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

Unspecified Adult Solid Tumor, Protocol Specific Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00138177
• Other study ID #: NCI-2009-00083
• Secondary ID: NCI-2009-00083CD
• Status: Completed
• Phase: Phase 1
• First received: August 29, 2005
• Last updated: September 27, 2013
• Start date: July 2005

Study information

• Verified date: September 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Rectal Neoplasms
• 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

Drug:
• oxaliplatin
Given IV
• leucovorin calcium
Given IV
• vorinostat
Given orally
• fluorouracil
Given IV

Locations

Country	Name	City	State
United States	Roswell Park Cancer Institute	Buffalo	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of vorinostat	Graded according to the NCI CTCAE.	2 weeks	Yes
Primary	Grade 3, 4, or 5 adverse events graded using the NCI CTCAE version 4.0		Up to 30 days after completion of study treatment	Yes
Secondary	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	No
Secondary	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	No
Secondary	Pharmacokinetic analysis for vorinostat and 5-FU		Days 1 and 15	No
Secondary	DPD activity	Tabulated by dose level.	Up to 8 days after the first dose of vorinostat (course 1)	No