A Study to Evaluate the Effect of Vitamin D on PFS in Indolent Non-Hodgkin's Lymphoma (ILyAD)

ILyAD (Indolent Lymphoma And Vitamin D) A Phase III Double Blind, Randomized Trial to Evaluate the Effect of Vitamin D on Progression-free Survival in Patients With Low Tumor-burden Indolent Non-Hodgkin Lymphoma Treated With Rituximab

Despite strong evidence suggesting that vitamin D deficiency is associated with undesirable outcomes in patients with numerous cancers, there has never been a thorough study of vitamin D treatment in subjects undergoing treatment for cancer. The purpose of this study is to evaluate whether modification of vitamin D levels in the blood, through supplementation, can improve outcomes.

Study Overview

• Status: Completed
• Conditions: Follicular Lymphoma; Marginal Zone Lymphoma; Small Lymphocytic Lymphoma; Mucosal-Associated Lymphoid Tissue Lymphoma
• Intervention / Treatment: Dietary supplement: Vitamin D; Biological: Rituximab; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University, Winship Cancer Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Institute at University of Rochester Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Each of the following criteria must be met in order for a patient to be considered eligible for registration:

• Biopsy proven (with hematopathology review at one of the participating sites to confirm correct histology in accordance with World Health Organization) indolent lymphoma to include the following diagnoses:

  • Grade 1, 2, or 3a follicular lymphoma
  • Small lymphocytic lymphoma (CLL excluded)
  • Marginal zone lymphoma (nodal or splenic)
  • Mucosal-associated lymphoid tissue
• Measurable disease defined by Lugano criteria
• No prior anti-lymphoma systemic therapy; prior radiation therapy allowed
• Age 18 or over
• Ann Arbor stages II, III or IV

• Patients with follicular lymphoma must have PET FDG-avid lymphoma and fulfill Low tumor burden by Groupe D'Etude des Lymphomes Folliculaires (GELF) criteria:

  • No mass > 7 cm
  • < 3 distinct masses of greater than 3 cm
  • No B symptoms
  • No splenomegaly > 16 cm by computed tomography (CT) scan
  • No risk of vital organ compression
  • No leukemic phase > 5000/µl circulating lymphocytes (except for in patients with splenic marginal zone diagnosis)
  • No cytopenias (platelets < 100,000/µl, hemoglobin < 10 g/dl, or absolute neutrophil count < 1500/µl)

Exclusion Criteria:

The following criteria will prevent inclusion of an inappropriate subject into the trial:

• Osteoporosis requiring prescription treatment
• Known symptomatic primary hyperparathyroidism
• Hypercalcemia defined as above the institutional normal range (corrected for albumin when albumin levels are below normal)
• History of calcium-related kidney stones
• Creatinine > 1.5X above upper limit of normal
• Women who are known to be pregnant or who plan to become pregnant while on rituximab treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin D plus rituximab; Rituximab was administered weekly x 4 (intravenous 375 mg/m^2 or subcutaneous equivalent) per institutional standards and vitamin D3, 2000 IU orally once daily. Participants took vitamin D3 until lack of response at week 13, disease progression, or initiation of a new treatment.	Dietary supplement: Vitamin D; vitamin D3 2,000 IU daily; Other Names: Cholecalciferol; Biological: Rituximab; Administered weekly x 4; Other Names: Rituxan
Placebo Comparator: Placebo plus rituximab; Rituximab was administered weekly x 4 (intravenous 375 mg/m^2 or subcutaneous equivalent) per institutional standards and placebo orally once daily. Participants took placebo until lack of response at week 13, disease progression, or initiation of a new treatment.	Biological: Rituximab; Administered weekly x 4; Other Names: Rituxan; Other: Placebo; methylcellulose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival	Event free survival (EFS) was defined as the time from randomization to lack of response at week 13, initiation of a new treatment, disease progression defined by Lugano criteria, or death, right-censored by time of last follow-up. Per Lugano criteria, progression is defined as a new FDG-avid lesion or an increase in intensity from baseline, an increase by >= 50% in lesion diameters, a new lymph node > 1.5 cm in any axis or a new extranodal site > 1.0 cm.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-Cause Mortality	Number of participants who died from any cause between day 1 of treatment and the time of last follow-up.	Participants were followed for survival beginning on day 1 of treatment until study closure with a maximum follow-up of 64 months.
Number of Participants With Treatment Response at 13 Weeks	Participants had imaging performed at week 13 to assess response to treatment. A response was defined as partial (PR) or complete response (CR) according to Lugano criteria. Per Lugano criteria for target lesions: PR includes reduced metabolic uptake or a ≥ 50% decrease in the sum of the products of the diameters compared to baseline. CR includes metabolic score of 1, 2 or 3 (out of 5) with or without residual mass or regression of target lesions to ≤ 1.5 cm in the longest dimension.	13 Weeks from the start of treatment

Collaborators and Investigators

• Sponsor: Jonathan Friedberg
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Jonathan W. Friedberg, MD, James P. Wilmot Cancer Institute at University of Rochester

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2017
• Primary Completion (Actual): July 21, 2023
• Study Completion (Actual): July 2, 2024

Study Registration Dates

• First Submitted: March 8, 2017
• First Submitted That Met QC Criteria: March 10, 2017
• First Posted (Actual): March 13, 2017

Study Record Updates

• Last Update Posted (Actual): September 4, 2024
• Last Update Submitted That Met QC Criteria: August 8, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma, B-Cell; Chronic Disease; Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell, Marginal Zone; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Rituximab
• Other Study ID Numbers: 66593; R01CA214890 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be made available to researchers upon reasonable request.
• IPD Sharing Time Frame: Data requests will be considered beginning in December 2024.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No