Combined Immunotherapies in Metastatic ER+ Breast Cancer

Official title

CIMER: Combined Immunotherapies in Metastatic ER+ Breast Cancer

Overview

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.

Interventions

• Radiation Stereotactic Body Radiation Therapy (SBRT) (50GY in 5 fractions)
  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-SB
• Drug Letrozole 2.5Mg Tab
  All patients start standard therapy with oral letrozole (Femara), day 1 of the study.
• Drug Palbociclib 125mg
  Patients randomized to arm 2 will start letrozole alone, and add palbociclib on day 21, after completion of I-SBRT.

Primary outcome measures

• Progression free survival (PFS) will be measured [Time frame: End of study, up to 36 months.]

Secondary outcome measures (5)

• Serial levels of Circulating tumor DNA (ctDNA) [Time frame: End of study, up to 36 months.]
• Circulating tumor DNA (ctDNA) levels [Time frame: End of study, up to 36 months.]
• Objective response rate (ORR) will be assessed. [Time frame: End of study, up to 36 months.]
• Overall survival(OS) will be assessed. [Time frame: End of study, up to 36 months.]
• Change in Number of Subjects with Adverse events [Time frame: End of study, up to 36 months.]

Eligibility criteria

Newly diagnosed advanced/metastatic breast cancer at diagnosis that progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) (AND/OR) Previously diagnosed and treated metastatic BC, for the first time being offered CDK4/6 inhibition with endocrine therapy ( can have progressed after endocrine therapy before) Male Breast cancer patients are eligible to participate on the trial.

Inclusion criteria

• Female ≥ 18 years of age pre and post-menopausal
• Metastatic disease (≤ 5 sites of measurable disease by RECIST)
• 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
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• Weill Cornell Medicine — New York
• Brooklyn Methodist Hospital - NewYork Presbyterian — New York
• New York Presbyterian Hospital - Queens — New York

Identifiers

NCT: NCT04563507 · 20-09022641

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗