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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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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

Intervention / Treatment
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* Drug: oxaliplatin
* Drug: leucovorin calcium
* Drug: vorinostat
* Drug: fluorouracil


Participation Criteria
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Eligibility Criteria
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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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (vorinostat, mFOLFOX)<br>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<br>* Given IV<br>* Other names: L-OHP;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of vorinostat | Graded according to the NCI CTCAE. | 2 weeks | 
| Grade 3, 4, or 5 adverse events graded using the NCI CTCAE version 4.0 |  | Up to 30 days after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response, evaluated using the new international criteria proposed by the RECIST committee | 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. | Up to 4 weeks after completion of study treatment | 
| Gene expression studies for evidence of up-regulation or down-regulation, obtained from microarray testing and changes in expression patterns of TS | Carried out with real time quantitative RT-PCR assays. | Up to 4 weeks after completion of study treatment | 
| Pharmacokinetic analysis for vorinostat and 5-FU |  | Days 1 and 15 | 
| DPD activity | Tabulated by dose level. | Up to 8 days after the first dose of vorinostat (course 1) |