Follicular Lymphoma, Marginal Zone Lymphoma, Mucosal-Associated Lymphoid Tissue Lymphoma, Small Lymphocytic Lymphoma
Conditions
Brief summary
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.
Interventions
DIETARY_SUPPLEMENTVitamin D
vitamin D3 2,000 IU daily
BIOLOGICALRituximab
Administered weekly x 4
OTHERPlacebo
methylcellulose
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Jonathan Friedberg
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival | 3 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-Cause Mortality | 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 who died from any cause between day 1 of treatment and the time of last follow-up. |
| Number of Participants With Treatment Response at 13 Weeks | 13 Weeks from the start of treatment | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 7 US academic medical centers between September 2017 and March 2022.
Participants by arm
| Arm | Count |
|---|---|
| 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, was taken orally once daily. Participants took vitamin D3 until lack of response at week 13, disease progression, or initiation of a new treatment. | 135 |
| Placebo Plus Rituximab Rituximab was administered weekly x 4 (intravenous 375 mg/m\^2 or subcutaneous equivalent) per institutional standards and placebo was taken orally once daily. Participants took placebo until lack of response at week 13, disease progression, or initiation of a new treatment. | 71 |
| Total | 206 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Ineligible | 2 | 0 |
| Overall Study | Lack of Efficacy | 62 | 31 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Second Malignancy | 4 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 6 |
| Overall Study | Withdrew before day 1 treatment | 2 | 1 |
Baseline characteristics
| Characteristic | Vitamin D Plus Rituximab | Placebo Plus Rituximab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 55 Participants | 35 Participants | 90 Participants |
| Age, Categorical Between 18 and 65 years | 80 Participants | 36 Participants | 116 Participants |
| Age, Continuous | 62 years | 64 years | 62 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 5 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 123 Participants | 63 Participants | 186 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 5 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 120 Participants | 62 Participants | 182 Participants |
| Region of Enrollment United States | 135 participants | 71 participants | 206 participants |
| Sex: Female, Male Female | 78 Participants | 40 Participants | 118 Participants |
| Sex: Female, Male Male | 57 Participants | 31 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 135 | 3 / 71 |
| other Total, other adverse events | 111 / 135 | 54 / 71 |
| serious Total, serious adverse events | 16 / 135 | 9 / 71 |
Outcome results
Primary
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.
Time frame: 3 years
Population: The analysis population included randomized and eligible participants that received at least one dose of vitamin D or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin D Plus Rituximab | Event Free Survival | 47.7 Percentage of Participants |
| Placebo Plus Rituximab | Event Free Survival | 49.5 Percentage of Participants |
p-value: 0.2695% CI: [0.83, 1.98]Regression, Cox
Secondary
All-Cause Mortality
Number of participants who died from any cause between day 1 of treatment and the time of last follow-up.
Time frame: Participants were followed for survival beginning on day 1 of treatment until study closure with a maximum follow-up of 64 months.
Population: The analysis population included randomized and eligible participants that received at least one dose of vitamin D or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin D Plus Rituximab | All-Cause Mortality | 4 Participants |
| Placebo Plus Rituximab | All-Cause Mortality | 3 Participants |
Secondary
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.
Time frame: 13 Weeks from the start of treatment
Population: The analysis population included randomized and eligible participants that received at least one dose of vitamin D or placebo and were evaluated for treatment response at 13 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin D Plus Rituximab | Number of Participants With Treatment Response at 13 Weeks | 113 Participants |
| Placebo Plus Rituximab | Number of Participants With Treatment Response at 13 Weeks | 59 Participants |