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Phase 2 Prospective Randomized Double Blind Trial Comparing Metastasectomy Plus Sulindac Versus Metastasectomy Alone in Patients With Stage IV Colorectal Cancer

Phase 2
18 Years
Open (Enrolling)
Colorectal Cancer, Liver Metastasis, Colorectal Adenocarcinoma

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Trial Information

Phase 2 Prospective Randomized Double Blind Trial Comparing Metastasectomy Plus Sulindac Versus Metastasectomy Alone in Patients With Stage IV Colorectal Cancer

- Despite strong evidence for a causative role of inflammatory mediators in intestinal
cancer, the underlying mechanisms remain obscure. Established evidence indicates
activation of the Wnt/beta-catenin pathway is an early step in the malignant
transformation of colorectal adenomas with persistent activation in 90% of colorectal
cancers. Activation of this pathway ultimately effects transcription of the S100A4

- S100A4 transcript serum levels have been shown to correlate with risk of recurrence in
colorectal cancer and patients with systemic metastases are found to have increased
S100A4 transcript expression.

- S100A4 may be a novel prognostic biomarker in colorectal cancer.

- Cyclooxygenase-2 is a key enzyme involved in the inflammatory response and is a key
target of molecular chemoprevention in colorectal adenoma prevention trials.

- Recent studies demonstrate mitigation of Wnt/beta-catenin signaling by COX-2 inhibition
via administration of the NSAID sulindac using in vitro and in vivo animal models.

- We hypothesize that sulindac administration will abrogate Wnt/beta-catenin mediated
signaling and thus decrease S100A4 activity in patients with colorectal metastases.

- We propose to define the benefit of sulindac administration to patients with colorectal
metastases following resection and validate the use of circulating S100A4 transcripts
as a novel biomarker for disease recurrence.

Inclusion Criteria


1. Histologically confirmed colorectal adenocarcinoma with metastatic disease confined
to the liver, or limited extrahepatic intra-abdominal disease Note: limited sites of
disease include:

- porta hepatis lymph node metastases

- pelvic lymph node metastases (internal iliac, external iliac or obturator)

2. Hepatic and intra-abdominal metastases must be measurable by CT, MRI and/or PET scan

3. Liver disease must be amenable to gross total resection (R0/R1) with adequate
functional liver remnant which requires preservation of at least 2 contiguous hepatic
segments with adequate inflow, outflow, and biliary drainage with a functional liver
remnant (FLR) volume of more than 20% (for healthy liver)

4. Greater than or equal to 18 years of age.

5. Must be able to understand and sign the Informed Consent Documentation.

6. Clinical performance status of ECOG less than or equal to 2.

7. Life expectancy of greater than six months.

8. Patients of both genders must be willing to practice birth control during and for one
week after taking sulindac/placebo.

9. Hematology:

- Absolute neutrophil count greater than 1500/mm3 without the support of

- Platelet count greater than 75,000/mm3.

- Hemoglobin greater than 8.0 g/dl.

10. Chemistry:

- Serum creatinine less than or equal to 1.5 mg/dl unless the measured creatinine
clearance is greater than 60mL/min/1.73m2.

- Total bilirubin less than or equal to 2 mg/dl, except for patients with
diagnosis of Gilbert's disease or hepatic pedicle obstruction then total
bilirubin must be less than or equal to 5 mg/dl.

11. INR less than or equal to 1.8.


- Age greater than 18

- Able to read and understand the informed consent

- No self-reported co morbidities of history of cancer


1. Women of child-bearing potential who are pregnant or breast feeding because of the
potentially dangerous effects of the chemotherapy on the fetus or infant.

2. Active systemic infections, coagulation disorders or other major medical illnesses
precluding major surgery.

3. Patients receiving warfarin anticoagulation, who cannot be transferred to other
agents, such as low molecular weight heparins, anti-Xa agents, etc.

4. Active bleeding disorders

5. Patients with uncontrolled hypertension (would suggest: SBP> 155, DBP> 90),
unstable coronary disease (unstable angina, evidence of CHF, or MI within 6-12 months
of study)

6. Childs B or C cirrhosis or with evidence of severe portal hypertension by history,
endoscopy, or radiologic studies or with evidence of moderate to severe ascites.

7. Prior history of GI bleeding unrelated to a cancer diagnosis

Note: Patients who have a normal upper and lower endoscopy may be enrolled at the
discretion of the PI.

8. Renal insufficiency Discretion of principle investigator.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Determine if there is a difference in circulating S100A4 transcript in patients receiving sulindac 150 mgBD by mouth following resection of colorectal cancer metastases compared to those who do not. Patients will be randomized between two arms i...

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Prakash K Pandalai, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

April 2013

Completion Date:

May 2019

Related Keywords:

  • Colorectal Cancer
  • Liver Metastasis
  • Colorectal Adenocarcinoma
  • Colorectal Cancer
  • Liver Metastasis
  • Sulindac
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Colorectal Neoplasms
  • Neoplasm Metastasis
  • Liver Neoplasms



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892