Cholecalciferol in Improving Survival in Patients With Newly Diagnosed Cancer With Vitamin D Insufficiency

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Mayo Clinic
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01787409
First received: February 6, 2013
Last updated: July 22, 2014
Last verified: July 2014
  Purpose

This partially randomized clinical trial studies cholecalciferol in improving survival in patients with newly diagnosed cancer with vitamin D insufficiency. Vitamin D replacement may improve tumor response and survival and delay time to treatment in patients with cancer who are vitamin D insufficient.


Condition Intervention
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-cell Lymphoma
Contiguous Stage II Adult Diffuse Large Cell Lymphoma
Hepatosplenic T-cell Lymphoma
Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
Peripheral T-cell Lymphoma
Small Intestine Lymphoma
Stage 0 Chronic Lymphocytic Leukemia
Stage I Adult Diffuse Large Cell Lymphoma
Stage I Chronic Lymphocytic Leukemia
Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
Stage I Small Lymphocytic Lymphoma
Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
Dietary Supplement: cholecalciferol
Other: placebo
Other: laboratory biomarker analysis

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Effect of Vitamin D Replacement on Tumor Response and Survival Parameters for Vitamin D Insufficient Patients With Cancer

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Event free survival (EFS) (Study I) [ Time Frame: Time from study registration to lymphoma progression, initiation of new anti-lymphoma therapy after completion or cessation of the original anthracycline based treatment, or death due to any cause, assessed at 12 months ] [ Designated as safety issue: No ]
    The proportion of successes will be estimated separately in the groups by the number of successes divided by the total number of evaluable patients. 95% confidence intervals for the true success proportion will be calculated by the exact binomial method.

  • Treatment free status (Study II) [ Time Frame: At 36 months ] [ Designated as safety issue: No ]
    The proportion of successes will be estimated separately in the groups by the number of successes divided by the total number of evaluable patients. 95% confidence intervals for the true success proportion will be calculated by the exact binomial method.

  • Bio-R response rate (Study II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Bio-R response rate will be calculated as the number of patients with Bio-R response divided by the number of evaluable patients.


Secondary Outcome Measures:
  • EFS time (Study I) [ Time Frame: From study registration to lymphoma progression, initiation of new anti-lymphoma therapy after completion or cessation of the original anthracycline based treatment, or death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of event-free survival time in each group will be estimated using the method of Kaplan-Meier. Differences between the groups will be evaluated using Cox proportional hazard models.

  • Overall survival (OS) time (Study I) [ Time Frame: From registration to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier. Differences between the groups will be evaluated using Cox proportional hazard models.

  • Overall response rate (Study II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Exact binomial 95% confidence intervals for the true overall response rate will be calculated.

  • Time to first treatment (Study II) [ Time Frame: From study registration to initiation of anti-CLL therapy, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of time to first treatment will be estimated using the method of Kaplan-Meier.

  • OS (Study II) [ Time Frame: From registration to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.


Other Outcome Measures:
  • Immune effector cell levels [ Time Frame: Up to 36 months ] [ Designated as safety issue: No ]
    On-study regulatory T cells (Treg) and monocyte levels will be compared between sufficient and insufficient patients using Wilcoxon rank sum tests for each subtype. The pre and post-replacement levels will be assessed in CLL patients receiving replacement to look for a reduction in Tregs and monocytes, using a one-sample t-test on the difference testing for a mean of zero.

  • Serum cytokine profile [ Time Frame: Up to 36 months ] [ Designated as safety issue: No ]
    A five-parameter regression formula will be used to calculate the sample concentrations from the standard curves and a change of 50% from the baseline value will be considered significant. Changes in all 30 cytokines in the kit will be evaluated with a focus on the tumor specific cytokines. In patients with abnormal cytokines, the pre and post-replacement cytokine level will be compared in patients receiving replacement to similar timepoints in patients not receiving replacement. The change in cytokine levels (post-pre) will be evaluated between the two groups using Wilcoxon rank sum tests.

  • Vitamin D metabolism single nucleotide polymorphisms (SNPs) [ Time Frame: Up to 36 months ] [ Designated as safety issue: No ]
    All analyses will be performed separately for each lymphoma subtype. Individual vitamin D receptor (VDR) SNPs will be evaluated using a co-dominant model. Principal components will be used to generate a gene level assessment of VDR variability. Host genetic VDR markers will be compared to onstudy vitamin D levels to look for association between VDR polymorphisms and vitamin D stores using logistic regression. Host genetic VDR markers will be compared to outcome (time to first treatment [TFT], EFS, OS) using Cox regression models.

  • Vitamin D receptor expression on tumor cells [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The results will be expressed as present or absent. In the case of immunohistochemistry for DLBCL, expression may be graded as 0-3+. In the case of CLL, the % cells positive will be reported. VDR expression from the tumor will be reported using summary tables. Expression will be compared with outcome (TFT, EFS, OS) using Cox models to examine if VDR expression is prognostic in these tumors. VDR expression will also be compared to polymorphisms in VDR using logistic regression or chi-square tests to look for associations of host-genetics in the VDR region and VDR function in tumor.

  • Gene expression profiles [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Analysis will be primarily hypothesis generating and of a discovery nature. Gene expression will be compared to on-study vitamin D levels using Spearman correlation to look for associations between genes and Vitamin D. Gene expression will also be compared to polymorphisms in VDR using logistic regression to look for associations of host-genetics in the VDR region and general gene function in tumor.


Estimated Enrollment: 965
Study Start Date: March 2013
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (cholecalciferol)
Patients receive cholecalciferol PO once weekly for 12 weeks and then once monthly for a total of 36 months.
Dietary Supplement: cholecalciferol
Given PO
Other Names:
  • Calciol
  • Vitamin D3
Other: laboratory biomarker analysis
Correlative studies
Active Comparator: Arm II (placebo and cholecalciferol)
Patients receive placebo PO once weekly for 12 weeks and then once monthly for a total of 12 months. Patients then receive cholecalciferol once monthly for up to 24 months.
Dietary Supplement: cholecalciferol
Given PO
Other Names:
  • Calciol
  • Vitamin D3
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine if vitamin D replacement in vitamin D insufficient patients with newly diagnosed untreated diffuse large B-cell lymphoma (DLBCL) can improve event free survival at 12 months to be equivalent to that of a control population of vitamin D sufficient patients. (Study I) II. To determine if vitamin D replacement in vitamin D insufficient patients with early stage chronic lymphocytic leukemia (CLL) being managed with observation can improve the percentage of patients requiring treatment with conventional therapy at 36 months to that of a control population of vitamin D sufficient patients. (Study II)

SECONDARY OBJECTIVES:

I. To assess the effect of vitamin D replacement in vitamin D insufficient patients with newly diagnosed untreated DLBCL on overall survival. (Study I) II. To assess the effect of vitamin D replacement in vitamin D insufficient patients with newly diagnosed untreated DLBCL on event free survival. (Study I) III. To assess the effect of vitamin D replacement in vitamin D insufficient patients with newly diagnosed untreated T cell lymphoma on event free and overall survival. (Study I) IV. To assess if vitamin D replacement will increase the tumor response rate in Vitamin D insufficient CLL patients. (Study II)

TERTIARY OBJECTIVES:

I. To study immune effector cells (lymphocytes, monocytes), serum cytokines, and tumor cells from vitamin D deficient and sufficient patients to learn the effects of vitamin D on both tumor cells and the patient's immune system. (Study I-II)

OUTLINE:

STUDY I: Vitamin D sufficient patients receive no intervention. Vitamin D insufficient patients receive cholecalciferol orally (PO) once weekly for 12 weeks and then once monthly for a total of 36 months.

STUDY II: Vitamin D sufficient patients receive no intervention. Vitamin D insufficient patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cholecalciferol PO once weekly for 12 weeks and then once monthly for a total of 36 months.

ARM II: Patients receive placebo PO once weekly for 12 weeks and then once monthly for a total of 12 months. Patients then receive cholecalciferol once monthly for up to 24 months.

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newly diagnosed aggressive lymphoma or CLL/small lymphocytic lymphoma (SLL) that meets disease specific criteria below:
  • Study 1 - Aggressive lymphoma

    • Newly diagnosed de-novo DLBCL or primary mediastinal B-cell lymphoma that will be treated with an anthracycline-containing regimen (rituximab-cyclophosphamide, doxorubicin hydrochloride, prednisone [R-CHOP] or equivalent); patients with composite lymphomas can also be enrolled as long as they have large cell component and will be treated with an anthracycline; in addition, patients with "B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma" or post-transplant DLBCL are also eligible as long as they meet other criteria; patients with typical Burkitt lymphoma are not eligible

      • NOTE: patients can be enrolled up through day 1 of cycle 3 of therapy; the patient is permitted to participate in any other therapeutic therapy for their disease as long as it does not concern vitamin D; patients can begin their chemotherapy while awaiting vitamin D results and treatment arm assignment or
    • Newly diagnosed untreated peripheral T-cell non-Hodgkin lymphoma (NHL) that will be treated with chemotherapy; NOTE: patients can be enrolled up through day 1 of cycle 3 of therapy; this includes the following disease types:

      • Peripheral T cell lymphoma, unspecified
      • Anaplastic large cell lymphoma (T and null cell type)
      • Extranodal NK/T-cell lymphoma, nasal type
      • Enteropathy-type T-cell lymphoma
      • Hepatosplenic T-cell lymphoma
      • Subcutaneous panniculitis-like T-cell lymphoma
      • Angioimmunoblastic T-cell lymphoma
      • Anaplastic large cell lymphoma - primary cutaneous type and
    • Willing to provide tissue for correlative research purposes
  • Study 2 - CLL/SLL

    • Newly diagnosed (< 12 months from pre-registration on this study) CLL according to the National Cancer Institute (NCI) criteria or SLL according to the World Health Organization (WHO) criteria; this includes previous documentation of:

      • Biopsy-proven small lymphocytic lymphoma
      • Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:

        • Peripheral blood lymphocyte count of > 5,000/mm^3; if present, prolymphocytes should be < 55%
        • Immunophenotyping consistent with CLL defined as:

          • The predominant population of lymphocytes share both B-cell antigens (cluster of differentiation [CD]19, CD20, or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
          • Dim surface immunoglobulin expression
          • Restricted surface kappa or lambda light chain expression
        • Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(immunoglobulin H [IgH]/cyclin D 1 [CCND1]) on peripheral blood or tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy
    • Rai stage 0 or 1
    • Previously untreated
    • Asymptomatic with the plan for observation
    • Life expectancy of at least 24 months
    • Willing to provide tissue for correlative research purposes
    • Willing to be randomized to placebo for one year
  • Both Studies:
  • Capable of swallowing intact study medication capsules
  • Serum calcium < 11 mg/dL; note: patients with hypercalcemia can be enrolled after the calcium is corrected with standard of care treatments
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

    • Note: During the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
  • Willing to provide blood samples for correlative research purposes
  • Vitamin D level (25 hydroxy D2 + hydroxyl D3) confirmed by central laboratory review
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01787409

Locations
United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Craig B. Reeder    507-538-7623    reeder.craig@mayo.edu   
Principal Investigator: Craig B. Reeder         
United States, Georgia
Emory University/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Christopher R. Flowers    404-778-1868    crflowe@emory.edu   
Principal Investigator: Christopher R. Flowers         
United States, Iowa
University of Iowa Not yet recruiting
Iowa City, Iowa, United States, 52242
Contact: Brian K. Link    800-237-1225    brian-link@uiowa.edu   
Principal Investigator: Brian K. Link         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Thomas E. Witzig    507-284-2511    witzig.thomas@mayo.edu   
Principal Investigator: Thomas E. Witzig         
United States, Wisconsin
University of Wisconsin Cancer Center Riverview Not yet recruiting
Wisconsin Rapids, Wisconsin, United States, 54494
Contact: Brad S. Kahl    608-265-9358    bsk@medicine.wisc.edu   
Principal Investigator: Brad S. Kahl         
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Thomas Witzig Mayo Clinic
  More Information

No publications provided

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT01787409     History of Changes
Other Study ID Numbers: LS1293, NCI-2013-00037, Mod12-007862-13, LS1293, P30CA015083
Study First Received: February 6, 2013
Last Updated: July 22, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Immunoblastic Lymphadenopathy
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Large B-Cell, Diffuse
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Lymphoma, T-Cell, Peripheral
Lymphoma, Large-Cell, Anaplastic
Lymphoma, Extranodal NK-T-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoma, B-Cell
Cholecalciferol
Vitamin D
Ergocalciferols
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on August 26, 2014