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

Phase 1

Completed

• Conditions: Lymphoma; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific
• Interventions: Drug: Azacitidine Injection; Drug: sodium phenylbutyrate

• Registration Number: NCT00005639
• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

Study Timeline

• Study Start: 2000-03
• Study First Submitted: 2000-05-02
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2005-07
• Study Completion: 2005-07
• Status Verified: 2019-01
• Last Update Submitted: 2019-01-09
• Last Update Posted: 2019-01-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Regimen A: 14-day 5-AC with intermittent phenylbutyrate	Azacitidine Injection	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
Regimen B: 7-day 5-AC with sequential phenylbutyrate	Azacitidine Injection	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
Regimen C: 21-day 5-AC with weekly phenylbutyrate	Azacitidine Injection	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
Regimen C: 21-day 5-AC with weekly phenylbutyrate	sodium 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
Regimen A: 14-day 5-AC with intermittent phenylbutyrate	sodium 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
Regimen B: 7-day 5-AC with sequential phenylbutyrate	sodium 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

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (1)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States