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

Primary Purpose

Aggressive Non-Hodgkin Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-Cell Lymphoma

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Cholecalciferol
Laboratory Biomarker Analysis
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aggressive Non-Hodgkin Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
  • 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

Sites / Locations

  • Mayo Clinic in Arizona
  • Emory University/Winship Cancer Institute
  • University of Iowa/Holden Comprehensive Cancer CenterRecruiting
  • Mayo ClinicRecruiting
  • Washington University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (cholecalciferol)

Arm Description

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

Outcomes

Primary Outcome Measures

Event free survival (EFS) (Study I)
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)
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.

Secondary Outcome Measures

Bio-R response rate (Study II)
Bio-R response rate will be calculated as the number of patients with Bio-R response divided by the number of evaluable patients. If a sufficient number of Bio-R responses are seen, differences in Bio-R rate between the two study groups will be evaluated using Fisher's exact test.
EFS time (Study I)
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.
OS (Study II)
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. These models will be assessed both unadjusted and adjusted for Rai stage and FISH [favorable (13q-, +12, no abnormalities) vs. unfavorable (11q-, 17p-)].
Overall response rate (Study II)
Exact binomial 95% confidence intervals for the true overall response rate will be calculated. If a sufficient number of responses are seen, differences in overall response rate between the two study groups will be evaluated using Fisher's exact test.
Overall survival (OS) time (Study I)
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. These models will be assessed both unadjusted and adjusted for Rai stage and FISH [favorable (13q-, +12, no abnormalities) vs. unfavorable (11q-, 17p-)].
Time to first treatment (Study II)
The distribution of time to first treatment will be estimated using the method of Kaplan-Meier. Differences between the two study groups will be evaluated using Cox proportional hazard models. These models will be assessed both unadjusted and adjusted for Rai stage and FISH [favorable (13q-, +12, no abnormalities) vs. unfavorable (11q-, 17p-)].

Full Information

First Posted
February 6, 2013
Last Updated
October 3, 2023
Sponsor
Mayo Clinic
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01787409
Brief Title
Cholecalciferol in Improving Survival in Patients With Newly Diagnosed Cancer With Vitamin D Insufficiency
Official Title
Effect of Vitamin D Replacement on Tumor Response and Survival Parameters for Vitamin D Insufficient Patients With Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 6, 2013 (Actual)
Primary Completion Date
September 4, 2024 (Anticipated)
Study Completion Date
September 4, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mayo Clinic
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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 assess the percentage of patients requiring treatment with conventional therapy at 36 in months in vitamin D insufficient patients with early stage chronic lymphocytic leukemia (CLL) being managed with observation who undergo vitamin D replacement. (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 the effect of vitamin D replacement in vitamin D insufficient CLL patients on Bio-r response rate and overall response rate. (Study II) V. To assess time to treatment and overall survival in vitamin D insufficient CLL patients who received vitamin D replacement. (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: 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. After completion of study treatment, patients are followed up for 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aggressive Non-Hodgkin Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-Cell Lymphoma, Chronic Lymphocytic Leukemia, Diffuse Large B-Cell Lymphoma, Enteropathy-Associated T-Cell Lymphoma, Hepatosplenic T-Cell Lymphoma, Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Mediastinal (Thymic) Large B-Cell Lymphoma, Nasal Type Extranodal NK/T-Cell Lymphoma, Peripheral T-Cell Lymphoma, Not Otherwise Specified, Primary Cutaneous Anaplastic Large Cell Lymphoma, Refractory Anaplastic Large Cell Lymphoma, Small Lymphocytic Lymphoma, Subcutaneous Panniculitis-Like T-Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
500 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (cholecalciferol)
Arm Type
Experimental
Arm Description
Vitamin D sufficient patients receive no intervention. Vitamin D insufficient patients receive cholecalciferol PO once weekly for 12 weeks and then once monthly for a total of 36 months.
Intervention Type
Dietary Supplement
Intervention Name(s)
Cholecalciferol
Other Intervention Name(s)
9,10-Secocholesta-5,7,10(19)-trien-3-ol, Calciol, Delsterol, Vitamin D3
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Event free survival (EFS) (Study I)
Description
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.
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
Title
Treatment free status (Study II)
Description
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.
Time Frame
At 36 months
Secondary Outcome Measure Information:
Title
Bio-R response rate (Study II)
Description
Bio-R response rate will be calculated as the number of patients with Bio-R response divided by the number of evaluable patients. If a sufficient number of Bio-R responses are seen, differences in Bio-R rate between the two study groups will be evaluated using Fisher's exact test.
Time Frame
Up to 5 years
Title
EFS time (Study I)
Description
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.
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
Title
OS (Study II)
Description
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. These models will be assessed both unadjusted and adjusted for Rai stage and FISH [favorable (13q-, +12, no abnormalities) vs. unfavorable (11q-, 17p-)].
Time Frame
From registration to death due to any cause, assessed up to 5 years
Title
Overall response rate (Study II)
Description
Exact binomial 95% confidence intervals for the true overall response rate will be calculated. If a sufficient number of responses are seen, differences in overall response rate between the two study groups will be evaluated using Fisher's exact test.
Time Frame
Up to 5 years
Title
Overall survival (OS) time (Study I)
Description
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. These models will be assessed both unadjusted and adjusted for Rai stage and FISH [favorable (13q-, +12, no abnormalities) vs. unfavorable (11q-, 17p-)].
Time Frame
From registration to death due to any cause, assessed up to 5 years
Title
Time to first treatment (Study II)
Description
The distribution of time to first treatment will be estimated using the method of Kaplan-Meier. Differences between the two study groups will be evaluated using Cox proportional hazard models. These models will be assessed both unadjusted and adjusted for Rai stage and FISH [favorable (13q-, +12, no abnormalities) vs. unfavorable (11q-, 17p-)].
Time Frame
From study registration to initiation of anti-CLL therapy, assessed up to 5 years
Other Pre-specified Outcome Measures:
Title
Gene expression profiles
Description
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.
Time Frame
Baseline
Title
Immune effector cell levels
Description
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.
Time Frame
Up to 36 months
Title
Serum cytokine profile
Description
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.
Time Frame
Up to 36 months
Title
Vitamin D metabolism single nucleotide polymorphisms (SNPs)
Description
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.
Time Frame
Up to 36 months
Title
Vitamin D receptor expression on tumor cells
Description
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.
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Witzig
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Emory University/Winship Cancer Institute
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
University of Iowa/Holden Comprehensive Cancer Center
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Brian K. Link
Phone
800-237-1225
Email
brian-link@uiowa.edu
First Name & Middle Initial & Last Name & Degree
Brian K. Link
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Thomas E. Witzig, M.D.
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Active, not recruiting

12. IPD Sharing Statement

Links:
URL
https://www.mayo.edu/research/clinical-trials
Description
Mayo Clinic Clinical Trials

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

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