Suberoylanilide Hydroxamic Acid, Fluorouracil, Leucovorin, and Oxaliplatin in Treating Patients With Progressive Metastatic or Unresectable Colorectal Cancer or Other Solid Tumors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00138177
First received: August 29, 2005
Last updated: September 27, 2013
Last verified: September 2013
  Purpose

This phase I trial is studying the side effects and best dose of suberoylanilide hydroxamic acid when given together with fluorouracil, leucovorin, and oxaliplatin in treating patients with progressive metastatic or unresectable colorectal cancer or solid tumor. Drugs used in chemotherapy, such as suberoylanilide hydroxamic acid, fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Suberoylanilide hydroxamic acid may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving more than one drug (combination chemotherapy) may kill more tumor cells.


Condition Intervention Phase
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage III Colon Cancer
Stage III Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: oxaliplatin
Drug: leucovorin calcium
Drug: vorinostat
Drug: fluorouracil
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Suberoylanilide Hydroxamic Acid (Vorinostat) in Combination With 5-Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX) in Patients With Colorectal Cancer and Other Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of vorinostat [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]
    Graded according to the NCI CTCAE.

  • Grade 3, 4, or 5 adverse events graded using the NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Response, evaluated using the new international criteria proposed by the RECIST committee [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: No ]
    To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed 4 weeks or more after the criteria for response are first met.

  • Gene expression studies for evidence of up-regulation or down-regulation, obtained from microarray testing and changes in expression patterns of TS [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: No ]
    Carried out with real time quantitative RT-PCR assays.

  • Pharmacokinetic analysis for vorinostat and 5-FU [ Time Frame: Days 1 and 15 ] [ Designated as safety issue: No ]
  • DPD activity [ Time Frame: Up to 8 days after the first dose of vorinostat (course 1) ] [ Designated as safety issue: No ]
    Tabulated by dose level.


Enrollment: 54
Study Start Date: July 2005
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, mFOLFOX)

Patients receive oral SAHA once or twice daily on days 1-3. Patients also receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 4 followed by fluorouracil IV over 46 hours on days 4-5. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A total of 10 patients are treated at the MTD.

Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of suberoylanilide hydroxamic acid when administered with fluorouracil, leucovorin calcium, and oxaliplatin in patients with progressive metastatic or unresectable colorectal cancer or other solid tumors.

SECONDARY OBJECTIVES:

I. Determine the toxicity of this regimen in these patients. II. Determine the pharmacokinetics of oxaliplatin, fluorouracil, and suberoylanilide hydroxamic acid in these patients.

OUTLINE: This is a dose-escalation study of suberoylanilide hydroxamic acid (SAHA).

Patients receive oral SAHA once or twice daily on days 1-3. Patients also receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 4 followed by fluorouracil IV over 46 hours on days 4-5. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A total of 10 patients are treated at the MTD.

After completion of study treatment, patients are followed for 4 weeks.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed colorectal cancer
  • Metastatic or unresectable disease OR diagnosis of solid tumor
  • No known brain metastases
  • ECOG 0-1 OR Karnofsky 70-100%
  • Life expectancy > 12 weeks
  • Absolute neutrophil count ≥ 1,500/mm^3
  • WBC ≥ 3,000/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Bilirubin normal
  • AST and ALT ≤ 3 times upper limit of normal
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 3 months after study participation
  • No ongoing or active infection
  • No neuropathy > grade 1
  • No history of allergic reaction attributed to compounds of similar chemical or biological composition to study drugs
  • No psychiatric illness or social situation that would preclude study compliance
  • No psychiatric illness or social situation that would preclude study compliance
  • No other uncontrolled illness
  • Prior bevacizumab and/or cetuximab allowed
  • No concurrent routine or prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)
  • More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
  • More than 4 weeks since prior radiotherapy
  • Recovered from prior therapy
  • At least 2 weeks since prior valproic acid
  • No concurrent combination anti-retroviral therapy for HIV-positive patients
  • No other concurrent investigational agents
  • No other concurrent anticancer therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00138177

Locations
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
Investigators
Principal Investigator: Marwan Fakih Roswell Park Cancer Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00138177     History of Changes
Other Study ID Numbers: NCI-2009-00083, NCI-2009-00083, CDR0000439445, I 55305, 6789
Study First Received: August 29, 2005
Last Updated: September 27, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colonic Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Oxaliplatin
Vorinostat
Leucovorin
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients

ClinicalTrials.gov processed this record on July 26, 2014