Vorinostat, Fluorouracil, and Leucovorin Calcium in Treating Patients With Metastatic Colorectal Cancer That Has Not Responded to Previous Treatment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Roswell Park Cancer Institute
ClinicalTrials.gov Identifier:
NCT00942266
First received: July 17, 2009
Last updated: September 20, 2012
Last verified: September 2012
  Purpose

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which dose of vorinostat is more effective when given together with combination chemotherapy in treating patients with metastatic colorectal cancer. PURPOSE: This randomized phase II trial is studying the best dose of vorinostat to see how well it works when given together with fluorouracil and leucovorin calcium in treating patients with metastatic colorectal cancer that has not responded to previous treatment.


Condition Intervention Phase
Adenocarcinoma of the Colon
Adenocarcinoma of the Rectum
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
Drug: fluorouracil
Drug: leucovorin calcium
Drug: vorinostat
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Two Dose-Levels of Vorinostat in Combination With 5-FU and Leucovorin in Patients With Refractory Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Roswell Park Cancer Institute:

Primary Outcome Measures:
  • Disease control rate (stable disease or objective response) [ Time Frame: At 2 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Median progression-free survival [ Time Frame: 2.1 months ] [ Designated as safety issue: No ]
  • Response rate [ Time Frame: Every 8 weeks ] [ Designated as safety issue: No ]
  • Toxicity [ Time Frame: Daily ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: Every 12 weeks ] [ Designated as safety issue: No ]
  • Vorinostat pharmacokinetics [ Time Frame: day 2 (cycle 1) ] [ Designated as safety issue: No ]
  • Fluorouracil steady-state pharmacokinetics [ Time Frame: Day 1 ] [ Designated as safety issue: No ]

Enrollment: 58
Study Start Date: July 2009
Study Completion Date: December 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I
Patients receive low-dose oral vorinostat once daily on days 1-3, leucovorin calcium IV over 2 hours on day 2, and fluorouracil IV over 46 hours on days 2 and 3. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
  • Adrucil
  • Efudex
  • FU
Drug: leucovorin calcium
Given IV
Other Names:
  • calcium folinate
  • CF
  • CFR
  • citrovorum factor
  • LV
  • Wellcovorin
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Other: pharmacological study
Correlative study
Other Name: pharmacological studies
Experimental: Arm II
Patients receive high-dose oral vorinostat once daily on days 1-3 and leucovorin calcium and fluorouracil as in arm I. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
  • Adrucil
  • Efudex
  • FU
Drug: leucovorin calcium
Given IV
Other Names:
  • calcium folinate
  • CF
  • CFR
  • citrovorum factor
  • LV
  • Wellcovorin
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Other: pharmacological study
Correlative study
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES: I. Describe the 2-months progression free rate on vorinostat 800mg/day x 3 in combination with 5-FU/L V every 2 weeks. (Arm I) II. Describe the 2-months progression free rate on vorinostat 1400mg/day x 3 in combination with 5-FU/L V every 2 weeks. (Arm II) SECONDARY OBJECTIVES: I. Describe the response rate on Arm 1 and Arm 2 of the study. II. Estimate the median progression free survival on both arms of the study. III. Describe the overall survival on Arm 1 and Arm 2 of the study. IV. Describe the toxicities on Arm 1 and Arm 2 of the study. V. Describe vorinostat pharmacokinetics on Arm 1 and Arm 2 of the study. VI. Describe 5-FU steady state pharmacokinetics on Arm 1 and Arm 2 of the study. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive low-dose oral vorinostat once daily on days 1-3, leucovorin calcium IV over 2 hours on day 2, and fluorouracil IV over 46 hours on days 2 and 3. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive high-dose oral vorinostat once daily on days 1-3 and leucovorin calcium and fluorouracil as in arm I. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up for 30 days and then every 3 months.

  Eligibility

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

Inclusion

  • Patients must have histologically or cytologically confirmed colorectal adenocarcinoma that is metastatic and which has failed standard treatment or for which no standard treatment is available
  • Patients should have fluoropyrimidine-refractory disease; radiographic evidence of progression within 4 weeks from the last dose of a fluoropyrimidine-based regimen (at least 6 weeks of fluoropyrimidine-based treatment)
  • Patients should have received and progressed on (or proved to be intolerant to) oxaliplatin and irinotecan; progression within 6 months from oxaliplatin-based therapy or irinotecan-based therapy is acceptable for eligibility
  • Patients with KRAS wild-type or unknown KRAS status tumors should have progressed on or within 6 months from last cetuximab or panitumumab-based therapy; no prior cetuximab therapy is required for KRAS mutant tumors
  • ECOG performance status =< 2
  • Life expectancy >= 12 weeks
  • Ability to understand and the willingness to sign a written informed consent document
  • Ability to swallow pills
  • Absolute neutrophil count >= 1,500/uL
  • Platelets >= 100,000/uL
  • Total bilirubin =< institutional upper limit of normal
  • AST(SGOT)/ALT(SGPT) =< 3 x institutional upper limit of normal in the absence of metastatic disease to the liver and =< 5 x institutional upper limit of normal in the setting of metastatic disease to the liver
  • Creatinine =< 1.5 x institutional upper limit of normal
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
  • Males undergoing study treatment should also agree to adequate measures of contraception (partner contraception and use of condoms or abstinence, or vasectomy)

Exclusion

  • Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from significant adverse events due to agents administered more than 3 weeks earlier
  • Patients may not be receiving any other investigational agents
  • Patients with known brain metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in study
  • Greater than Grade 2 neuropathy as defined by CTCAE version 3.0
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Baseline EKG with QTc prolongation that is grade 2 or higher by CTCAE version 3.0
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with vorinostat
  • Patients should not have taken valproic acid or other histone deacetylase inhibitors, for at least 4 weeks prior to enrollment
  • Patients with known HIV infection or known active viral hepatitis
  • Prior treatment with vorinostat
  • Other non-study medications known to increase the QTc interval
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00942266

Locations
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
Roswell Park Cancer Institute
Investigators
Principal Investigator: Wen Wee MA, MD Roswell Park Cancer Institute
  More Information

No publications provided

Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT00942266     History of Changes
Other Study ID Numbers: I 142808, NCI-2009-01523
Study First Received: July 17, 2009
Last Updated: September 20, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Colonic Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Calcium, Dietary
Fluorouracil
Vorinostat
Leucovorin
Levoleucovorin
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 16, 2014