Clinical Trials /

Impact of Endocrine Therapy and Abemaciclib on Host and Tumor Immune Cell Repertoire/Function in Advanced ER+/HER2- Breast Cancer

NCT04352777

Description:

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.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: Pro00103625
  • NCT ID: NCT04352777

Conditions

  • Metastatic Breast Cancer
  • Locally Advanced Breast Cancer
  • Hormone Receptor Positive Tumor

Interventions

DrugSynonymsArms
AbemaciclibCohort 1
FulvestrantCohort 1
Aromatase InhibitorsCohort 2

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1Active ComparatorFulvestrant plus abemaciclib
  • Abemaciclib
  • Fulvestrant
Cohort 2Active ComparatorAromatase inhibitor plus abemaciclib (with or without ovarian suppression)
  • Abemaciclib
  • Aromatase Inhibitors

Eligibility Criteria

        Inclusion Criteria:

          1. Women age ≥ 18

          2. Locally advanced/unresectable or metastatic breast cancer

          3. 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

          4. 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

          5. Patients should be willing and able to undergo fresh biopsy pretreatment and at 4
             weeks into treatment.

          6. 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.

          7. 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).

          8. Patients who received radiotherapy must have completed and fully recovered from the
             acute effects of radiotherapy.

          9. The patient is able to swallow oral medications.

         10. 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.

         11. Able and willing to complete the informed consent process

         12. Agree to have bio-specimens stored for future research

        Exclusion Criteria:

          1. History of concurrent active malignancy within last 5 years (excluding basal cell skin
             cancer, resected squamous cell carcinoma of the skin)

          2. Current use of hormonal birth control (copper IUD allowed) or estrogen replacement
             therapy

          3. 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.

          4. History of a serious or life-threatening allergic reaction to local anesthetics (e.g.,
             lidocaine, xylocaine) used during a biopsy procedure

          5. 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

          6. Concurrent use of other oncologic therapies in the adjuvant setting other than
             bisphosphonates

          7. Patients with disease not amenable to biopsy

          8. 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).

          9. Females who are pregnant or lactating.

         10. 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.

         11. 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.

         12. History of bleeding disorder that would make serial biopsies unsafe.

         13. Patients of active anticoagulation for history of venous thromboembolism,
             cardiovascular conditions.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Time Frame:Through study completion, approximately 2 years
Safety Issue:
Description:Estrogen levels in the blood will be assessed to correlate with changes in immune cell populations within the tumor.

Secondary Outcome Measures

Measure:Changes in tumor immune cell populations in response to fulvestrant and aromatase inhibitor therapy plus abemaciclib, measured by sequential biopsies
Time Frame:Baseline, 4 weeks
Safety Issue:
Description:Changes in tumor immune cell populations will be assessed by sequential biopsies via single cell RNA sequencing analysis of fresh tissue
Measure: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
Time Frame:Baseline, 4 weeks
Safety Issue:
Description:Tumor immune cell and peripheral blood monoclonal cell changes assessed by sequential biopsies via single cell RNA sequencing analysis of fresh tissue
Measure:To correlate unique immune cell populations identified with progression free survival in the overall population
Time Frame:Through study completion, approximately 2 years
Safety Issue:
Description:Unique immune cell populations will be identified via single cell RNA sequencing and correlated to progression free survival measured by RECIST1.1.
Measure:Best overall response rate of abemaciclib and endocrine therapy in both treatment arms
Time Frame:Through study completion, approximately 2 years
Safety Issue:
Description:Best overall response rate to both treatment arms measured by RECIST 1.1
Measure:Progression free survival in response to abemaciclib and endocrine therapy in both treatment arms
Time Frame:Through study completion, approximately 2 years
Safety Issue:
Description:Progression free survival rate to both treatment arms measured by RECIST 1.1
Measure:Number of participants with at least one serious adverse event
Time Frame:Through study completion, approximately 2 years
Safety Issue:
Description:Serious adverse events will include only those related to abemaciclib, endocrine therapy, and/or study-related biopsies

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Duke University

Trial Keywords

  • metastatic breast cancer
  • abemaciclib
  • endocrine therapy

Last Updated

April 20, 2020