Combined Immunotherapies in Metastatic ER+ Breast Cancer

Study Overview
=================
Brief Summary
-----------------
Women with Hormone Receptor (HR)+ Human Epidermal growth factor Receptor (HER)2- metastatic breast cancer are eligible to a randomized trial. Patients receiving standard first line therapy for metastatic HR+ Breast cancer(BC) (letrozole+palbociclib) are randomly assigned to also receive Stereotactic Body Radiation Therapy(SBRT) to each metastatic lesion.

Official Title
-----------------
CIMER: Combined Immunotherapies in Metastatic ER+ Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Radiation: Stereotactic Body Radiation Therapy (SBRT) (50GY in 5 fractions)
* Drug: Letrozole 2.5Mg Tab
* Drug: Palbociclib 125mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female ≥ 18 years of age pre and post-menopausal Metastatic disease (≤ 5 sites of measurable disease) Eligible for treatment with CDK4/6 + aromatase inhibitors Premenopausal status is defined as either: Patient had last menstrual period within the last 12 months, OR If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, OR In case of therapy-induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range. Patients who have undergone bilateral oophorectomy are eligible. Post-menopausal status defined as either 1) at least 2 years without menstrual period or 2) patients older than 50 with serological evidence of post-menopausal status or 3) hysterectomized patients of any age with FSH confirmation of post-menopausal status. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Biopsy proven diagnosis of HR+HER2- metastatic breast cancer. ER expression is >10% Patient needs to be able to understand and demonstrate a willingness to sign a written informed consent document Hematological WBC ≥ 2000/uL Absolute neutrophil count (ANC) ≥1500/µL Platelets ≥100 000/µL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La Renal Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for the participant with creatinine levels >1.5 × institutional ULN Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy if PT or aPTT is within the therapeutic range of intended use of anticoagulants Exclusion Criteria: Active connective tissue disorders, such as lupus or scleroderma requiring flare therapy Current use of systemic chemotherapy, endocrine therapy or HER2-neu targeted therapy Male breast cancer patients Any lesion >5 cm in greatest diameter. Inability to obtain histologic proof of metastatic breast cancer Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Has a known additional malignancy (second primary) that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has an active infection requiring systemic therapy. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Patients with uncontrolled brain metastases

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ARM 1 - Letrozole and Palbociclib<br>Patients randomized to arm 1 will start standard Letrozole followed by Palbociclib at day 21. | Drug: Letrozole 2.5Mg Tab<br>* All patients start standard therapy with oral letrozole (Femara), day 1 of the study.<br>Drug: Palbociclib 125mg<br>* Patients randomized to arm 2 will start letrozole alone, and add palbociclib on day 21, after completion of I-SBRT.<br>|
| Active Comparator: ARM 2 - Letrozole and Palbociclib + I-SBRT<br>Patients randomized to arm 2 will start letrozole alone, and add palbociclib on day 21, after completion of I-SBRT. Treatment may be given daily (to keep the total I-SBRT treatment time to ≤ 12 days) and lesions targeted with I-SBRT will thus be alternated each day to accommodate for the 48 hour interval between fractions. | Radiation: Stereotactic Body Radiation Therapy (SBRT) (50GY in 5 fractions)<br>* Patients randomized to arm 2 will start letrozole alone, and add palbociclib on day 21, after completion of I-SBRT. They will undergo tumor Immunogenic-SBRT(I-SBRT) days 1-12 (+/-2 days, to enable inclusion of holidays). During the week preceding day 1, they will undergo simulation and planning for radiotherapy. Each oligometastatic lesion will be treated with I-SBRT every 48 hours. Treatment may be given daily (to keep the total I-SBRT treatment time to ≤ 12 days) and lesions targeted with I-SBRT will thus be alternated each day to accommodate for the 48 hour interval between fractions<br>Drug: Letrozole 2.5Mg Tab<br>* All patients start standard therapy with oral letrozole (Femara), day 1 of the study.<br>Drug: Palbociclib 125mg<br>* Patients randomized to arm 2 will start letrozole alone, and add palbociclib on day 21, after completion of I-SBRT.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) will be measured | Progression free survival (PFS) is defined as the time from the start of study treatment until the disease progression or death. | End of study, up to 36 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serial levels of Circulating tumor DNA (ctDNA) | Serial levels ctDNA can be an early indication of progression | End of study, up to 36 months. | 
| Circulating tumor DNA (ctDNA) levels | Circulating tumor DNA (ctDNA) levels will be measured to determine baseline cancer heterogeneity and its response to treatment | End of study, up to 36 months. | 
| Objective response rate (ORR) will be assessed. | ORR is defined as the percentage of subjects with either a confirmed complete response (CR) or partial response (PR). | End of study, up to 36 months. | 
| Overall survival(OS) will be assessed. | OS is defined as the time from the start of treatment until death. | End of study, up to 36 months. | 
| Change in Number of Subjects with Adverse events | Adverse events will be collected from patients based on CTCAE version 5.0. | End of study, up to 36 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic Breast cancer, HR+HER2-, HR + BC, SBRT