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A Randomized Phase II Study of Two Dose-Levels of Vorinostat in Combination With 5-FU and Leucovorin in Patients With Refractory Metastatic Colorectal Cancer


Phase 2
18 Years
N/A
Not Enrolling
Both
Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

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Trial Information

A Randomized Phase II Study of Two Dose-Levels of Vorinostat in Combination With 5-FU and Leucovorin in Patients With Refractory Metastatic Colorectal Cancer


PRIMARY OBJECTIVES: I. Describe the 2-months progression free rate on vorinostat 800mg/day x
3 in combination with 5-FU/L V every 2 weeks. (Arm I) II. Describe the 2-months progression
free rate on vorinostat 1400mg/day x 3 in combination with 5-FU/L V every 2 weeks. (Arm II)
SECONDARY OBJECTIVES: I. Describe the response rate on Arm 1 and Arm 2 of the study. II.
Estimate the median progression free survival on both arms of the study. III. Describe the
overall survival on Arm 1 and Arm 2 of the study. IV. Describe the toxicities on Arm 1 and
Arm 2 of the study. V. Describe vorinostat pharmacokinetics on Arm 1 and Arm 2 of the study.
VI. Describe 5-FU steady state pharmacokinetics on Arm 1 and Arm 2 of the study. OUTLINE:
Patients are randomized to 1 of 2 treatment arms. ARM I: 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. ARM II: 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.
After completion of study therapy, patients are followed up for 30 days and then every 3
months.

Inclusion 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease control rate (stable disease or objective response)

Outcome Time Frame:

At 2 months

Safety Issue:

No

Principal Investigator

Wen Wee MA, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

I 142808

NCT ID:

NCT00942266

Start Date:

July 2009

Completion Date:

December 2011

Related Keywords:

  • Adenocarcinoma of the Colon
  • Adenocarcinoma of the Rectum
  • Recurrent Colon Cancer
  • Recurrent Rectal Cancer
  • Stage IV Colon Cancer
  • Stage IV Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Colorectal Neoplasms

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263