Vorinostat, Fluorouracil, and Leucovorin Calcium in Treating Patients With Metastatic Colorectal Cancer That Has Not Responded to Previous Treatment
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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 |
- Disease control rate (stable disease or objective response) [ Time Frame: At 2 months ] [ Designated as safety issue: No ]
- 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:
Drug: leucovorin calcium
Given IV
Other Names:
Drug: vorinostat
Given orally
Other Names:
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:
Drug: leucovorin calcium
Given IV
Other Names:
Drug: vorinostat
Given orally
Other Names:
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 |
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| United States, New York | |
| Roswell Park Cancer Institute | |
| Buffalo, New York, United States, 14263 | |
| 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 Adenocarcinoma, Mucinous Colonic Neoplasms Rectal Neoplasms Colorectal Neoplasms Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Neoplasms, Cystic, Mucinous, and Serous 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 |
ClinicalTrials.gov processed this record on June 13, 2013