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

NCT00942266 | Completed Phase 2 Results DMC

• 2 other identifiers: I 142808NCI-2009-01523
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Median Progression-free Survival

  Every 8 weeks, up to 100 weeks.

• Response Rate

  Every 8 weeks; up to 100 weeks.

• Toxicity

  Daily

• Overall Survival

  Every 12 weeks

• Vorinostat Pharmacokinetics

  day 2 (cycle 1)

Study Arms (2)

Arm I

EXPERIMENTAL

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; Drug: leucovorin calcium; Drug: vorinostat; Other: pharmacological study

Arm II

EXPERIMENTAL

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; Drug: leucovorin calcium; Drug: vorinostat; Other: pharmacological study

Interventions

fluorouracil DRUG

Given IV

Also known as: 5-fluorouracil, 5-Fluracil, 5-FU, Adrucil, Efudex, FU

Arm I; Arm II

leucovorin calcium DRUG

Given IV

Also known as: calcium folinate, CF, CFR, citrovorum factor, LV, Wellcovorin

Arm I; Arm II

vorinostat DRUG

Given orally

Also known as: L-001079038, SAHA, suberoylanilide hydroxamic acid, Zolinza

Arm I; Arm II

pharmacological study OTHER

Correlative study

Also known as: pharmacological studies

Arm I; Arm II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Roswell Park Cancer Institute: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

MeSH Terms

Conditions

Colonic Neoplasms; Rectal Neoplasms

Interventions

Fluorouracil; Leucovorin; Vorinostat

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Results Point of Contact

• Title: Senior Administrator, Compliance - Clinical Research Services
• Organization: Roswell Park Cancer Institute

716-845-2300

Study Officials

• Wen Wee MA, MD

  Roswell Park Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2009
• First Posted: July 20, 2009
• Study Start: July 1, 2009
• Primary Completion: May 1, 2011
• Study Completion: December 1, 2011
• Last Updated: June 23, 2014
• Results First Posted: June 23, 2014

Record last verified: 2014-05

Locations

US (1)