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Impact of Vitamin D Supplementation on the Rate of Pathologic Complete Response in Vitamin D Deficient Patients

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ClinicalTrials.gov Identifier: NCT04677816
Recruitment Status : Withdrawn (Study team has decided not to rework the trial to correct inconsistencies and will resubmit to IRB as a new study at a later date.)
First Posted : December 21, 2020
Last Update Posted : February 21, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Wake Forest University Health Sciences

Brief Summary:
A two arm pilot study investigating the rate of pathologic complete response in patients with vitamin D deficiency and triple negative breast cancer undergoing standard neoadjuvant chemotherapy + vitamin D supplementation, including an observational arm to describe response in patients who are not deficient. Investigators hypothesize that vitamin D supplementation during neoadjuvant chemotherapy in operable triple negative breast cancer patients with vitamin D deficiency, will increase the rate of pathologic complete response chain reaction to that of vitamin D sufficient patients based on historical controls.

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Vitamin D Deficiency Drug: Standard of Care Neoadjuvant Chemotherapy Dietary Supplement: Vitamin D3 Other: Drug Diary Phase 2

Detailed Description:

Primary Objective: To determine if pathologic complete response in vitamin D deficient patients receiving vitamin D supplementation during neoadjuvant chemotherapy for operable triple negative breast cancer is greater than or equal to 60% or less than or equal to pathologic complete response in historical controls (30%) using a one-stage phase II design.

Secondary Objective(s):

  • To estimate the proportion of patients with residual cancer burden (RCB) classes I, II, and III in vitamin D deficient patients receiving vitamin D supplementation during neoadjuvant chemotherapy for operable triple negative breast cancer.
  • To estimate pathologic complete response reaction in the observational arm of vitamin D sufficient patients receiving neoadjuvant chemotherapy for operable triple negative breast cancer.
  • To determine the feasibility of delivery of vitamin D supplementation with standard of care chemotherapy.
  • To determine the safety and tolerability of the combination of vitamin D supplementation with standard of care chemotherapy.
  • To estimate the change in vitamin D receptor (VDR) expression from pre- and post-neoadjuvant treatment breast tumor tissue samples of vitamin D deficient patients.
  • To estimate the change in VDR expression from pre- to post-neoadjuvant treatment breast tumor tissue samples in a sample of 5 vitamin D sufficient patients.
  • To estimate the changes in the fecal microbiome and mammary gland microbiome of vitamin D deficient patients from pre- to post-neoadjuvant treatment, and to explore the concordance in the changes between the mammary and fecal microbiome.
  • To estimate the changes in the fecal microbiome and mammary gland microbiome in a sample of 5 vitamin D sufficient patients from pre- to post-neoadjuvant treatment.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Impact of Vitamin D Supplementation on the Rate of Pathologic Complete Response in Vitamin D Deficient Patients Receiving Neoadjuvant Chemotherapy for Operable Triple Negative Breast Cancer
Estimated Study Start Date : February 2021
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : May 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Vitamin D

Arm Intervention/treatment
Experimental: Vitamin D Supplementation Group - Deficient Levels
Along with standard of care neoadjuvant chemotherapy treatments and procedures, participants will receive oral 50,000 international units of Vitamin D3 supplementation at the initiation of chemotherapy once a week.
Drug: Standard of Care Neoadjuvant Chemotherapy
Participants will receive standard of care neoadjuvant chemotherapy with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles followed by paclitaxel (80 mg/m2) weekly for 12 cycles. Doxorubicin and cyclophosphamide (AC) may be administered on a classical every 3 week or dose dense every 2-week (with growth factor support) schedule at the treating physician's discretion. Routine incorporation of carboplatin is not required, however use of carboplatin (AUC 1.5 to 2 weekly or AUC 6 on week 1, 4, 7, and 10) with paclitaxel is allowed at the treating investigator's discretion.

Dietary Supplement: Vitamin D3
Participants with deficient levels of vitamin D will receive vitamin D supplementation at the initiation of chemotherapy with 50,000 international units of oral vitamin D3 (cholecalciferol) once a week to be continued throughout the course of standard of care neoadjuvant chemotherapy

Other: Drug Diary
Participants that will receive Vitamin D will be asked to fill out a drug diary on a daily basis.

Active Comparator: Observational Arm - Vitamin D at Normal Levels
Standard of care neoadjuvant chemotherapy
Drug: Standard of Care Neoadjuvant Chemotherapy
Participants will receive standard of care neoadjuvant chemotherapy with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles followed by paclitaxel (80 mg/m2) weekly for 12 cycles. Doxorubicin and cyclophosphamide (AC) may be administered on a classical every 3 week or dose dense every 2-week (with growth factor support) schedule at the treating physician's discretion. Routine incorporation of carboplatin is not required, however use of carboplatin (AUC 1.5 to 2 weekly or AUC 6 on week 1, 4, 7, and 10) with paclitaxel is allowed at the treating investigator's discretion.




Primary Outcome Measures :
  1. Proportion of Pathologic Complete Response (pCR) in Vitamin D Supplementation Group [ Time Frame: Up to 4 weeks ]
    Investigators will determine whether the proportion responding (pCR) is less than or equal to 30% or greater than or equal to 60% using a one-stage phase II design. All participants in the intervention group who are evaluable will be included in the analysis.


Secondary Outcome Measures :
  1. Proportion of Participants with Residual Cancer Burden (RCB) Index - Vitamin D Supplementation Group [ Time Frame: Up to 12 weeks ]
    Five variables are included in the calculation formula. These include: 1) Primary tumor bed area, defined as the largest two dimensions (mms) of the residual tumor bed in the breast (largest tumor bed if multicentric disease), 2) Overall cancer cellularity (as percentage of area), 3) Percentage of cancer that is in situ disease, 4) Number of positive lymph nodes and 5) Diameter of largest metastasis. The calculated residual cancer burden index will be categorized as one of four residual cancer burden classes RCB-0 (pathologic complete response), minimal residual disease (RCB-I), moderate residual disease (RCB-II), or extensive residual disease (RCB-III).

  2. Proportion of Participants with Residual Cancer Burden (RCB) Index - Observational Arm [ Time Frame: Up to 12 weeks ]
    Five variables are included in the calculation formula. These include: 1) Primary tumor bed area, defined as the largest two dimensions (mms) of the residual tumor bed in the breast (largest tumor bed if multicentric disease), 2) Overall cancer cellularity (as percentage of area), 3) Percentage of cancer that is in situ disease, 4) Number of positive lymph nodes and 5) Diameter of largest metastasis. The calculated residual cancer burden index will be categorized as one of four residual cancer burden classes RCB-0 (pathologic complete response), minimal residual disease (RCB-I), moderate residual disease (RCB-II), or extensive residual disease (RCB-III).

  3. Accrual Rate [ Time Frame: Up to 12 weeks ]
    Will be calculated as the number of women who agreed to participate divided by the number of months of recruitment. Estimates and 95% confidence intervals will be calculated for all study participants and for the subset of evaluable participants.

  4. Participation Rate [ Time Frame: Up to 12 weeks ]
    Will be calculated as the percent of eligible participants who agreed to participate. Estimates and 95% confidence intervals will be calculated for all study participants and for the subset of evaluable participants.

  5. Retention Rate [ Time Frame: Up to 12 weeks ]
    Will be calculated as the number of participants on whom investigators can obtain the final surgery pathology report by the number who consented to participate. Estimates and 95% confidence intervals will be calculated for all study participants and for the subset of evaluable participants.

  6. Adherence Rate [ Time Frame: Up to 12 weeks ]
    will be defined by the proportion of Vitamin D supplements consumed and the proportion of women who took at least 80% of pills. Estimates and 95% confidence intervals will be calculated for all study participants and for the subset of evaluable participants.

  7. Number of Adverse Events [ Time Frame: Up to 30 days after last day of study intervention ]
    To determine safety of intervention all adverse events will be documented and analyzed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for adverse event reporting using frequencies of events, grade and attribution.

  8. Change in Vitamin D Receptor (VDR) Expression [ Time Frame: At baseline and up to 30 days after surgery ]
    Investigators will use a paired t-test to examine the change in Vitamin D receptor expression from pre-post neoadjuvant treatment.

  9. Change in Fecal and Mammary Gland Microbiomes [ Time Frame: At baseline and up to 30 days after surgery ]
    Investigators will examine the proportion of different bacteria taxa at each time point, and will use a marginalized two-part beta regression model to account for the compositional nature of the data. A list of all the microbiologic species will be recorded, along with their relative abundance recorded as a percentage relative abundance of the total microbiome.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women or men with histologically confirmed invasive mammary carcinoma.
  • Known triple negative ER/PR/HER2 receptor status as defined by: ER and PR < 10% and
  • HER2 negative based on one of the following: IHC 0 or 1+, IHC 2+ and FISH negative, IHC 2+ and FISH equivocal and no indication for HER2 targeted therapy based on the treating investigators discretion (i.e., HER2: CEP17 ratio < 2.0 or HER2 total copy number <6)
  • Patients who are scheduled to undergo definitive surgical treatment with lumpectomy or mastectomy with axillary lymph node staging after neoadjuvant chemotherapy.
  • ECOG performance status of 0, 1 or 2.
  • Age ≥ 18.
  • The effects of high dose vitamin D on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative).

Exclusion Criteria:

  • Patients with nephrolithiasis within the past year.
  • Patients with known sarcoidosis.
  • Patients with corrected calcium >10.5 mg/dL within 30 days prior to initiation of chemotherapy.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to vitamin D.
  • Pregnant women are excluded from this study because vitamin D supplementation greater than the recommended daily allowance (RDA) is a pregnancy class C agent with no adequate or well controlled studies in humans.
  • Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with high dose vitamin D (greater than RDA), women who are breastfeeding are excluded from this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04677816


Sponsors and Collaborators
Wake Forest University Health Sciences
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Emily H Douglas, MD Wake Forest University Health Sciences
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Responsible Party: Wake Forest University Health Sciences
ClinicalTrials.gov Identifier: NCT04677816    
Other Study ID Numbers: IRB00070680
WFBCCC 02120 ( Other Identifier: Wake Forest Baptist Comprehensive Cancer Center )
P30CA012197 ( U.S. NIH Grant/Contract )
First Posted: December 21, 2020    Key Record Dates
Last Update Posted: February 21, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Vitamin D Deficiency
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders
Vitamin D
Cholecalciferol
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents