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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00138177

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: oxaliplatin Drug: leucovorin calcium Drug: vorinostat Drug: fluorouracil	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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:

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).

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

54 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2005

Actual Primary Completion Date :

Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (vorinostat, mFOLFOX) 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 Given IV Other Names: 1-OHP Dacotin Dacplat Eloxatin L-OHP Drug: leucovorin calcium Given IV Other Names: CF CFR LV Drug: vorinostat Given orally Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza Drug: fluorouracil Given IV Other Names: 5-fluorouracil 5-Fluracil 5-FU

Arm

Intervention/Treatment

Experimental: Treatment (vorinostat, mFOLFOX)

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

Given IV

Other Names:

1-OHP

Dacotin

Dacplat

Eloxatin

L-OHP

Drug: leucovorin calcium

Given IV

Other Names:

CFR

Drug: vorinostat

Given orally

Other Names:

L-001079038

SAHA

suberoylanilide hydroxamic acid

Zolinza

Drug: fluorouracil

Given IV

Other Names:

5-fluorouracil

5-Fluracil

5-FU

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of vorinostat [2 weeks]
Graded according to the NCI CTCAE.
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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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