Transcriptional Targets of Vitamin D in Patients with Stage I-III Colon Cancer or Resectable Colon Cancer Liver Metastases Receiving Preoperative Cholecalciferol

Status: Active

Description

This partially randomized pilot early phase I trial studies the transcriptional targets of vitamin D in patients with stage I-III colon cancer or colon cancer that has spread to the liver and can be removed by surgery who are receiving preoperative cholecalciferol. The vitamin D receptor is found in colon cancer cells. When vitamin D binds to the receptor in the cancer cells, it may stop cancer cells from growing abnormally and may cause cell death. Studying vitamin D-bound sites and vitamin D-regulated genes may help doctors understand how cholecalciferol works in treating colorectal cancer and help doctors plan better treatment.

Eligibility Criteria

Inclusion Criteria

  • Participants must have histologically confirmed adenocarcinoma of the colon that is localized, with no evidence of distant metastasis (stage I, II, or III), and for which surgical resection of the primary tumor is being planned; OR participants must have histologically or cytologically confirmed adenocarcinoma of the colon with resectable liver metastases for which liver resection is being planned; OR participants may have a colon biopsy that is suspicious for adenocarcinoma if clinical and/or endoscopic findings strongly support the presence of malignancy, and if surgical resection is being planned; NOTE: in the unlikely event that the final pathology of the surgical resection specimen is consistent with high-grade adenoma or dysplasia, the patient will not be considered ineligible and collected research samples will still be utilized
  • No prior radiation therapy or systemic treatment is allowed for patients undergoing resection of stage I, II, or III colon cancer
  • Prior systemic treatment or radiation therapy is allowed for patients with resectable 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 prior to liver resection
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Participants must have serum calcium (corrected for albumin level) =< 1 x institutional upper limit of normal (ULN)
  • Patients must be considered an appropriate candidate for surgery by a qualified surgeon
  • Non-pregnant and not nursing * Women of child-bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 28 days prior to study entry; women of child-bearing potential include any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months; or women on hormone replacement therapy with documented serum follicle stimulating hormone level > 35 mIU/mL); women who are using oral, implanted, or injectable contraceptive hormones or mechanical products such as intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child-bearing potential * 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; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • Paraffin-embedded and/or snap-frozen tumor tissue samples from the diagnostic procedure must be available for study-related correlative studies; if paraffin-embedded and/or snap-frozen tumor tissue samples are not available, at least 15 unstained tumor slides will be requested

Exclusion Criteria

  • Prior systemic therapy, radiotherapy, or investigational agent for treatment of colon cancer in participants undergoing surgery for stage I, II, or III colon cancer
  • Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for bevacizumab) of liver resection
  • Concurrent use of other anti-cancer therapy, including chemotherapy agents, targeted agents, biological agents, immunotherapy, or investigational agents not otherwise specified in this protocol
  • Inability to swallow pills
  • History of malabsorption or uncontrolled vomiting or diarrhea, or any other disease significantly affecting gastrointestinal function that could interfere with absorption of oral medications
  • History of allergic reactions attributed to compounds of similar chemical or biologic 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 the protocol-prescribed study treatment is not allowed during the treatment period of this clinical trial * In order to maintain blinding, vitamin D levels should not be routinely checked at screening or during the study by the treating investigator; vitamin D levels will be assayed only as part of the research blood samples collected during the study; if there are concerns related to a participant’s vitamin D status, the lead principal investigator should be contacted for further discussion
  • Use of chronic oral corticosteroid therapy, lithium, phenytoin, quinidine, isoniazid, and/or rifampin; short-term use of corticosteroids as anti-emetic therapy for chemotherapy is permitted
  • Regular use of thiazide diuretics (i.e., hydrochlorothiazide), which can lead to hypercalcemia, and unwillingness or inability to discontinue or switch to an alternative anti-hypertensive agent
  • Pre-existing hypercalcemia (defined as baseline serum calcium above the institutional ULN, corrected for albumin level if albumin is not within institutional limits of normal) * The use of supplemental calcium or supplements containing calcium is prohibited during the treatment period of this clinical trial
  • Known active hyperparathyroid disease or other serious disturbance of calcium metabolism in the past 5 years
  • History of symptomatic genitourinary stones within the past year
  • Any 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, in the opinion of the investigator, may increase the risks associated with study participation or study treatment, limit compliance with study requirements, or interfere with the interpretation of study results
  • Pregnant or nursing women or men/women of child-bearing potential who are unwilling to employ adequate contraception * Pregnant and nursing women are excluded from this study; breastfeeding should be discontinued if the mother is enrolled on the study
  • Presence of synchronous malignancy for which the patient is currently receiving active treatment
  • Known positive test for human immunodeficiency virus (HIV), hepatitis C virus, or acute or chronic hepatitis B infection

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Joel Edward Goldberg
Phone: 617-724-5200
Email: jgoldberg1@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: Kimmie Ng
Phone: 617-632-4150
Email: KNG4@PARTNERS.ORG

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To identify vitamin D receptor (VDR) binding sites in malignant and normal colonic and hepatic tissue collected from colon cancer patients treated with high-dose vitamin D3 (cholecalciferol) versus placebo.

SECONDARY OBJECTIVES:

I. To evaluate the transcriptome in malignant and normal colonic and hepatic tissue collected from colon cancer patients treated with high-dose preoperative vitamin D3 versus placebo, and correlate expressed genes with identified VDR binding sites.

II. To identify VDR binding sties in the immediate vicinity of known colorectal cancer risk loci in malignant and normal colonic and hepatic tissue collected from colon cancer patients treated with high-dose preoperative vitamin D3 versus placebo.

III. To evaluate the toxicity of vitamin D3 supplementation with 50,000 international units (IU) daily x 7 days followed by 10,000 IU daily.

EXPLORATORY OBJECTIVES:

I. To collect primary colon or liver metastasis tumor tissue for creation of conditionally re-programmed colon cancer cell lines as part of a companion research protocol, and to utilize these cell lines to confirm chromatin immunoprecipitation sequencing (ChIP-seq) findings from human tissue.

II. To correlate plasma 25-hydroxy vitamin D [25(OH)D] levels and change in plasma 25(OH)D with vitamin D binding profiles.

III. To assess inflammatory markers and immune-related factors in primary tumor and liver metastasis tissue collected from colon cancer patients treated with high-dose preoperative vitamin D3 versus placebo.

OUTLINE: This is a run-in phase study followed by a randomized phase study.

RUN-IN PHASE: Patients receive cholecalciferol orally (PO) once daily (QD) for 7-28 days until the day of surgery.

RANDOMIZED PHASE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cholecalciferol PO QD for 7-28 days until the date of surgery.

ARM B: Patients receive placebo PO QD for 7-28 days until the date of surgery.

Trial Phase & Type

Trial Phase

No phase specified

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Kimmie Ng

Trial IDs

Primary ID 14-091
Secondary IDs NCI-2014-02032
Clinicaltrials.gov ID NCT02172651