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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00005639
• Other study ID #: J9982
• Secondary ID: U01CA070095R01CA
• Status: Completed
• Phase: Phase 1
• Start date: March 2000
• Est. completion date: July 2005

Study information

• Verified date: January 2019
• Source: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: July 2005
• Est. primary completion date: July 2005
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Intestinal Neoplasms
• Lymphoma
• Small Intestine Cancer
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

Drug:
• Azacitidine Injection
subcutaneous injection (SC)
• sodium phenylbutyrate
continuous intravenous (CIV)

Locations

Country	Name	City	State
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 tumor — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	up to 6 months
Secondary	Toxicity as assessed by number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v2.0		up to 6 months
Secondary	Pharmacokinetics of Azacitidine combined with Phenylbutyrate as measured by maximal plasma concentration (Cmax)		Up to 24 hours
Secondary	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