Rosuvastatin in Treating Patients With Stage I or Stage II Colon Cancer That Was Removed By Surgery

OBJECTIVES:

Primary

- To compare the effect of rosuvastatin vs placebo on the 5-year occurrence of
adenomatous polyps of the colon or rectum, metachronous colorectal carcinoma, or colon
cancer recurrence (APMC+R) in patients with resected stage I or II colon cancer.

Secondary

- To determine whether the effect of rosuvastatin vs placebo is of the same magnitude in
patients taking aspirin (regardless of dose) compared to patients not taking aspirin.

- To determine whether taking aspirin (regardless of dose) vs no aspirin will decrease
the occurrence or APMC+R and, if there is an effect, to explore the relationship to
dose.

- To determine the effect of rosuvastatin in patients with familial colorectal cancer.

- To determine the effect of rosuvastatin in patients with microsatellite unstable tumors
(i.e., tumors displaying loss of MLH1 or MSH2 expression by IHC).

- To determine the relationship between rosuvastatin therapy and features of colorectal
adenomas as well as the size and number of colorectal adenomas.

- To compare the time to APMC+R in patients treated with rosuvastatin vs placebo.

- To compare the disease-free survival of patients treated with rosuvastatin vs placebo.

- To compare the overall survival of patients treated with rosuvastatin vs placebo.

- To compare the rate of recurrence of colon cancer in patients treated with rosuvastatin
vs placebo.

- To compare the rate of second non-colorectal primary cancers in patients treated with
rosuvastatin vs placebo.

- To determine the effect of rosuvastatin on health-related quality of life, global
quality of life, and self-reported symptoms.

- To compare the incidence and severity of adverse events associated with rosuvastatin vs
placebo.

- To assess relevant tumor and blood markers that may affect the metabolism, activity, or
effect of the study drugs, such as HMG-CoA reductase, UGT1A6, P450-2C9, PTGS2 (COX-2),
and other possible markers.

OUTLINE: This is a multicenter study. Patients are stratified according to family history of
a first-degree relative with colorectal cancer (yes vs no), intended aspirin dose (none vs
81 mg vs 325 mg), and adjuvant therapy for colon cancer (yes vs no). Patients are randomized
to 1 of 2 treatment arms.

- Group 1: Patients receive oral placebo once daily for 5 years.

- Group 2: Patients receive oral rosuvastatin once daily for 5 years.

Patients may complete a quality-of-life questionnaire at baseline and at 6, 12, 36, 60, and
84 months.

Tumor tissue, serum, and blood samples may be collected periodically for biomarker and other
analyses.

After completion of study treatment, patients are followed up periodically for up to 2
years.

Inclusion Criteria

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 or 1.

- Patients must have the ability to swallow oral medication.

- Patients must have resected adenocarcinoma of the colon staged as American Joint
Committee on Cancer (AJCC) Stage 0, I, II, or III.

- Patients must have had surgical resection of the colon adenocarcinoma with curative
intent within 1 year prior to randomization. (Laparoscopically-assisted colectomy is
permitted.)

- Patients must have completed any adjuvant therapy prior to randomization.

- Patients who are taking cardioprotective low-dose aspirin at study entry must not
have clinically significant toxicity, as determined by the investigator, that
precludes continuation of aspirin, and the patient must be willing to continue
aspirin therapy (81 mg or 325 mg) throughout study therapy.

- Colonoscopy requirements within 180 days prior to randomization:

- The patient must have either undergone a preoperative or postoperative documented
colonoscopy to the cecum (or small bowel anastomosis) with adequate bowel
preparation.

- All observed polyps must have been removed. (Polyps can be removed during colonoscopy
or surgery performed prior to randomization.)

- Postoperative serum creatinine performed within 90 days prior to randomization must
be less than or equal to 1.5 x upper limit of normal (ULN) for the lab.

- The following criteria for evidence of adequate hepatic function based on
postoperative testing performed within 90 days prior to randomization must be met:
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than or equal
to 3.0 x ULN for the lab, and Total bilirubin less than or equal to 1.5 x ULN for the
lab

Exclusion Criteria

- Tumor with the distal border located less than 12 cm from the anal verge.

- Total colectomy or total proctocolectomy.

- Classic Familial Adenomatous Polyposis, Attenuated Familial Adenomatous Polyposis
(i.e., 20 or more adenomas, either synchronous or metachronous), or Hereditary
Nonpolyposis Colorectal Cancer (Lynch Syndrome).

- Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of
the stomach or small bowel, or other disease significantly affecting gastrointestinal
function.

- History of documented upper GI bleeding or upper GI ulcerative disease.

- Statin use within 30 days prior to randomization.

- Hyperlipidemia with clinical indication for statin therapy or other prescribed
medication. Determination of acceptable fasting lipid values, within 90 days prior to
randomization, should be in accordance with current dyslipidemia management
guidelines.

- Unwillingness to discontinue chronic use of nonsteroidal antiinflammatory drugs
(NSAIDs) (other than cardioprotective low-dose aspirin 81 mg or 325 mg) prior to
randomization.

- Anticipated need for chronic use of NSAIDs (other than cardioprotective low-dose
aspirin 81 mg or 325 mg).

- Inadequately treated hypothyroidism, as determined by the investigator.

- History of myopathy or rhabdomyolysis.

- Hypersensitivity or intolerance to statins.

- Chronic drug therapy with cyclosporine, coumarin anticoagulants, gemfibrozil, some
other lipid-lowering therapies (fibrates or niacin), lopinavir/ritonavir, or drugs
(such as ketoconazole, spironolactone, or cimetidine) that lower levels or activity
of steroid hormones.

- Pregnancy or lactation at the time of study entry. (Pregnancy testing must be
performed within 14 days prior to randomization according to institutional standards
for women of childbearing potential.)

- Previous malignancies unless the patient has been disease-free for 5 or more years
prior to randomization and is deemed by the physician to be at low risk for
recurrence. Patients with the following cancers are eligible if diagnosed and treated
within the past 5 years: all in situ cancers and basal cell and squamous cell
carcinoma of the skin.

- Other non-malignant systemic disease that would preclude a patient from receiving
rosuvastatin or would prevent prolonged follow-up.

- Administration of any investigational agent within 30 days before randomization.