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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Intervention / Treatment
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* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: vorinostat
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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<br>* Given IV<br>* Other names: FU;Drug: leucovorin calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Other: pharmacological study<br>* Correlative study<br>* Other names: pharmacological studies;|
| Experimental: Arm II<br>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<br>* Given IV<br>* Other names: FU;Drug: leucovorin calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Other: pharmacological study<br>* Correlative study<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every 8 weeks, up to 100 weeks. | 
| 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. | Every 8 weeks; up to 100 weeks. | 
| Toxicity | Number of participants with an adverse event. Please refer to the adverse event reporting for more detail. | Daily | 
| Overall Survival |  | Every 12 weeks | 
| 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. | day 2 (cycle 1) | 
| 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. | Day 1 |