Vitamin D in Patients With Stage I-III Colon Cancer or Resectable Colon Cancer Liver Metastases

Inclusion Criteria:

Participants must meet the following criteria on screening examination to be eligible to participate in the study:

• Participants must have histologically confirmed adenocarcinoma of the colon that islocalized, with no evidence of distant metastasis (stage I, II, or III), and forwhich surgical resection of the primary tumor is being planned;

--OR

• Participants must have histologically or cytologically confirmed adenocarcinoma ofthe colon with resectable liver metastases for which liver resection is beingplanned.

• No prior radiation therapy or systemic treatment is allowed for patients undergoingresection of stage I, II, or III colon cancer.

• Prior systemic treatment or radiation therapy is allowed for patients withresectable liver metastases.

• The last dose of chemotherapy or radiation must have been administered at least 4 weeks prior to liver surgery.

• The last dose of bevacizumab must have been administered at least 6 weeks priorto liver resection.

• Age ≥18 years.

• ECOG performance status ≤ 1 (see Appendix A)

• Participants must have normal organ and marrow function as defined below:

• Total bilirubin ≤1.5× institutional upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN, or <5x ULN if clearlyattributable to liver metastases

• Serum calcium (corrected for albumin level) ≤ 1x institutional ULN

• Serum creatinine within normal institutional limits or creatinine clearance ≥60mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.

• Participants on full-dose anticoagulation are eligible if the following criteria aremet:

• Participant has an in-range INR (usually 2-3) on a stable dose of warfarin oris on a stable dose of low molecular weight heparin

• Participant has no active bleeding or pathological condition that carries ahigh risk of bleeding (i.e., tumor involving major vessels or known varices)

• Participants receiving anti-platelet agents are eligible. In addition, patientswho are on daily prophylactic aspirin or anticoagulation for atrialfibrillation are eligible.

• Discontinuation of anticoagulation, aspirin, and/or anti-platelet agents priorto surgery will occur according to institutional standards of care.

• Non-pregnant and not nursing

• Women of child-bearing potential must have a negative serum or urine pregnancytest (minimum sensitivity 25 IU/L or equivalent units of HCG) within 14 daysprior to study entry. Women of child-bearing potential include any female whohas experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is notpostmenopausal (defined as amenorrhea ≥12 consecutive months; or women onhormone replacement therapy with documented serum follicle stimulating hormonelevel >35 mIU/mL). Women who are using oral, implanted, or injectablecontraceptive hormones or mechanical products such as intrauterine device orbarrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or whoare practicing abstinence or where partner is sterile (e.g., vasectomy), shouldbe considered to be of child-bearing potential.

• The effects of higher-dose vitamin D3 and colon or liver surgery (andassociated perioperative medications and anesthesia) on the developing humanfetus are unknown and may pose unacceptable risk. For this reason, women ofchild-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entryand for the duration of study participation. Should a woman become pregnant orsuspect she is pregnant while participating in this study, she should informher treating physician immediately.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.

• Prior systemic therapy, radiotherapy, or investigational agent in participantsundergoing surgery for stage I, II, or III colon cancer.

• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks forbevacizumab) of liver resection.

• Concurrent use of other anti-cancer therapy, including chemotherapy agents, targetedagents, biological agents, immunotherapy, or investigational agents not otherwisespecified in this protocol.

• Inability to swallow pills.

• History of malabsorption or uncontrolled vomiting or diarrhea, or any other diseasesignificantly affecting gastrointestinal function that could interfere withabsorption of oral medications.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to vitamin D.

• Regular use of supplemental vitamin D totaling ≥ 2,000 IU/day in the past year.

• Use of supplemental vitamin D or supplements containing vitamin D beyond theprotocol-prescribed study treatment is not allowed during the treatment periodof this clinical trial.

• In order to maintain blinding, vitamin D levels should not be routinely checkedat screening or during the study by the treating investigator. Vitamin D levelswill be assayed only as part of the research blood samples collected during thestudy. If there are concerns related to a participant's vitamin D status, thelead Principal Investigator should be contacted for further discussion.

• Use of chronic oral corticosteroid therapy, lithium, phenytoin, quinidine,isoniazid, and/or rifampin (all of which can cause vitamin D depletion). Short-termuse of corticosteroids as anti-emetic therapy for chemotherapy is permitted.

• Regular use of thiazide diuretics (i.e., hydrochlorothiazide), which can lead tohypercalcemia, and unwillingness or inability to discontinue or switch to analternative anti-hypertensive agent.

• Pre-existing hypercalcemia (defined as baseline serum calcium above theinstitutional ULN, corrected for albumin level if albumin is not withininstitutional limits of normal).

-- The use of supplemental calcium or supplements containing calcium is prohibitedduring the treatment period of this clinical trial.

• Known active hyperparathyroid disease or other serious disturbance of calciummetabolism in the past 5 years.

• History of symptomatic genitourinary stones within the past year.

• Any uncontrolled intercurrent illness including, but not limited to, ongoing oractive infection, symptomatic congestive heart failure, unstable angina pectoris,cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion ofthe investigator, may increase the risks associated with study participation orstudy treatment, limit compliance with study requirements, or interfere with theinterpretation of study results.

• Pregnant or nursing women or men/women of child-bearing potential who are unwillingto employ adequate contraception.

-- Pregnant and nursing women are excluded from this study because there is anunknown but potential risk of adverse events related to higher-dose vitamin D3 andcolon or liver surgery (and associated perioperative medications and anesthesia) onthe human fetus. Consequently, breastfeeding should be discontinued if the mother isenrolled on the study.

• History of prior or synchronous malignancy except:

• A malignancy that was treated with curative intent, for which there has been noknown active disease for >3 years prior to randomization, and for which therisk of recurrence is low as determined by the investigator.

• Curatively treated non-melanoma skin malignancy, cervical cancer in situ, orprostatic intraepithelial neoplasia without evidence of prostate cancer.

• Known positive test for human immunodeficiency virus (HIV), hepatitis C virus, oracute or chronic hepatitis B infection.

• Participants with these infections are ineligible because they are at increasedrisk of significant complications in the perioperative period, particularly foractive hepatitis B or C patients undergoing liver resection. Appropriatestudies will be undertaken in participants receiving combination antiretroviraltherapy when indicated.