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

Metastatic Breast Cancer Clinical Trial

— SAFE-D  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02186015
• Other study ID #: 206519
• Status: Completed
• Phase: Phase 2
• Start date: February 2015
• Est. completion date: November 9, 2017

Study information

• Verified date: May 2021
• Source: Loyola University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: November 9, 2017
• Est. primary completion date: March 8, 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Metastatic breast cancer (Stage IV)

2. Histologically confirmed estrogen receptor positive disease

3. Female

4. Serum 25(OH) <30 ng/ml

5. Age = 18 years

6. Pre or post-menopausal

7. ECOG Performance status 0-2

8. Adequate organ function as defined as GFR> 30 mls/min and serum calcium = 10.4 mg/dl

9. Any race/ethnicity

10. English speaking

11. No changes to MBC treatments within 30 days of enrollment and/or deemed clinically stable by their treating physician

12. Willingness to sign a written informed consent and complete questionnaires

13. Cease ingestion of vitamin D supplementation not study related

Exclusion Criteria:

1. Women with Stage I-III breast cancer

2. Serum 25(OH)D levels = 30 ng/ml

3. Untreated CNS involvement

4. History of kidney stones

5. History of renal failure

6. History of hyperparathyroidism

7. History of hypersensitivity to vitamin D

8. Non-English speaking

9. Currently pregnant or lactating, or anticipating pregnancy

10. Unwilling to cease ingestion of calcium supplements (>1000 mg/d)

11. Unwilling or unable to complete informed consent or study questionnaires

12. Psychiatric or other clinical conditions that preclude study compliance

13. 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

Related Conditions & MeSH terms

• Adult Women
• Breast Neoplasms
• Estrogen Receptor Positive
• Metastatic Breast Cancer

Intervention

Drug:
• Cholecalciferol
Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.

Locations

Country	Name	City	State
United States	Loyola University Medical Center	Maywood	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Loyola University

Country where clinical trial is conducted

United States, 

References & Publications (43)

Amir E, Simmons CE, Freedman OC, Dranitsaris G, Cole DE, Vieth R, Ooi WS, Clemons M. A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases. Cancer. 2010 Jan 15;116(2):284-91. doi: 10.1002/cncr.24749. — View Citation

Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, Deasy S, Cobleigh M, Shiomoto G. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument. J Clin Oncol. 1997 Mar;15(3):974-86. — View Citation

Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res. 1998 Jul;45(1):5-13. — View Citation

Castel LD, Hartmann KE, Mayer IA, Saville BR, Alvarez J, Boomershine CS, Abramson VG, Chakravarthy AB, Friedman DL, Cella DF. Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort. Cancer. 2013 Jul 1;119(13):2375-82. doi: 10.1002/cncr.28016. Epub 2013 Apr 10. — View Citation

Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38. Review. — View Citation

Cummings SR, Block G, McHenry K, Baron RB. Evaluation of two food frequency methods of measuring dietary calcium intake. Am J Epidemiol. 1987 Nov;126(5):796-802. — View Citation

Din OS, Dodwell D, Wakefield RJ, Coleman RE. Aromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more? Breast Cancer Res Treat. 2010 Apr;120(3):525-38. doi: 10.1007/s10549-010-0757-7. Epub 2010 Feb 16. Review. — View Citation

Eastell R, Adams JE, Coleman RE, Howell A, Hannon RA, Cuzick J, Mackey JR, Beckmann MW, Clack G. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol. 2008 Mar 1;26(7):1051-7. doi: 10.1200/JCO.2007.11.0726. — View Citation

Enjuanes A, Garcia-Giralt N, Supervia A, Nogués X, Mellibovsky L, Carbonell J, Grinberg D, Balcells S, Díez-Pérez A. Regulation of CYP19 gene expression in primary human osteoblasts: effects of vitamin D and other treatments. Eur J Endocrinol. 2003 May;148(5):519-26. — View Citation

Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D. Assessment of quality of life in women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat. 1999 May;55(2):189-99. — View Citation

Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C. Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res Clin Pract. 2007 Jul;77(1):47-57. Epub 2006 Nov 16. — View Citation

Glanz K, Yaroch AL, Dancel M, Saraiya M, Crane LA, Buller DB, Manne S, O'Riordan DL, Heckman CJ, Hay J, Robinson JK. Measures of sun exposure and sun protection practices for behavioral and epidemiologic research. Arch Dermatol. 2008 Feb;144(2):217-22. doi: 10.1001/archdermatol.2007.46. — View Citation

Godin G, Shephard RJ. A simple method to assess exercise behavior in the community. Can J Appl Sport Sci. 1985 Sep;10(3):141-6. — View Citation

Gonnelli S, Cadirni A, Caffarelli C, Petrioli R, Montagnani A, Franci MB, Lucani B, Francini G, Nuti R. Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane. Bone. 2007 Jan;40(1):205-10. Epub 2006 Aug 14. — View Citation

Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clin Oncol. 2009 Aug 10;27(23):3757-63. doi: 10.1200/JCO.2008.20.0725. Epub 2009 May 18. — View Citation

Herrmann C. International experiences with the Hospital Anxiety and Depression Scale--a review of validation data and clinical results. J Psychosom Res. 1997 Jan;42(1):17-41. Review. — View Citation

Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. doi: 10.1210/jc.2011-0385. Epub 2011 Jun 6. Erratum in: J Clin Endocrinol Metab. 2011 Dec;96(12):3908. — View Citation

Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81. Review. — View Citation

Irvin W Jr, Muss HB, Mayer DK. Symptom management in metastatic breast cancer. Oncologist. 2011;16(9):1203-14. doi: 10.1634/theoncologist.2011-0159. Epub 2011 Aug 31. Review. — View Citation

Islander U, Jochems C, Lagerquist MK, Forsblad-d'Elia H, Carlsten H. Estrogens in rheumatoid arthritis; the immune system and bone. Mol Cell Endocrinol. 2011 Mar 15;335(1):14-29. doi: 10.1016/j.mce.2010.05.018. Epub 2010 Jun 8. Review. — View Citation

Johnson RH, Chien FL, Bleyer A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA. 2013 Feb 27;309(8):800-5. doi: 10.1001/jama.2013.776. Erratum in: JAMA. 2013 Mar 27;309(12):1229. — View Citation

Krishnan AV, Swami S, Peng L, Wang J, Moreno J, Feldman D. Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy. Endocrinology. 2010 Jan;151(1):32-42. doi: 10.1210/en.2009-0855. Epub 2009 Nov 11. — View Citation

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. — View Citation

Lønning PE, Geisler J, Krag LE, Erikstein B, Bremnes Y, Hagen AI, Schlichting E, Lien EA, Ofjord ES, Paolini J, Polli A, Massimini G. Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol. 2005 Aug 1;23(22):5126-37. Epub 2005 Jun 27. — View Citation

May E, Asadullah K, Zügel U. Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs. Curr Drug Targets Inflamm Allergy. 2004 Dec;3(4):377-93. Review. — View Citation

Napoli N, Vattikuti S, Ma C, Rastelli A, Rayani A, Donepudi R, Asadfard M, Yarramaneni J, Ellis M, Armamento-Villareal R. High prevalence of low vitamin D and musculoskeletal complaints in women with breast cancer. Breast J. 2010 Nov-Dec;16(6):609-16. doi: 10.1111/j.1524-4741.2010.01012.x. — View Citation

Neuhouser ML, Sorensen B, Hollis BW, Ambs A, Ulrich CM, McTiernan A, Bernstein L, Wayne S, Gilliland F, Baumgartner K, Baumgartner R, Ballard-Barbash R. Vitamin D insufficiency in a multiethnic cohort of breast cancer survivors. Am J Clin Nutr. 2008 Jul;88(1):133-9. — View Citation

Niravath P. Aromatase inhibitor-induced arthralgia: a review. Ann Oncol. 2013 Jun;24(6):1443-9. doi: 10.1093/annonc/mdt037. Epub 2013 Mar 6. Review. — View Citation

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. — View Citation

Penckofer S, Kouba J, Byrn M, Estwing Ferrans C. Vitamin D and depression: where is all the sunshine? Issues Ment Health Nurs. 2010 Jun;31(6):385-93. doi: 10.3109/01612840903437657. — View Citation

Peterson CA, Heffernan ME. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J Inflamm (Lond). 2008 Jul 24;5:10. doi: 10.1186/1476-9255-5-10. — View Citation

Piper BF, Dibble SL, Dodd MJ, Weiss MC, Slaughter RE, Paul SM. The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nurs Forum. 1998 May;25(4):677-84. — View Citation

Rantanen T, Era P, Heikkinen E. Maximal isometric strength and mobility among 75-year-old men and women. Age Ageing. 1994 Mar;23(2):132-7. — View Citation

Rantanen T, Volpato S, Ferrucci L, Heikkinen E, Fried LP, Guralnik JM. Handgrip strength and cause-specific and total mortality in older disabled women: exploring the mechanism. J Am Geriatr Soc. 2003 May;51(5):636-41. — View Citation

Reed E, Simmonds P, Haviland J, Corner J. Quality of life and experience of care in women with metastatic breast cancer: a cross-sectional survey. J Pain Symptom Manage. 2012 Apr;43(4):747-58. doi: 10.1016/j.jpainsymman.2011.05.005. Epub 2011 Nov 16. — View Citation

Rose AA, Elser C, Ennis M, Goodwin PJ. Blood levels of vitamin D and early stage breast cancer prognosis: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013 Oct;141(3):331-9. doi: 10.1007/s10549-013-2713-9. Epub 2013 Oct 9. Review. — View Citation

Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006 Apr;83(4):754-9. — View Citation

Shao T, Klein P, Grossbard ML. Vitamin D and breast cancer. Oncologist. 2012;17(1):36-45. doi: 10.1634/theoncologist.2011-0278. Epub 2012 Jan 10. Review. — View Citation

Sherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med. 1991;32(6):705-14. — View Citation

Simmons C, Amir E, Dranitsaris G, Clemons M, Wong B, Veith R, Cole DE. Altered calcium metabolism in patients on long-term bisphosphonate therapy for metastatic breast cancer. Anticancer Res. 2009 Jul;29(7):2707-11. — View Citation

Soares MJ, Murhadi LL, Kurpad AV, Chan She Ping-Delfos WL, Piers LS. Mechanistic roles for calcium and vitamin D in the regulation of body weight. Obes Rev. 2012 Jul;13(7):592-605. doi: 10.1111/j.1467-789X.2012.00986.x. Epub 2012 Mar 2. Review. — View Citation

Trukova KP, Grutsch J, Lammersfeld C, Liepa G. Prevalence of vitamin D insufficiency among breast cancer survivors. Nutr Clin Pract. 2012 Feb;27(1):122-8. doi: 10.1177/0884533611431461. Epub 2012 Jan 6. — View Citation

Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA. 1995 Jan 4;273(1):59-65. — View Citation

* Note: There are 43 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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