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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effect of Vitamin D Replacement on Tumor Response and Survival Parameters for Vitamin D Insufficient Patients With Cancer

Conditions
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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

Intervention / Treatment
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* Dietary Supplement: Cholecalciferol
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cholecalciferol)<br>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. | Dietary Supplement: Cholecalciferol<br>* Given PO<br>* Other names: Vitamin D3;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | At 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 5 years | 
| 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. | 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 | 
| 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-)]. | From registration to death due to any cause, assessed up to 5 years | 
| 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. | Up to 5 years | 
| 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-)]. | From registration to death due to any cause, assessed up to 5 years | 
| 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-)]. | From study registration to initiation of anti-CLL therapy, assessed up to 5 years |