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

Johns Hopkins Medicine

Status and phase: Completed; Phase 1

Conditions: Unspecified Adult Solid Tumor, Protocol Specific; Lymphoma; Small Intestine Cancer

Treatments: Drug: sodium phenylbutyrate; Drug: Azacitidine Injection

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00005639

U01CA070095 (U.S. NIH Grant/Contract)

P30CA006973 (U.S. NIH Grant/Contract)

J9982

P50CA058236 (U.S. NIH Grant/Contract)

99-12-03-02 (Other Identifier)

CDR0000067799

R01CA075525 (U.S. NIH Grant/Contract)

NCI-270

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 34 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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34 participants in 3 patient groups

Regimen A: 14-day 5-AC with intermittent phenylbutyrate

Experimental group

Description:

Participants receive low-dose regimen of 5-AC with intermittent phenylbutyrate 400 mg/m2/day by continuous intravenous (CIV) over 24 hours on Days 6 and 13. Each cycle lasts 35 days. Cohort A1: 25 mg/m2/day subcutaneous (SC) Cohort A-1: 18.75 mg/m2/day SC Cohort A-2: 15 mg/m2/day SC Cohort A-3: 10 mg/m2/day SC

Treatment:

Drug: Azacitidine Injection

Drug: sodium phenylbutyrate

Regimen B: 7-day 5-AC with sequential phenylbutyrate

Experimental group

Description:

Participants receive 5-AC 75mg/m2/day SC for 7 days, followed sequentially by two different doses of phenylbutyrate CIV starting on Day 8 and continuing for 7 days. Each cycle lasts 35 days Cohort B1: Phenylbutyrate 200 mg/m2/day CIV Cohort B2: Phenylbutyrate 400 mg/m2/day CIV

Treatment:

Drug: Azacitidine Injection

Drug: sodium phenylbutyrate

Regimen C: 21-day 5-AC with weekly phenylbutyrate

Experimental group

Description:

Participants receive two different daily doses of 5-AC SC for 21 days and phenylbutyrate 400 mg/m2/day CIV over 24 hours once-per-week. Each cycle lasts 42 days. Cohort C1: 5-AC 10mg/m2/day SC Cohort C2: 5-AC 12.5mg/m2/day SC

Treatment:

Drug: Azacitidine Injection

Drug: sodium phenylbutyrate