Combined Immunotherapies in Metastatic ER+ Breast Cancer

• ClinicalTrials.gov Identifier: NCT04563507
• Recruitment Status: Recruiting
• First Posted: September 24, 2020
• Last Update Posted: June 30, 2022
• Sponsor: Weill Medical College of Cornell University
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Radiation: Stereotactic Body Radiation Therapy (SBRT) (50GY in 5 fractions); Drug: Letrozole 2.5Mg Tab; Drug: Palbociclib 125mg	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CIMER: Combined Immunotherapies in Metastatic ER+ Breast Cancer
• Actual Study Start Date: November 12, 2020
• Estimated Primary Completion Date: October 31, 2023
• Estimated Study Completion Date: October 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: ARM 1 - Letrozole and Palbociclib; Patients randomized to arm 1 will start standard Letrozole followed by Palbociclib at day 21.	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.
Active Comparator: ARM 2 - Letrozole and Palbociclib + I-SBRT; 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); 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Progression free survival (PFS) will be measured [ Time Frame: End of study, up to 36 months. ]
   Progression free survival (PFS) is defined as the time from the start of study treatment until the disease progression or death.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Charles Ekeh, M.D.; 646-962-2196; che4005@med.cornell.edu

Contact: Pragya Yadav, Ph.D.; 646-962-2199; pry2003@med.cornell.edu

Locations

United States, New York

Weill Cornell Medicine; Recruiting

New York, New York, United States, 10065

Contact: Charles Ekeh, M.D. 646-962-2196 che4005@med.cornell.edu

Contact: Pragya Yadav, Ph.D. 646-962-2199 pry2003@med.cornell.edu

Principal Investigator: Silvia Formenti, M.D.

Brooklyn Methodist Hospital - NewYork Presbyterian; Recruiting

New York, New York, United States, 11215

Contact: Sharanya Chandrasekhar, M.S. 646-962-2196 shc2043@med.cornell.edu

Contact: Pragya Yadav, Ph.D. 6469622199 pry2003@med.cornell.edu

Principal Investigator: Hani Ashamalla, M.D.

New York Presbyterian Hospital - Queens; Recruiting

New York, New York, United States, 11355

Contact: Sarah Stankiewicz, B.S. 718-661-7246 sas9306@nyp.org

Contact: Sharanya Chandrasekhar, M.S. 646-962-2196 shc2043@med.cornell.edu

Sub-Investigator: Akkamma Ravi, M.D.

Principal Investigator: Silvia Formenti, M.D.

United States, Pennsylvania

UPMC Hillman Cancer Center; Not yet recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contact: Veronica Wahula, B.S. 412-641-2283 wahuvf@upmc.edu

Principal Investigator: Leisha Emens, M.D.

United States, Texas

Houston Methodist Cancer Center; Not yet recruiting

Houston, Texas, United States, 77030

Contact: Mary Rose Silvas 713-441-1952 msilvas@houstonmethodist.org

Principal Investigator: Jenny Chang, M.D.

Sponsors and Collaborators

Weill Medical College of Cornell University

Investigators

• Principal Investigator: Silvia Formenti, M.D.; Weill Medical College of Cornell University

More Information

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT04563507
• Other Study ID Numbers: 20-09022641
• First Posted: September 24, 2020
• Last Update Posted: June 30, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Weill Medical College of Cornell University:

metastatic Breast cancer; HR+HER2-; HR + BC; SBRT

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Letrozole; Palbociclib; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Protein Kinase Inhibitors