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

NCT ID: NCT00005639

Last Updated: 2019-01-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-03-31
• Study Completion Date: 2005-07-31

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.

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Azacitidine Injection

Intervention Type: DRUG

subcutaneous injection (SC)

sodium phenylbutyrate

Intervention Type: DRUG

continuous intravenous (CIV)

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

Group Type: EXPERIMENTAL

Azacitidine Injection

Intervention Type: DRUG

subcutaneous injection (SC)

sodium phenylbutyrate

Intervention Type: DRUG

continuous intravenous (CIV)

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

Group Type: EXPERIMENTAL

Azacitidine Injection

Intervention Type: DRUG

subcutaneous injection (SC)

sodium phenylbutyrate

Intervention Type: DRUG

continuous intravenous (CIV)

Interventions

Azacitidine Injection

subcutaneous injection (SC)

Intervention Type: DRUG

sodium phenylbutyrate

continuous intravenous (CIV)

Intervention Type: DRUG

Other Intervention Names

AC; 5-AC

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael A. Carducci, MD

Role: STUDY_CHAIR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Countries

United States

References

Lin J, Gilbert J, Rudek MA, Zwiebel JA, Gore S, Jiemjit A, Zhao M, Baker SD, Ambinder RF, Herman JG, Donehower RC, Carducci MA. A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clin Cancer Res. 2009 Oct 1;15(19):6241-9. doi: 10.1158/1078-0432.CCR-09-0567. Epub 2009 Sep 29.

Reference Type: RESULT

PMID: 19789320 (View on PubMed)

Other Identifiers

U01CA070095

Identifier Type: NIH

Identifier Source: secondary_id

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R01CA075525

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P50CA058236

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA006973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000067799

Identifier Type: -

Identifier Source: secondary_id

NCI-270

Identifier Type: -

Identifier Source: secondary_id

99-12-03-02

Identifier Type: OTHER

Identifier Source: secondary_id

J9982

Identifier Type: -

Identifier Source: org_study_id