Safety, Feasibility and Efficacy of Vitamin D Supplementation in Women With Metastatic Breast Cancer (SAFE-D)

Study Overview
=================
Brief Summary
-----------------
Background: Several clinical trials are underway to investigate if variable forms of vitamin D (D2 vs. D3) prescribed at different doses (10,000-50,000 IUs/week) can improve the side-effects associated with treatment for estrogen receptor positive (ER+) breast cancer, specifically aromatase inhibitors (AIs.) Presumably for generalizability and potential safety purposes, these trials predominantly exclude women with metastatic breast cancer (MBC); a rapidly expanding sector of the cancer survivor population who experience significant treatment-related side-effects. Evaluation of the safety of vitamin D3 supplementation is crucial since supplementation can lead to high calcium and importantly, in lab studies have shown that vitamin D3 affects a gene that increases estrogen production. To assure that vitamin D3 does not affect the clinical effects of anti-estrogen therapies, the effect of vitamin D3 supplements on estrogen production requires an evaluation that further explores and defines its potential role in symptom management for this population. Objectives: This pilot study will evaluate the feasibility of vitamin D3 supplementation in women with MBC, providing much needed data on the preliminary safety and efficacy of this treatment in this patient population. This study will determine: 1) if weekly supplementation of high dose vitamin D3 increases serum vitamin D levels without adverse effects related to such therapy (primary aim); 2) the effects of vitamin D3 supplementation on symptom management (secondary aim); and 3) if vitamin D3 supplementation is associated with improved inflammation (exploratory aim.) Methods: This is an 8 week proof of concept study to monitor laboratory parameters and to assess potential effects on short-term outcomes. Adult, female patients (>=18 years) with ER+ MBC (Stage IV) of any race/ethnicity and a history of vitamin D < 30 mg/dl will be recruited from within and around LUMC. Following current clinical practice guidelines, eligible participants will receive 50,000 IUs of vitamin D3 weekly for 8 weeks. Laboratory values, muscle function and inflammation will be examined pre- and post-supplementation, while symptoms will be assessed at baseline, 4 and 8 weeks post-supplementation. We will assess if increases in vitamin D are associated with clinically significant improvements in symptoms and QOL, and decreased inflammation.

Detailed Description
-----------------
Study Aims Several clinical trials are underway to investigate if vitamin D2 or D3 provided at various doses (10,000-50,000 IUs/week) can improve the side-effects associated with anti-estrogen therapies, specifically aromatase inhibitors (AIs). However, these current trials use variable forms of vitamin D and predominantly include women with Stage I-III disease, excluding women with metastatic breast cancer. Evaluation of the safety of vitamin D3 supplementation is crucial since supplementation can lead to hypercalcemia and importantly, in vitro studies have shown that vitamin D3 influences the transcription of a gene that increases estrogen production.27,28 To assure that vitamin D3 does not abrogate the clinical effects of anti-estrogen therapies, the effect of vitamin D3 supplementation on estrogen production requires evaluation. Therefore, the overarching goal of this pilot study is to evaluate the safety, feasibility and efficacy of vitamin D3 supplementation in women with MBC. We will address and test the following aims and hypotheses, respectively: Aim 1: To determine if weekly supplementation of 50,000 IUs of vitamin D3 raises serum levels of 25(OH)D to >30 mg/dl without adverse effects. Hypothesis 1: Women who are compliant with vitamin D3 supplementation, as evidenced by normalization (>30 mg/dl) or increases in their serum 25(OH)D levels, will not experience significant changes in serum calcium, parathyroid hormone or serum estradiol levels. Aim 2: To determine the effect of vitamin D3 supplementation on symptom management. Hypothesis 2: Women who achieve serum concentrations of 25 (OH)D ≥30 mg/dl or experience significant increases in 25(OH)D will exhibit improvements in pain, fatigue, sleep, mood, muscle function and overall quality of life. Exploratory Aim: To explore the mechanistic effects of vitamin D3 supplementation on inflammatory markers and its potential association with symptom management. Summary: Evidence from studies involving early stage breast cancer participants confirms that musculoskeletal pain, endocrine related symptoms and mood disturbances are commonly associated with breast cancer treatment, particularly hormone deprivation therapies. The high prevalence of vitamin D deficiency/insufficiency among breast cancer survivors is well accepted and further hypothesized to aggravate treatment-related side effects, particularly arthralgias. Women with MBC are excluded from the majority of on-going vitamin D supplementation trials for safety and generalizability purposes. However, novel therapies are continuing to improve and prolong the lives of these women, resulting in a rapidly expansive group of breast cancer survivors. While vitamin D supplementation is prescribed to correct an underlying nutrient deficiency in the clinical context of preserving bone health, emerging evidence suggests it may have more systemic effects. Thus, vitamin D repletion/supplementation has profound potential implications for women with MBC, whose primary goal of treatment is to minimize the side-effects of treatment in support of optimal quality of life. This study reflects a highly innovative, yet simple therapy that could ultimately provide these survivors with a much needed evidence-based supportive care strategies.

Official Title
-----------------
Safety, Feasibility and Efficacy of Vitamin D Supplementation in Women With Metastatic Breast Cancer (SAFE-D)

Conditions
-----------------
Adult Women, Metastatic Breast Cancer, Estrogen Receptor Positive

Intervention / Treatment
-----------------
* Drug: Cholecalciferol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Metastatic breast cancer (Stage IV) Histologically confirmed estrogen receptor positive disease Female Serum 25(OH) <30 ng/ml Age ≥ 18 years Pre or post-menopausal ECOG Performance status 0-2 Adequate organ function as defined as GFR> 30 mls/min and serum calcium ≤ 10.4 mg/dl Any race/ethnicity English speaking No changes to MBC treatments within 30 days of enrollment and/or deemed clinically stable by their treating physician Willingness to sign a written informed consent and complete questionnaires Cease ingestion of vitamin D supplementation not study related Exclusion Criteria: Women with Stage I-III breast cancer Serum 25(OH)D levels ≥ 30 ng/ml Untreated CNS involvement History of kidney stones History of renal failure History of hyperparathyroidism History of hypersensitivity to vitamin D Non-English speaking Currently pregnant or lactating, or anticipating pregnancy Unwilling to cease ingestion of calcium supplements (>1000 mg/d) Unwilling or unable to complete informed consent or study questionnaires Psychiatric or other clinical conditions that preclude study compliance Other important medical or safety considerations at the discretion of the investigator and/or study physician, including non-compliance with the study therapy or other activities

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cholecalciferol<br>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks. | Drug: Cholecalciferol<br>* Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.<br>* Other names: Vitamin D;|
| No Intervention: Vitamin D sufficient<br>All participants were ineligible for the intervention due to sufficient serum 25(OH)D levels at screening/baseline. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum 25(OH)D | Change in laboratory serum value of 25(OH)D at 8 weeks post-supplementation for participants who received weekly supplementation of 50,000 IUs of vitamin D3. Change is expressed as laboratory serum value of 25(OH)D at 8 weeks minus baseline. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Worst Pain Rating From the Beck Pain Scale | Assessment of pain using the Beck Pain Scale at weeks 0 and 8. This is a Likert scale item where a score of 0 corresponds to no pain and a score of 10 corresponds to worst pain. Change is calculated as the worst pain rating at 8 weeks minus the worst pain rating at 0 weeks.Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 
| Change in Fatigue | Assessment of fatigue using the Piper Fatigue Scale at weeks 0 and 8. The Piper Fatigue Scale is the average of 22 numeric items, with higher scores indicating greater fatigue [range of scores: 0-10]. Change is calculated as the fatigue score at 8 weeks minus fatigue score at 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 
| Change in Mood | Assessment of mood using the Patient Health Questionnaire 8 (PHQ-8) at weeks 0 and 8. The PHQ-8 ranges from 0-24 with higher scores indicating more distress. Change was assessed as PHQ-8 score at 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 
| Change in Muscle Function | Assessment of muscle function using a hand dynamometer at weeks 0 and 8. Change in dominant handgrip strength in kilograms was calculated as 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 
| Change in Sleep Quality Assessment | Assessment of sleep using the Pittsburgh Sleep Quality Index (PSQI) at weeks 0 and 8. Scores range from 0-21 with higher scores indicating poorer sleep quality. Change was calculated as week 8 minus week 0 PSQI. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 
| Change in Functional Assessment of Cancer Therapy-breast | Assessment of quality of life using the functional assessment of cancer therapy-breast symptoms at weeks 0 and 8. Scores range from 0-40 with higher scores indicating better quality of life. Change was calculated as week 8 score minus week 0 score. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 
| Change in Functional Assessment of Cancer Therapy-endocrine | Assessment of quality of life using the functional assessment of cancer therapy- endocrine symptoms at weeks 0 and 8. Scores range from 0-76 with higher scores indicating better quality of life. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time. | 0, 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic Breast Cancer, MBC, Vitamin D Supplementation, Symptom Management