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

January 9, 2019 updated by: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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

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.

Study Overview

Status

Completed

Conditions

Intervention / 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 Type

Interventional

Enrollment (Actual)

34

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21231
        • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 120 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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
  • 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
  • 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
  • AC
Drug: sodium phenylbutyrate
continuous intravenous (CIV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Minimal Effective Dose (MED) of Azacitidine with Phenylbutyrate
Time Frame: 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.
up to 6 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Toxicity as assessed by number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v2.0
Time Frame: up to 6 months
up to 6 months
Pharmacokinetics of Azacitidine combined with Phenylbutyrate as measured by maximal plasma concentration (Cmax)
Time Frame: Up to 24 hours
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
Time Frame: Change from baseline to up to 6 months
Change from baseline to up to 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

National Cancer Institute (NCI)

Investigators

  • Study Chair: Michael A. Carducci, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2000

Primary Completion (Actual)

July 1, 2005

Study Completion (Actual)

July 1, 2005

Study Registration Dates

First Submitted

May 2, 2000

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Actual)

January 11, 2019

Last Update Submitted That Met QC Criteria

January 9, 2019

Last Verified

January 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • J9982
  • P30CA006973 (U.S. NIH Grant/Contract)
  • U01CA070095 (U.S. NIH Grant/Contract)
  • R01CA075525 (U.S. NIH Grant/Contract)
  • P50CA058236 (U.S. NIH Grant/Contract)
  • CDR0000067799
  • NCI-270
  • 99-12-03-02 (Other Identifier: JHM IRB)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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