Suberoylanilide Hydroxamic Acid, Fluorouracil, Leucovorin, and Oxaliplatin in Treating Patients With Progressive Metastatic or Unresectable Colorectal Cancer or Other Solid Tumors
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Purpose
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 | Intervention | 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 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: 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 |
- Maximum tolerated dose of vorinostat [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]Graded according to the NCI CTCAE.
- Grade 3, 4, or 5 adverse events graded using the NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
- Response, evaluated using the new international criteria proposed by the RECIST committee [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: No ]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 [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: No ]Carried out with real time quantitative RT-PCR assays.
- Pharmacokinetic analysis for vorinostat and 5-FU [ Time Frame: Days 1 and 15 ] [ Designated as safety issue: No ]
- DPD activity [ Time Frame: Up to 8 days after the first dose of vorinostat (course 1) ] [ Designated as safety issue: No ]Tabulated by dose level.
| Enrollment: | 54 |
| Study Start Date: | July 2005 |
| Primary Completion Date: | December 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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:
Drug: leucovorin calcium
Given IV
Other Names:
Drug: vorinostat
Given orally
Other Names:
Drug: fluorouracil
Given IV
Other Names:
|
Detailed 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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00138177 History of Changes |
| Other Study ID Numbers: | NCI-2009-00083, I 55305 |
| Study First Received: | August 29, 2005 |
| Last Updated: | January 29, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Colonic Neoplasms Rectal Neoplasms Colorectal Neoplasms Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Gastrointestinal Diseases Colonic Diseases Intestinal Diseases Rectal Diseases Fluorouracil Oxaliplatin |
Vorinostat Leucovorin Levoleucovorin Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antimetabolites, Antineoplastic Antineoplastic Agents Therapeutic Uses Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Vitamin B Complex Vitamins Micronutrients |
ClinicalTrials.gov processed this record on May 23, 2013