Overview

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.

Eligibility

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.