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

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)

Overall Status

Completed

CT.gov ID

NCT00005639

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arms

Actual Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma Small Intestine Cancer Unspecified Adult Solid Tumor, Protocol Specific	Drug: Azacitidine Injection Drug: sodium phenylbutyrate	Phase 1

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

34 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 1, 2000

Actual Primary Completion Date :

Jul 1, 2005

Actual Study Completion Date :

Jul 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen A: 14-day 5-AC with intermittent phenylbutyrate 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	Drug: Azacitidine Injection subcutaneous injection (SC) Other Names: AC 5-AC Drug: sodium phenylbutyrate continuous intravenous (CIV)
Experimental: Regimen B: 7-day 5-AC with sequential phenylbutyrate 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	Drug: Azacitidine Injection subcutaneous injection (SC) Other Names: AC 5-AC Drug: sodium phenylbutyrate continuous intravenous (CIV)
Experimental: Regimen C: 21-day 5-AC with weekly phenylbutyrate 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	Drug: Azacitidine Injection subcutaneous injection (SC) Other Names: AC 5-AC Drug: sodium phenylbutyrate continuous intravenous (CIV)

Arm

Intervention/Treatment

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

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

Drug: Azacitidine Injection

subcutaneous injection (SC)

Other Names:

5-AC

Drug: sodium phenylbutyrate

continuous intravenous (CIV)

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

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

Drug: Azacitidine Injection

subcutaneous injection (SC)

Other Names:

5-AC

Drug: sodium phenylbutyrate

continuous intravenous (CIV)

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

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

Drug: Azacitidine Injection

subcutaneous injection (SC)

Other Names:

5-AC

Drug: sodium phenylbutyrate

continuous intravenous (CIV)

Outcome Measures

Primary Outcome Measures

Minimal Effective Dose (MED) of Azacitidine with Phenylbutyrate [up to 6 months]
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.

Secondary Outcome Measures

Toxicity as assessed by number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v2.0 [up to 6 months]
Pharmacokinetics of Azacitidine combined with Phenylbutyrate as measured by maximal plasma concentration (Cmax) [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 [Change from baseline to up to 6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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