Ribociclib And Endocrine Treatment of Physician's Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer

Study Overview
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Brief Summary
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This is an open label, multicenter, single arm phase II study to evaluate the efficacy and safety of ribociclib and ET in patients with locoregional recurrence of HR-positive, HER2-negative breast cancer.

Detailed Description
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Collection of Correlative Samples at First Recurrence (Stage I consent) If feasible, optional correlative blood and fresh tissue will be collected during surgical excision of their 1st recurrence. Patients should then complete radiation therapy if that is indicated. Enrollment to the Treatment Phase will occur within 6 months of the last local treatment, surgery or radiation treatment, whichever occurred last. Study Treatment (Stage II/ main consent) Treatment includes: Ribociclib: Oral ribociclib at a dose of 600 mg daily for 21 days out of a 28-day cycle. Ribociclib will be used in combination with ET per physician choice. Physician's Choice Endocrine Therapy: ET consists of one of the following: Intramuscular fulvestrant Oral anastrozole Oral letrozole Oral exemestane Concomitant use with tamoxifen is not allowed. Ribociclib administration is planned for 36 months and ET administration is planned for 60 months.

Official Title
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A Phase II Study of Ribociclib And Endocrine Treatment of Physician's Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer

Conditions
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Locoregional Recurrence, Hormone Receptor-positive Breast Cancer, HER2-negative Breast Cancer

Intervention / Treatment
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* Drug: Ribociclib
* Drug: Fulvestrant
* Drug: Anastrozole
* Drug: Letrozole
* Drug: Exemestane


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria to Collect Optional Correlative Blood and Tissue at 1st Recurrence Written informed consent (stage I) and HIPAA authorization for release of personal health information obtained prior to performing any study-specific procedures. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Male or female age ≥ 18 years at the time of consent. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. Patient has locoregional recurrence of breast cancer: locoregional recurrence is defined as invasive recurrence in the ipsilateral breast, axilla, regional nodes, and chest wall. Inclusion Criteria for Treatment Phase: Subject must meet all of the following applicable inclusion criteria to participate in this study: Written informed consent (stage II/ main consent) and HIPAA authorization for release of personal health information obtained prior to performing any study-specific screening procedures. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Male or female age ≥ 18 years at the time of consent. NOTE: Both pre- and post-menopausal women are eligible. Pre-menopausal status is defined as: --Age <60 and amenorrhea for the last 12 or more months(in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range. ECOG Performance Status of 0-1 within 28 days prior to registration. If patient is receiving tamoxifen or toremifene, a washout period of 28 days prior to registration is required. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. Patients have had adequate local treatment for locoregional recurrence (LRR) of breast cancer. Locoregional recurrence is defined as recurrence in the ipsilateral breast, axilla, regional lymph nodes, and chest wall. Local treatment is defined as surgery and/or radiation therapy if indicated. Adequate local therapy is surgery with negative microscopic margins. Radiation therapy is mandated for patients with microscopically involved margins and recommended for all patients who had not received radiotherapy as part of their primary treatment. Patients who have distant metastatic disease will not be eligible. Prior treatment with neo- adjuvant and adjuvant chemotherapy and ET is allowed. Patients must enroll within 6 months of the last local treatment, surgery or radiation, whichever occurred last. Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET. Subjects who have already started adjuvant ET within 3 months prior to registration are allowed. Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 28 days prior to registration. Hematological Absolute Neutrophil Count (ANC): ≥ 1.5 x 109/L Platelets: ≥ 100 x 109/L Hemoglobin (Hgb): ≥ 9.0 g/dL Renal ---Estimated glomerular filtration rate (eGFR): ≥ 30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula Hepatic Bilirubin: < upper limit of normal (ULN) except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN Aspartate aminotransferase (AST): ≤ 2.5 × ULN except for patients with liver metastasis, who are only included if the AST is < 5 × ULN Alanine aminotransferase (ALT): ≤ 2.5 × ULN except for patients with liver metastasis, who are only included if the ALT is < 5 × ULN Coagulation ---International Normalized Ratio (INR) : ≤ 1.5 × ULN (unless is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug) Electrolytes ---Potassium, Magnesium, and Total Calcium (corrected for serum albumin): Within normal limits or corrected to within normal limits with supplements. Standard 12-lead ECG values defined as QTcF interval at screening < 450 msec (QT interval using Fridericia's correction) Resting heart rate 50-90 bpm (determined from the ECG) Females of childbearing potential who are sexually active with a male able to father a child must have a negative pregnancy test (serum or urine) within 14 days prior to registration and must be willing to use a highly effective method of contraception that does not contain estrogen and/or progesterone. See the protocol for definition of childbearing potential. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Ability to swallow and retain oral medication. Exclusion Criteria for Treatment Phase: Subjects meeting any of the criteria below may not participate in the study: Patient with a known hypersensitivity to any of the excipients of ribociclib. Patient who has received prior CDK4/6 inhibitor for recurrent disease. Patients who received a CDK4/6 inhibitor in the adjuvant setting may participate if they have been off therapy for at least 1 year prior to diagnosis of recurrent disease. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects. Pregnant or breastfeeding or planning to become pregnant during the trial (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial. Patients with distant metastases of breast cancer beyond regional lymph nodes as defined by AJCC (8th edition). Treatment with any investigational drug within 30 days prior to registration or participation in any other type of medical research judged not to be scientifically or medically compatible with this study. Enrollment or planned enrollment in another study that does not involve an investigational drug will be allowed at the discretion of the treating investigator. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol: (e.g., chronic pancreatitis, chronic active hepatitis, HIV, active untreated or uncontrolled fungal, bacterial or viral infections, etc.) Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry Documented cardiomyopathy Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug) Inability to determine the QTcF interval Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third-degree AV block) Systolic Blood Pressure (SBP) >160 or <90 mmHg Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1: Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pummelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5, Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular). Patient with an uncontrolled psychiatric condition that, in the investigator's judgment, may cause unacceptable safety risks, impede research integrity and compliance, or interfere with the objectives of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Group<br>The drug ribociclib will be taken orally at a dose of 600 mg daily for 21 days out of a 28-day cycle. Ribociclib will be used in combination with ET per physician choice. Physician's choice of endocrine therapy includes: 500 mg of fulvestrant received intramuscularly. This will be taken on Day 1 and Day 15 of Cycle 1 and on Day 1 of Cycle 2 and beyond. 1 mg of anastrozole taken orally daily of the 28 day cycle. 2.5 mg of letrozole taken orally daily of the 28 day cycle. 25 mg of exemestane taken orally daily of the 28 day cycle. Concomitant use with tamoxifen is not allowed. Premenopausal subjects must also be treated with ovarian suppression according to institutional standards or have undergone bilateral oophorectomy. | Drug: Ribociclib<br>* 600 mg orally once daily Days 1-21 (28 day Cycle)<br>* Other names: Kisqali;Drug: Fulvestrant<br>* 500 mg intramuscularly on Day 1 and 15 of Cycle 1 then Day 1 of Cycle 2+<br>* Other names: Faslodex;Drug: Anastrozole<br>* 1 mg orally once daily<br>* Other names: Arimidex;Drug: Letrozole<br>* 2.5 mg orally once daily<br>* Other names: Femara;Drug: Exemestane<br>* 25 mg orally once daily<br>* Other names: Aromasin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence Free Survival (RFS) | Estimate subsequent recurrence-free survival (RFS) at 3 years for ribociclib when administered with ET (AIs or fulvestrant). RFS is defined as interval from registration until invasive or DCIS recurrence in the ipsilateral breast or locoregionally, invasive recurrence at a distant site, or death from breast cancer or any other cause, whichever occurs first. The censoring time is the completion of study at 6 years (3 years of patient accrual and 3 years of follow up time). The RFS at 3 years will be also treated as the primary endpoint in the power and sample size calculation. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distant Metastasis-Free Survival | Estimate the Distant metastasis-free survival. Distant metastasis-free survival is defined as interval from registration to any recurrence or death from any cause. | 3 years | 
| Overall Survival (OS) | Estimate the OS. OS is defined as interval from registration to death from any cause. | 3 years | 
| Assess adverse events | Evaluate safety and tolerability of the study regimen. Safety will be evaluated by recording frequency and severity of adverse events; grading of toxicities will be done using the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE v5). | 3 months |