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

A Phase I Dose Escalation to Maximally Tolerated Dose Trial of 5-Azacytidine (5 AC, NSC 102816) in Combination With Sodium Phenylbutyrate (PB, NSC 657802) in Patients With Refractory Solid Tumors

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.

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