Impact of Endocrine Therapy and Abemaciclib on Host and Tumor Immune Cell Repertoire/Function in Advanced ER+/HER2- Breast Cancer
Primary Purpose
Metastatic Breast Cancer, Locally Advanced Breast Cancer, Hormone Receptor Positive Tumor
Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Abemaciclib
Fulvestrant
Aromatase Inhibitors
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Breast Cancer focused on measuring metastatic breast cancer, abemaciclib, endocrine therapy
Eligibility Criteria
Inclusion Criteria:
- Women age ≥ 18
- Locally advanced/unresectable or metastatic breast cancer
Histologically documented estrogen receptor positive adenocarcinoma of the breast that is (any progesterone status allowed):
- ER positive defined as ≥ 10 % tumor cells positive for ER by immunohistochemistry (IHC), irrespective of staining intensity.
- HER2 negative status is determined by:
- IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumor cells, or
- IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within ≤ 10% of the invasive tumor cells, or
- FISH negative based on:
- Single-probe average HER2 copy number < 4.0 signals / cell, or
- Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals /cell
- Patients should have plans to initiate standard of care endocrine therapy with non-steroidal aromatase inhibitor (letrozole, anastrazole) OR fulvestrant plus abemaciclib in the advanced/metastatic first-line or second-line setting per treating oncologist discretion
- Patients should be willing and able to undergo fresh biopsy pretreatment and at 4 weeks into treatment.
- Patients should have an accessible lesion representative of recurrent or metastatic breast cancer for biopsy. Patients will undergo a tissue biopsy or tissue collection for research purposes only. Sites for tissue acquisition include the breast, skin/chest wall, soft tissue, liver, bone. Research directed lung biopsies and brain biopsies are not permitted. Procedures for tissue acquisition are restricted to those performed under local anesthesia or IV conscious sedation; biopsies that require general anesthesia are not permitted in this situation.
- Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and randomization (provided the patient did not receive radiotherapy).
- Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy.
- The patient is able to swallow oral medications.
The patient has adequate organ function for all of the following criteria, as defined in below.
- Hematologic
- ANC ≥1.5 × 10^9/L
- Platelets ≥100 × 10^9/L
- Hemoglobin ≥ 8 g/dL. * Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.
- Hepatic
- Total bilirubin ≤1.5 × ULN *Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted.
ALT and AST ≤ 3 × ULN
- Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of normal.
- Able and willing to complete the informed consent process
- Agree to have bio-specimens stored for future research
Exclusion Criteria:
- History of concurrent active malignancy within last 5 years (excluding basal cell skin cancer, resected squamous cell carcinoma of the skin)
- Current use of hormonal birth control (copper IUD allowed) or estrogen replacement therapy
- Active autoimmune disease that has required systemic treatment in past 6 months (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or similar treatment) is not considered a form of systemic treatment.
- History of a serious or life-threatening allergic reaction to local anesthetics (e.g., lidocaine, xylocaine) used during a biopsy procedure
- Immunodeficient subjects, E.G., receiving systemic steroid therapy greater than physiologic doses or any other form of immunosuppressive therapy within 30 days prior to the first dose of endocrine therapy treatment
- Concurrent use of other oncologic therapies in the adjuvant setting other than bisphosphonates
- Patients with disease not amenable to biopsy
- The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
- Females who are pregnant or lactating.
- The patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
- The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
- History of bleeding disorder that would make serial biopsies unsafe.
- Patients of active anticoagulation for history of venous thromboembolism, cardiovascular conditions.
Sites / Locations
- Duke University Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Cohort 1
Cohort 2
Arm Description
Fulvestrant plus abemaciclib
Aromatase inhibitor plus abemaciclib (with or without ovarian suppression)
Outcomes
Primary Outcome Measures
Changes in serum estrogen (E1 and E2) levels compared to changes in tumor immune cell repertoire and function in response to endocrine therapy and CDK 4/6 inhibition
Estrogen levels in the blood will be assessed to correlate with changes in immune cell populations within the tumor.
Changes in serum estrogen (E1 and E2) levels compared to peripheral blood mononuclear cell repertoire and function in response to endocrine therapy and CDK 4/6 inhibition
Estrogen levels in the blood will be assessed to correlate with changes in the characterization and functionality of peripheral blood mononuclear cells including regulatory T cell populations, B cells, myeloid-derived suppressor cell populations, T cell activation and T cell exhaustion.
Secondary Outcome Measures
Changes in tumor immune cell populations in response to fulvestrant and aromatase inhibitor therapy plus abemaciclib, measured by sequential biopsies
Changes in tumor immune cell populations will be assessed by sequential biopsies via single cell RNA sequencing analysis of fresh tissue
Differences in tumor immune cell infiltrate and peripheral blood mononuclear cells in response to fulvestrant versus aromatase inhibition plus CDK4/6 inhibition, measured by sequential biopsies and blood collection
Tumor immune cell and peripheral blood monoclonal cell changes assessed by sequential biopsies via single cell RNA sequencing analysis of fresh tissue
To correlate unique immune cell populations identified with progression free survival in the overall population
Unique immune cell populations will be identified via single cell RNA sequencing and correlated to progression free survival measured by RECIST1.1.
Best overall response rate of abemaciclib and endocrine therapy in both treatment arms
Best overall response rate to both treatment arms measured by RECIST 1.1
Progression free survival in response to abemaciclib and endocrine therapy in both treatment arms
Progression free survival rate to both treatment arms measured by RECIST 1.1
Number of participants with at least one serious adverse event
Serious adverse events will include only those related to abemaciclib, endocrine therapy, and/or study-related biopsies
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04352777
Brief Title
Impact of Endocrine Therapy and Abemaciclib on Host and Tumor Immune Cell Repertoire/Function in Advanced ER+/HER2- Breast Cancer
Official Title
Evaluation of the Effects of Endocrine Therapy and Abemaciclib on Host and Tumor Immune Cell Repertoire/Function in Advanced ER+/HER2- Breast Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 14, 2020 (Actual)
Primary Completion Date
December 30, 2023 (Anticipated)
Study Completion Date
December 30, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
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
The purpose of this study is to perform an in depth analysis of changes in the tumor immune microenvironment in patients undergoing treatment with standard of care endocrine therapy and abemaciclib in the advanced setting via singe cell RNA sequencing. The investigators will also correlate changes in serum estrogen levels to changes in tumor and peripheral immune cell repertoire and function (including regulatory T cell populations, B cells, myeloid-derived suppressor cell populations, T cell activation and T cell exhaustion).This study has two cohorts with 15 patients in each cohort.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Breast Cancer, Locally Advanced Breast Cancer, Hormone Receptor Positive Tumor
Keywords
metastatic breast cancer, abemaciclib, endocrine therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Active Comparator
Arm Description
Fulvestrant plus abemaciclib
Arm Title
Cohort 2
Arm Type
Active Comparator
Arm Description
Aromatase inhibitor plus abemaciclib (with or without ovarian suppression)
Intervention Type
Drug
Intervention Name(s)
Abemaciclib
Intervention Description
50 - 150mg tablet BID as prescribed per standard of care
Intervention Type
Drug
Intervention Name(s)
Fulvestrant
Intervention Description
500mg as prescribed per standard of care
Intervention Type
Drug
Intervention Name(s)
Aromatase Inhibitors
Intervention Description
Letrozole, anastrozole as prescribed per standard of care
Primary Outcome Measure Information:
Title
Changes in serum estrogen (E1 and E2) levels compared to changes in tumor immune cell repertoire and function in response to endocrine therapy and CDK 4/6 inhibition
Description
Estrogen levels in the blood will be assessed to correlate with changes in immune cell populations within the tumor.
Time Frame
Through study completion, approximately 2 years
Title
Changes in serum estrogen (E1 and E2) levels compared to peripheral blood mononuclear cell repertoire and function in response to endocrine therapy and CDK 4/6 inhibition
Description
Estrogen levels in the blood will be assessed to correlate with changes in the characterization and functionality of peripheral blood mononuclear cells including regulatory T cell populations, B cells, myeloid-derived suppressor cell populations, T cell activation and T cell exhaustion.
Time Frame
Through study completion, approximately 2 years
Secondary Outcome Measure Information:
Title
Changes in tumor immune cell populations in response to fulvestrant and aromatase inhibitor therapy plus abemaciclib, measured by sequential biopsies
Description
Changes in tumor immune cell populations will be assessed by sequential biopsies via single cell RNA sequencing analysis of fresh tissue
Time Frame
Baseline, 4 weeks
Title
Differences in tumor immune cell infiltrate and peripheral blood mononuclear cells in response to fulvestrant versus aromatase inhibition plus CDK4/6 inhibition, measured by sequential biopsies and blood collection
Description
Tumor immune cell and peripheral blood monoclonal cell changes assessed by sequential biopsies via single cell RNA sequencing analysis of fresh tissue
Time Frame
Baseline, 4 weeks
Title
To correlate unique immune cell populations identified with progression free survival in the overall population
Description
Unique immune cell populations will be identified via single cell RNA sequencing and correlated to progression free survival measured by RECIST1.1.
Time Frame
Through study completion, approximately 2 years
Title
Best overall response rate of abemaciclib and endocrine therapy in both treatment arms
Description
Best overall response rate to both treatment arms measured by RECIST 1.1
Time Frame
Through study completion, approximately 2 years
Title
Progression free survival in response to abemaciclib and endocrine therapy in both treatment arms
Description
Progression free survival rate to both treatment arms measured by RECIST 1.1
Time Frame
Through study completion, approximately 2 years
Title
Number of participants with at least one serious adverse event
Description
Serious adverse events will include only those related to abemaciclib, endocrine therapy, and/or study-related biopsies
Time Frame
Through study completion, approximately 2 years
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Women age ≥ 18
Locally advanced/unresectable or metastatic breast cancer
Histologically documented estrogen receptor positive adenocarcinoma of the breast that is (any progesterone status allowed):
ER positive defined as ≥ 10 % tumor cells positive for ER by immunohistochemistry (IHC), irrespective of staining intensity.
HER2 negative status is determined by:
IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumor cells, or
IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within ≤ 10% of the invasive tumor cells, or
FISH negative based on:
Single-probe average HER2 copy number < 4.0 signals / cell, or
Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals /cell
Patients should have plans to initiate standard of care endocrine therapy with non-steroidal aromatase inhibitor (letrozole, anastrazole) OR fulvestrant plus abemaciclib in the advanced/metastatic first-line or second-line setting per treating oncologist discretion
Patients should be willing and able to undergo fresh biopsy pretreatment and at 4 weeks into treatment.
Patients should have an accessible lesion representative of recurrent or metastatic breast cancer for biopsy. Patients will undergo a tissue biopsy or tissue collection for research purposes only. Sites for tissue acquisition include the breast, skin/chest wall, soft tissue, liver, bone. Research directed lung biopsies and brain biopsies are not permitted. Procedures for tissue acquisition are restricted to those performed under local anesthesia or IV conscious sedation; biopsies that require general anesthesia are not permitted in this situation.
Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and randomization (provided the patient did not receive radiotherapy).
Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy.
The patient is able to swallow oral medications.
The patient has adequate organ function for all of the following criteria, as defined in below.
Hematologic
ANC ≥1.5 × 10^9/L
Platelets ≥100 × 10^9/L
Hemoglobin ≥ 8 g/dL. * Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.
Hepatic
Total bilirubin ≤1.5 × ULN *Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted.
ALT and AST ≤ 3 × ULN
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of normal.
Able and willing to complete the informed consent process
Agree to have bio-specimens stored for future research
Exclusion Criteria:
History of concurrent active malignancy within last 5 years (excluding basal cell skin cancer, resected squamous cell carcinoma of the skin)
Current use of hormonal birth control (copper IUD allowed) or estrogen replacement therapy
Active autoimmune disease that has required systemic treatment in past 6 months (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or similar treatment) is not considered a form of systemic treatment.
History of a serious or life-threatening allergic reaction to local anesthetics (e.g., lidocaine, xylocaine) used during a biopsy procedure
Immunodeficient subjects, E.G., receiving systemic steroid therapy greater than physiologic doses or any other form of immunosuppressive therapy within 30 days prior to the first dose of endocrine therapy treatment
Concurrent use of other oncologic therapies in the adjuvant setting other than bisphosphonates
Patients with disease not amenable to biopsy
The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
Females who are pregnant or lactating.
The patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
History of bleeding disorder that would make serial biopsies unsafe.
Patients of active anticoagulation for history of venous thromboembolism, cardiovascular conditions.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sarah Sammons, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Impact of Endocrine Therapy and Abemaciclib on Host and Tumor Immune Cell Repertoire/Function in Advanced ER+/HER2- Breast Cancer
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