Vorinostat, Fluorouracil, and Leucovorin Calcium in Treating Patients With Metastatic Colorectal Cancer That Has Not Responded to Previous Treatment
Condition: Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer
MeSH terms: Adenocarcinoma; Rectal Neoplasms; Colonic Neoplasms; Recurrence
Intervention: fluorouracil; leucovorin calcium; vorinostat; pharmacological study
Intervention description: Given IV; Given IV; Given orally; Correlative study
Intervention MeSH terms: Calcium, Dietary; Leucovorin; Fluorouracil; Vorinostat; Calcium; Levoleucovorin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 58.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion

          -  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)

        Exclusion

          -  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