Summary

This randomized, phase II trial studies how well fulvestrant or exemestane with or without ribociclib works in treating patients with hormone receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer that has progressed after treatment with an aromatase inhibitor or cyclin-dependent kinase 4/6 inhibitor (recurrent), cannot be removed by surgery (unresectable), or has spread to other parts of the body (metastatic). Hormone therapy using fulvestrant or exemestane may fight breast cancer by blocking the use of estrogen by the tumor cells or reducing the amount of estrogen made by the body. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving fulvestrant or exemestane with ribociclib may be an effective treatment for patients with breast cancer.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the progression-free survival (PFS) of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibitor in patients with hormone receptor positive (HR+), HER2- breast cancer.

SECONDARY OBJECTIVES:
I. To assess the overall response rate (ORR = complete + partial response rate) and clinical benefit rate (CBR= ORR + stable disease rate at >= 24 weeks of follow up) in the study population in both arms of the trial, post-randomization.
II. To assess the PFS, ORR, CBR, and safety of ribociclib with an aromatase inhibitor in patients with metastatic or unresectable HR+ HER2- breast cancer.
III. To explore differences in clinical outcome (PFS, ORR, CBR) in patients receiving an aromatase inhibitor plus ribociclib versus (vs.) palbociclib vs. abemaciclib (scenario 1), both prior to randomization and then after continuation of CDK4/6 inhibition.
IV. To evaluate the rates of adverse events and tolerability of the combination of fulvestrant or exemestane with and without ribociclib.
V. To explore potential predictive tumor and blood-based predictive biomarkers.
VI. To assess the impact of the combination therapy vs. fulvestrant or exemestane alone on patient reported global health assessment and quality of life.

OUTLINE: Patients are assigned to Scenario 1 or Scenario 2.

Scenario 1: Patients receive ribociclib orally (PO) once daily (QD) on days 1-21 and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression are then assigned to Scenario 2.

Scenario 2: Patients are randomized to 1 of 2 arms.

Arm A: Patients receive ribociclib PO QD on days 1-21. Patients also receive fulvestrant intramuscularly (IM) every 2 weeks for 6 weeks then every 4 weeks or exemestane PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arm B: Patients receive placebo PO QD on days 1-21 and fulvestrant IM or exemestane PO as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 12 weeks thereafter.

Eligibility

1. Men or women at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of the breast with unresectable or metastatic disease.
2. Most recent tumor biopsy or surgical resection specimen must be either estrogen receptor (ER) positive, progesterone receptor (PgR) positive, or both, as defined by immunohistochemistry (IHC) >= 1% (as per the American Society of Clinical Oncology-College of American Pathologists [ASCO-CAP] guidelines)
3. Human epidermal growth factor receptor 2 (HER2)-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0 or 1+; if IHC is 2+ (i.e. indeterminate), a negative in situ hybridization (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], or silver in situ hybridization [SISH]) test is required by local laboratory testing; (as per the ASCO-CAP guidelines)
4. Postmenopausal status or receiving ovarian ablation with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin * Postmenopausal status is defined by any one of the following criteria: ** Prior bilateral oophorectomy ** Age >= 60 years ** Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in the postmenopausal range per local normal * If the patient does not meet criteria for postmenopausal status but is receiving ovarian ablation therapy with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin, the patient is eligible for this study, provided that the GnRH agonist is started at least 2 weeks prior to cycle 1 day 1 (C1D1) of anti-estrogen therapy
5. Have evidence of measurable or unmeasurable disease
6. Eastern Cooperative Group (ECOG) performance status of 0 or 1
7. Scenario 1: No prior cdk 4/6 inhibitor (Closed to Accrual); if patient has not previously received letrozole, letrozole will be supplied by Novartis; if previously progressed on letrozole, another aromatase inhibitor that the patient has not previously received is allowed, per standard of care (anastrozole or exemestane, not supplied by study); ribociclib will be supplied by Novartis; if patient has previously received letrozole, anastrozole, and exemestane, (s)he is not eligible; for scenario 1, patients are allowed to have started the aromatase inhibitor within 4 consecutive weeks prior to protocol registration; for instance, it is acceptable for patient who will be treated with letrozole in scenario #1, to have started letrozole within 4 consecutive weeks prior to protocol registration; no prior fulvestrant allowed
8. Scenario 2: the patient must have received an aromatase inhibitor (letrozole, arimidex, exemestane) or tamoxifen or fulvestrant plus palbociclib as standard of care or received a CDK4/6 inhibitor (palbociclib or ribociclib or abemaciclib), and demonstrated evidence of disease progression; if the patient was enrolled in a randomized clinical trial involving ribociclib or abemaciclib or palbociclib (such as the MONALEESA or PALOMA series of trials), then it must be known after study discontinuation and unblinding that the patient received the investigational drug and not placebo; ribociclib or abemaciclib or palbociclib can also be given as standard of care; documentation of progression and duration of response on aromatase inhibitor or tamoxifen plus CDK 4/6 inhibitor should be provided whenever possible; if patient received prior fulvestrant, exemestane must be the hormone therapy backbone in the randomization; if patient received prior exemestane, fulvestrant must be the hormone therapy backbone in the randomization; if neither has been administered, selection of fulvestrant or exemestane in the randomization will be per investigator discretion
9. Absolute neutrophil count >= 1500 per microliter
10. Platelets >= 75,000 per microliter
11. Hemoglobin level >= 8.0 gm/dL on screening complete blood count
12. Potassium and total calcium (corrected only in the case of hypoalbuminemia) within normal limits of the local laboratory (screening values can be rechecked after electrolyte repletion and before the first dose of study medication, if necessary)
13. Serum creatinine level =< 1.5 mg/dL or estimated glomerular filtration rate >= 50 mL/min
14. In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 x the upper limit of normal (ULN); if the patient has liver metastases, ALT and AST should be < 5 x ULN
15. Total bilirubin =< 1.5 x ULN; (in patients with well documented Gilbert’s syndrome, total bilirubin =< 3 x ULN with direct bilirubin within normal range)
16. International normalized ratio (INR) =< 1.5
17. Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization obtained from the subject/legal representative prior to performing any protocol-related procedures
18. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
19. Must be able to swallow ribociclib and oral aromatase inhibitor, such as letrozole or exemestane