Azacitidine Plus Phenylbutyrate in Treating Patients With Advanced or Metastatic Solid Tumors That Have Not Responded to Previous Treatment

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins34 enrolled

Overview

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of azacitidine plus phenylbutyrate in treating patients with advanced or metastatic solid tumors that have not responded to previous treatment.

OBJECTIVES: * Evaluate the safety and toxicity of azacitidine plus phenylbutyrate in patients with refractory solid tumors. * Determine the maximum tolerated dose of this treatment regimen where maximal gene reexpression occurs in these patients. * Evaluate the pharmacokinetics of these drugs in these patients. * Determine the minimally effective dose of azacitidine in combination with phenylbutyrate that elicits a biological or clinical response in these patients. OUTLINE: This is a dose escalation study. Patients receive azacitidine subcutaneously for 14-21 days and sodium phenylbutyrate IV continuously for 1-7 days. Treatment repeats every 35 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses and durations of treatment with azacitidine and phenylbutyrate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose limiting toxicities. PROJECTED ACCRUAL: Approximately 3-50 patients will be accrued for this study within 12-18 months.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Lymphoma

Eligibility

Sex: ALLMin age: 18 YearsMax age: 120 Years

Medical Language ↔ Plain English

Inclusion criteria: DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor not amenable to curative therapy * Lymphoma allowed * Progressive disease * Evaluable disease * No CNS metastases by CT scan or MRI PATIENT CHARACTERISTICS: Age: * 18 and over Performance status: * ECOG 0-2 Life expectancy: * Not specified Hematopoietic: * Hemoglobin at least 8 g/dL (may be achieved by transfusion) * Absolute neutrophil count at least 1,500/mm\^3 * Platelet count at least 100,000/mm\^3 Hepatic: * Bilirubin no greater than 2 mg/dL (unless due to hemolysis or Gilbert's syndrome) * SGOT and SGPT less than 2 times upper limit of normal Renal: * Creatinine no greater than 2.0 mg/dL Other: * No active infection * HIV negative * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception for 2 weeks before, during, and 3 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy: * Not specified Chemotherapy: * At least 4 weeks since prior adjuvant chemotherapy for advanced or metastatic disease and recovered Endocrine therapy: * Not specified Radiotherapy: * At least 4 weeks since prior radiotherapy and recovered Surgery: * Not specified

Outcomes

Primary Outcomes

Minimal Effective Dose (MED) of Azacitidine with Phenylbutyrate

MED (milligrams) of combined Azacitidine and Phenylbutyrate that results in clinical response, as defined by Standard World Health Organization (WHO) criteria and/or target inhibition.

Time frame: up to 6 months

Secondary Outcomes

Toxicity as assessed by number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v2.0

Time frame: up to 6 months

Pharmacokinetics of Azacitidine combined with Phenylbutyrate as measured by maximal plasma concentration (Cmax)

Time frame: Up to 24 hours

Gene-re-expression of epigenetic modulation in Peripheral Blood Mononuclear Cells (PBMC) as measured by change in Epstein-Barr Virus (EBV) viral load (number of copies per 1 million cells) after treatment with Azacitidine

Time frame: Change from baseline to up to 6 months