLT).
• : Patients receive decitabine as in stage 1 and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of valproic acid in combination with the MEPD of decitabine (determined in stage 1) 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. Once the MTD of valproic acid is determined, 6 patients are treated at the MTD and at 1 lower dose level to determine the MEPD of valproic acid in combination with decitabine. The MEPD of the combination is defined as the plasma level of valproic acid at which either an 80% of histone deacetylase (HDAC) enzyme inhibition OR a 100% increase in baseline H3 and H4 acetylation AND a 100% increase in re-expression of the methylated target genes (DAP-kinase, p15^INK4b, or p16^INK4a) occurs in 5 of 6 patients AND ≤ 1 of 6 patients experiences DLT.

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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• 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 NOTE: *Patients with evidence of transformed lymphoma/Richter's transformation are eligible at the time of transformation
• 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 NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3*
• Platelet count ≥ 75,000/mm^3* NOTE: *Unless related to lymphoma

Hepatic

• AST and ALT ≤ 2.5 times upper limit of normal
• Bilirubin ≤ 1.5 mg/dL

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• 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 CONCURRENT THERAPY: Biologic therapy

• Prior stem cell transplantation allowed
• At least 21 days since prior immunotherapy and recovered

Chemotherapy

• At least 21 days since prior chemotherapy and recovered
• No other concurrent chemotherapy unless it is used in the chronic daily setting for other medical conditions, including pulmonary, rheumatologic, or adrenal disorders

Endocrine therapy

• No concurrent corticosteroids unless they are used in the chronic daily setting for other medical conditions, including pulmonary, rheumatologic, or adrenal disorders

Radiotherapy

• At least 21 days since prior radiotherapy and recovered
• No concurrent palliative radiotherapy

Surgery

• Not specified

Other

• At least 21 days since prior investigational agents
• No concurrent anticonvulsants, including valproic acid (except as used in this study)

Please refer to this study by ClinicalTrials.gov identifier  NCT00109824

Study chairs or principal investigators

Kristie A. Blum, MD,  Study Chair,  Arthur G. James Cancer Hospital & Richard J. Solove Research Institute   

Study ID Numbers:  CDR0000426523; OSU-2004C0119; NCI-6997; OSU-0475; NCT00109824
Record last reviewed:  April 2005
Last Updated:  May 12, 2005
Record first received:  May 3, 2005
ClinicalTrials.gov Identifier:  NCT00109824
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-05-17