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

Primary Purpose

Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum, Recurrent Colon Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
fluorouracil
leucovorin calcium
vorinostat
pharmacological study
Sponsored by
Roswell Park Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adenocarcinoma of the Colon

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Roswell Park Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I

Arm II

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Disease Control Rate (Stable Disease or Objective Response)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

Median Progression-free Survival
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Toxicity
Number of participants with an adverse event. Please refer to the adverse event reporting for more detail.
Overall Survival
Vorinostat Pharmacokinetics
Blood samples (5 ml of blood each) will be collected in red-top vacutainers (no anticoagulant) at 0 (pre- vorinostat), 0.5, 1, 2, 3, 4, 6, and 8 hours after the vorinostat dose on the first day of 5-FU infusion on cycle 1 (day 2 of cycle 1). Mean area under the curve is presented with 95% CI.
Fluorouracil Steady-state Pharmacokinetics
Blood samples will be collected for determination of plasma 5-FU steady state concentration at 6 hours after start of 5-FU continuous infusion. The mean per treatment arm are presented.

Full Information

First Posted
July 17, 2009
Last Updated
May 22, 2014
Sponsor
Roswell Park Cancer Institute
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT00942266
Brief Title
Vorinostat, Fluorouracil, and Leucovorin Calcium in Treating Patients With Metastatic Colorectal Cancer That Has Not Responded to Previous 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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
July 2009 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Roswell Park Cancer Institute
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
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 Title
Arm II
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
fluorouracil
Other Intervention Name(s)
5-fluorouracil, 5-Fluracil, 5-FU, Adrucil, Efudex, FU
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
leucovorin calcium
Other Intervention Name(s)
calcium folinate, CF, CFR, citrovorum factor, LV, Wellcovorin
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
vorinostat
Other Intervention Name(s)
L-001079038, SAHA, suberoylanilide hydroxamic acid, Zolinza
Intervention Description
Given orally
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative study
Primary Outcome Measure Information:
Title
Disease Control Rate (Stable Disease or Objective Response)
Description
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame
At 2 months
Secondary Outcome Measure Information:
Title
Median Progression-free Survival
Description
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame
Every 8 weeks, up to 100 weeks.
Title
Response Rate
Description
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame
Every 8 weeks; up to 100 weeks.
Title
Toxicity
Description
Number of participants with an adverse event. Please refer to the adverse event reporting for more detail.
Time Frame
Daily
Title
Overall Survival
Time Frame
Every 12 weeks
Title
Vorinostat Pharmacokinetics
Description
Blood samples (5 ml of blood each) will be collected in red-top vacutainers (no anticoagulant) at 0 (pre- vorinostat), 0.5, 1, 2, 3, 4, 6, and 8 hours after the vorinostat dose on the first day of 5-FU infusion on cycle 1 (day 2 of cycle 1). Mean area under the curve is presented with 95% CI.
Time Frame
day 2 (cycle 1)
Title
Fluorouracil Steady-state Pharmacokinetics
Description
Blood samples will be collected for determination of plasma 5-FU steady state concentration at 6 hours after start of 5-FU continuous infusion. The mean per treatment arm are presented.
Time Frame
Day 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wen Wee MA, MD
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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