Ribociclib and Aromatase Inhibitor in Treating Older Participants With Hormone Receptor Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase IIA trial studies the side effects of ribociclib and aromatase inhibitor and how well they work in treating participants with hormone receptor positive breast cancer that has spread to other places in the body. Ribociclib and aromatase inhibitors may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the safety and tolerability of the combination of ribociclib and an aromatase inhibitor in adults age 70 or older with hormone receptor positive metastatic breast cancer. SECONDARY OBJECTIVES: I. To describe the full toxicity profile including all grades. II. To estimate the rate of worst grades of myelosuppression (neutropenia, leukopenia, thrombocytopenia, and anemia), neutropenic fever, gastrointestinal (GI) side effects (nausea, diarrhea, decreased appetite, vomiting, stomatitis), fatigue, neuropathy, and thromboembolism. III. To describe rates of dose reductions, dose holds, and hospitalizations. IV. To estimate objective response rate and clinical benefit rate as defined by modified Response Evaluation Criteria in Solid Tumors (RECIST) (1.1) criteria. V. To estimate median progression-free and overall survival. EXPLORATORY OBJECTIVES: I. To estimate the rate of adherence to ribociclib. II. To explore factors other than chronologic age that can affect toxicity rates as identified using a cancer-specific geriatric assessment. III. To describe the results of the Was It Worth It (WIWI) and the results of the Overall Treatment Utility (OTU) Questionnaires. OUTLINE: Participants receive ribociclib orally (PO) once daily (QD) on days 1-21 and aromatase inhibitor per treating investigator's discretion. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 days, then annually thereafter.

Official Title
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A Phase IIA Trial Assessing the Tolerability of Ribociclib in Combination With an Aromatase Inhibitor in Patients Aged 70 and Older With Hormone Receptor Positive Metastatic Breast Cancer

Conditions
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Estrogen Receptor and/or Progesterone Receptor Positive, HER2/Neu Negative, Stage IV Breast Cancer AJCC v6 and v7

Intervention / Treatment
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* Drug: Aromatase Inhibitor
* Other: Laboratory Biomarker Analysis
* Other: Pharmacokinetic Study
* Other: Questionnaire Administration
* Drug: Ribociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has signed the informed consent (ICF) prior to any study procedures being performed and is able to comply with protocol requirements Must be able to swallow ribociclib Age: >= 70 years at time of enrollment >= 70 to < 74 years, >= 75 years * NOTE: A minimum of 20 participants must be >= 75 years. The remaining 20 participants may be >= 70 to < 74 years OR >= 75 years Subjects must be able to communicate with the investigator and comply with the requirements of the study procedures Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer, HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+, and metastatic breast cancer First or second line endocrine therapy for metastatic disease. One prior line of chemotherapy for metastatic disease is allowed Absolute neutrophil count >= 1.5 x 10^9 /L, at screening Platelets >= 100 x 10^9 /L, at screening Hemoglobin >= 9.0 g/dL, at screening Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplement before the first dose of study medication: Sodium Potassium Magnesium Total calcium (corrected for serum albumin) Phosphorous Serum creatinine < 1.5 mg/dL or creatinine clearance >= 50 mL/min, at screening In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN); if the patient has liver metastases, ALT and AST < 5 x ULN, at screening Total bilirubin < ULN; or total bilirubin =< 3.0 x ULN or direct bilirubin =< 1.5 x ULN in patients with well-documented Gilbert's syndrome, at screening Patient with available standard 12-lead electrocardiogram (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs): Fridericia's corrected QT (QTcF) interval at screening < 450msec (using Fridericia's correction) Resting heart rate 50-90 beats per minute (bpm) Exclusion Criteria: Patient received prior treatment with any CDK4/6 inhibitor Patient has a known hypersensitivity to any of the excipients of ribociclib Patients with a prior malignancy diagnosed within 2 years AND with evidence of disease (except adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer) Patient with concurrent malignancy that is not clinically stable AND needs tumor-directed therapy Patients with central nervous system (CNS) involvement unless they meet ALL the following criteria: Untreated brain metastases (e.g., lesions < 1cm) not needing immediate local therapy Previously treated brain metastases not needing immediate local therapy At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following: History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening Documented cardiomyopathy 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). 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 hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication Inability to determine the QT interval on screening (QTcF, using Fridericia's correction) Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug: Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5 Herbal preparations/medications, dietary supplements Warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), newer anticoagulation agents such as direct factor Xa inhibitors, or fondaparinux is allowed 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 * The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular) Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., 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, active untreated or uncontrolled fungal, bacterial or viral infections, etc.) Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer Patient has had major surgery and/or radiotherapy within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery) Patient with a Child-Pugh score B or C Patient has not recovered from the acute effects of prior systemic therapy (until the toxicity resolves to either baseline or at least grade 1) except for residual alopecia or peripheral neuropathy Patient has a history of non-compliance to medical regimen or inability to grant consent Sexually active males unless they use a condom during intercourse while taking the drug and for 21 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Ages Eligible for Study
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Minimum Age: 70 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: Treatment (ribociclib, aromatase inhibitor)<br>Participants receive ribociclib orally PO QD on days 1-21 and aromatase inhibitor per treating investigator's discretion. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Aromatase Inhibitor<br>* Aromatase inhibitor per treating investigator's discretion<br>* Other names: Estrogen Synthetase Inhibitor;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacokinetic Study<br>* Correlative studies<br>* Other names: PK Study;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Ribociclib<br>* Given PO<br>* Other names: LEE011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 2 and Above Toxicities Attributed to Ribociclib | Number of participants with grade 2 and above toxicities attributed (possible, probable or definite) to ribociclib | Up to 30 days of last study drug, about 3 years and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Reductions |  | Up to 3.5 years | 
| Number of Participants With Dose Delays |  | Up to 3.5 years | 
| Number of Participants With Dose Discontinuations |  | Up to 3.5 years | 
| Objective Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Objective response rate (defined as complete response [CR] + partial response [PR]) as determined by RECIST criteria Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when the lymph node has decreased to less than 10mm in the short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | Up to 3.5 years | 
| Clinical Benefit Rate as Determined by RECIST | Clinical benefit rate (defined as CR+PR+ stable disease) as determined by RECIST Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when the lymph node has decreased to less than 10mm in the short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Up to 3.5 years |