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

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ClinicalTrials.gov Identifier: NCT00005639
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : January 11, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
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 : March 2000
Actual Primary Completion Date : July 2005
Actual Study Completion Date : July 2005

Resource links provided by the National Library of Medicine


Arms and Interventions
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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)


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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 ]
  2. Pharmacokinetics of Azacitidine combined with Phenylbutyrate as measured by maximal plasma concentration (Cmax) [ Time Frame: Up to 24 hours ]
  3. 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 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00005639


Locations
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United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Investigators
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Study Chair: Michael A. Carducci, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
More Information
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Publications of Results:

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT00005639    
Other Study ID Numbers: J9982
U01CA070095 ( U.S. NIH Grant/Contract )
R01CA075525 ( U.S. NIH Grant/Contract )
P50CA058236 ( U.S. NIH Grant/Contract )
P30CA006973 ( U.S. NIH Grant/Contract )
CDR0000067799
NCI-270
99-12-03-02 ( Other Identifier: JHM IRB )
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: January 11, 2019
Last Verified: January 2019
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
stage III adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
recurrent adult Hodgkin lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
small intestine lymphoma
unspecified adult solid tumor, protocol specific
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse large cell lymphoma
stage III adult immunoblastic large cell lymphoma
 stage III adult lymphoblastic lymphoma
stage III adult Burkitt lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV adult Burkitt lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent adult diffuse small cleaved cell lymphoma
Additional relevant MeSH terms:
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Lymphoma
Intestinal Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
 Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Azacitidine
4-phenylbutyric acid
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors