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

Primary Purpose

Triple Negative Breast Cancer, Vitamin D Deficiency, Invasive Breast Cancer

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Standard of Care Neoadjuvant Chemotherapy
Vitamin D3
Drug Diary
Sponsored by
Wake Forest University Health Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Triple Negative Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 less than or equal to 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.
  • Prior treatment for this malignancy including surgery, radiation therapy, chemotherapy, hormonal therapy or investigational agent prior to study entry.
  • Patients currently taking Vitamin D at a dose of 50,000 International Units (IU) once weekly.

Sites / Locations

  • Wake Forest Baptist Health SciencesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Vitamin D Supplementation Group - Deficient Levels

Observational Arm - Vitamin D at Normal Levels

Arm Description

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.

Standard of care neoadjuvant chemotherapy

Outcomes

Primary Outcome Measures

Number of Pathologic Complete Response (pCR) in Vitamin D Supplementation Group
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. Pathologic complete response, which is also characterized as residual cancer burden 0, is defined as a final surgical pathologic diagnosis of ypT0 ypN0 or ypTis ypN0.

Secondary Outcome Measures

Number of Participants with Residual Cancer Burden (RCB) Index - Vitamin D Supplementation Group
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).
Number of Participants with Residual Cancer Burden (RCB) Index - Observational Arm
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).
Accrual Rate
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.
Participation Rate
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.
Retention Rate
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.
Adherence Rate
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.
Number of Adverse Events
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.
Change in Vitamin D Receptor (VDR) Expression
Investigators will use a paired t-test to examine the change in Vitamin D receptor expression from pre-post neoadjuvant treatment.
Change in Fecal Microbiomes
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.
Change in Mammary Gland Microbiomes
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.

Full Information

First Posted
December 15, 2020
Last Updated
June 5, 2023
Sponsor
Wake Forest University Health Sciences
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT04677816
Brief Title
Impact of Vitamin D Supplementation on the Rate of Pathologic Complete Response in Vitamin D Deficient Patients
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 22, 2021 (Actual)
Primary Completion Date
October 2023 (Anticipated)
Study Completion Date
October 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wake Forest University Health Sciences
Collaborators
National Cancer Institute (NCI)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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. Patients will be followed for a minimum of 30 days after the last study intervention is administered for adverse events monitoring. Patients will be followed for 30 days after removal from study or until death, whichever occurs first. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Triple Negative Breast Cancer, Vitamin D Deficiency, Invasive Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Vitamin D Supplementation Group - Deficient Levels
Arm Type
Experimental
Arm Description
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.
Arm Title
Observational Arm - Vitamin D at Normal Levels
Arm Type
Active Comparator
Arm Description
Standard of care neoadjuvant chemotherapy
Intervention Type
Drug
Intervention Name(s)
Standard of Care Neoadjuvant Chemotherapy
Intervention Description
Participants will receive standard of care neoadjuvant chemotherapy with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles and 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. Upon completion of neoadjuvant chemotherapy, all patients will undergo definitive surgery with either breast conservation or mastectomy with axillary lymph node staging. Type of surgery will be determined by the treating physician.
Intervention Type
Dietary Supplement
Intervention Name(s)
Vitamin D3
Intervention Description
Participants with deficient levels of vitamin D will receive vitamin D supplementation at the initiation of chemotherapy with 50,000 IU of oral vitamin D3 (cholecalciferol) once a week to be continued for 20 weeks during neoadjuvant chemotherapy.
Intervention Type
Other
Intervention Name(s)
Drug Diary
Intervention Description
Participants that will receive Vitamin D will be asked to fill out a drug diary on a daily basis. Compliance and feasibility will be assessed through a drug diary and pill counts at set time points.
Primary Outcome Measure Information:
Title
Number of Pathologic Complete Response (pCR) in Vitamin D Supplementation Group
Description
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. Pathologic complete response, which is also characterized as residual cancer burden 0, is defined as a final surgical pathologic diagnosis of ypT0 ypN0 or ypTis ypN0.
Time Frame
Up to 4 weeks
Secondary Outcome Measure Information:
Title
Number of Participants with Residual Cancer Burden (RCB) Index - Vitamin D Supplementation Group
Description
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).
Time Frame
Up to 20 weeks
Title
Number of Participants with Residual Cancer Burden (RCB) Index - Observational Arm
Description
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).
Time Frame
Up to 20 weeks
Title
Accrual Rate
Description
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.
Time Frame
Up to 20 weeks
Title
Participation Rate
Description
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.
Time Frame
Up to 20 weeks
Title
Retention Rate
Description
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.
Time Frame
Up to 20 weeks
Title
Adherence Rate
Description
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.
Time Frame
Up to 20 weeks
Title
Number of Adverse Events
Description
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.
Time Frame
Up to 30 days after last day of study intervention
Title
Change in Vitamin D Receptor (VDR) Expression
Description
Investigators will use a paired t-test to examine the change in Vitamin D receptor expression from pre-post neoadjuvant treatment.
Time Frame
At baseline and up to 30 days after surgery
Title
Change in Fecal Microbiomes
Description
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.
Time Frame
At baseline and up to 30 days after surgery
Title
Change in Mammary Gland Microbiomes
Description
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.
Time Frame
At baseline and up to 30 days after surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 less than or equal to 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. Prior treatment for this malignancy including surgery, radiation therapy, chemotherapy, hormonal therapy or investigational agent prior to study entry. Patients currently taking Vitamin D at a dose of 50,000 International Units (IU) once weekly.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Study Nurse
Phone
336-713-3155
Email
anhowell@wakehealth.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emily H Douglas, MD
Organizational Affiliation
Wake Forest University Health Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
Wake Forest Baptist Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Study Nurse
First Name & Middle Initial & Last Name & Degree
Emily H Douglas, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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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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