DNA Changes That Affect Vitamin D Metabolism in Patients With Colorectal Cancer Receiving Vitamin D Supplements

Identification of 24-Hydroxylase Polymorphisms and Splicing Variants That Modulate Vitamin D Oxidative Metabolism and Serum Pharmacokinetics in Patients With Colorectal Cancer on Cholecalciferol Therapy

RATIONALE: Studying samples of blood from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and identify biomarkers related to cancer.

PURPOSE: This clinical trial is studying changes in DNA that affect vitamin D metabolism in patients with colorectal cancer receiving vitamin D supplements.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Dietary supplement: cholecalciferol; Genetic: polymerase chain reaction; Genetic: polymorphism analysis; Genetic: protein expression analysis; Genetic: reverse transcriptase-polymerase chain reaction; Genetic: western blotting; Other: high performance liquid chromatography; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: adjuvant therapy; Procedure: immunoscintigraphy

Detailed Description

OBJECTIVES:

• To identify CYP24 single nucleotide polymorphisms (SNPs) using peripheral blood mononuclear cell genomic DNA from patients with colorectal cancer receiving cholecalciferol supplementation.
• To evaluate the effects of these CYP24 SNPs on baseline serum vitamin D_3 metabolites (25-D_3, 24,25-D_3, and 1,25-D_3), and parathyroid hormone levels (PTH).
• To evaluate the effects of these CYP24 SNPs on serum vitamin D_3 metabolites and PTH levels during cholecalciferol treatment.
• To examine CYP24 splicing, protein expression, and enzyme activity at baseline and during cholecalciferol treatment.
• To determine the relationship, if any, between serum cholecalciferol pharmacokinetic parameters and CYP24 SNPs, splicing variants, and enzyme activity.

OUTLINE: Patients receive oral cholecalciferol 2000 IU once daily for 1 year. Patients without response to vitamin D supplementation (serum 25-D_3 level < 32 ng/mL) by 6 months will have their cholecalciferol dose increased to 4000 IU once daily.

Blood is collected at baseline and on days 14, 30, 60, 90, 180, 270, and 360. Peripheral blood mononuclear cells for CYP24 genotyping, protein expression, enzyme activity, and splicing variants are analyzed by polymerase chain reaction (PCR), western blot, high performance liquid chromatography, and reverse transcriptase PCR, respectively. Serum is analyzed for vitamin D_3 metabolite levels (by radioimmunoassay), calcium (to monitor for hypercalcemia), and parathyroid hormone assays (to measure vitamin D effect).

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Prior or current documented diagnosis of colorectal cancer

  • All stages
• 25OH-D3 level < 50 ng/mL

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy > 6 months
• Serum creatinine < 2.0 mg/dL
• Serum bilirubin < 2.0 mg/dL
• No prior or current hypercalcemia (defined as albumin corrected serum calcium < 10.2 mg/dL)
• No known contraindication for vitamin D supplementation
• No genitourinary stones within the past 5 years
• No severe comorbid conditions such as uncompensated heart failure or active infection

PRIOR CONCURRENT THERAPY:

• No supplemental vitamin D beyond what is provided through the study

• At least 2 months since prior vitamin D supplementation exceeding 800 International Units (IU)

  • Nondietary vitamin D supplements should not have exceeded 800 IU/day within the past 2 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Oral Cholecalciferol; Patients receive oral cholecalciferol 2000 IU once daily for 1 year

Dietary supplement: cholecalciferol; Oral; Genetic: polymerase chain reaction; companion study; Genetic: polymorphism analysis; companion study; Genetic: protein expression analysis; companion study; Genetic: reverse transcriptase-polymerase chain reaction; companion study; Genetic: western blotting; companion study; Other: high performance liquid chromatography; companion study; Other: laboratory biomarker analysis; companion study; Other: pharmacological study; companion study; Procedure: adjuvant therapy; Additional therapy; Procedure: immunoscintigraphy; additional testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Identification of CYP24 single nucleotide polymorphisms (SNPs)	Baseline, days 14, 30, 60, 90, 180, 270, 360
Effect of CYP24 SNPs on baseline serum vitamin D3 metabolites (25-D3, 24,25-D3, and 1,25-D3), and parathyroid hormone levels (PTH)	At baseline
Effect of CYP24 SNPs on serum vitamin D3 metabolites and PTH levels during cholecalciferol treatment	Baseline, days 14, 30, 60, 90, 180, 270, 360
CYP24 splicing, protein expression, and enzyme activity at baseline and during cholecalciferol treatment	Baseline, days 14, 30, 60, 90, 180, 270, 360
Relationship between serum cholecalciferol pharmacokinetic parameters and CYP24 SNPs, splicing variants, and enzyme activity	Baseline, days 14, 30, 60, 90, 180, 270, 360

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Marwan Fakih, MD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: October 25, 2007
• First Submitted That Met QC Criteria: October 25, 2007
• First Posted (Estimate): October 30, 2007

Study Record Updates

• Last Update Posted (Actual): April 4, 2017
• Last Update Submitted That Met QC Criteria: March 31, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: stage IV rectal cancer; stage IV colon cancer; recurrent colon cancer; recurrent rectal cancer; stage III colon cancer; stage II rectal cancer; stage III rectal cancer; stage II colon cancer; stage I rectal cancer; stage I colon cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: I 99207; RPCI-I-99207

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No