This phase II trial studies how well ribociclib and letrozole work in treating patients with estrogen receptor (ER) positive ovarian, fallopian tube, primary peritoneal, or endometrial cancer that has returned (come back) after a period of improvement. Ribociclib may stop the growth of tumor cells by blocking some enzymes needed for cell growth. Cancer cells that are estrogen receptor positive may need estrogen to grow. Letrozole lowers the amount of estrogen made by the body and this may stop the growth of tumor cells that need estrogen to grow. Giving ribociclib together with letrozole may be an effective treatment in patients with ovarian, fallopian tube, primary peritoneal, or endometrial cancer.

PRIMARY OBJECTIVES:

I. Demonstrate if the combination of letrozole and ribociclib (LEE011) leads to a higher percentage of patients who are progression free at 12 weeks (PFS 12) as compared with that observed in prior studies with single agent letrozole.

SECONDARY OBJECTIVES:

I. Demonstrate if the combination of letrozole and ribociclib (LEE011) leads to a higher cancer antigen 125 (CA-125) response rate in patients with relapsed ER positive ovarian cancers and endometrial cancers as compared to that observed in previously reported single agent letrozole studies.

II. Median progression-free survival (PFS), overall survival (OS), the confirmed response rate, and adverse events.

TERTIARY OBJECTIVES:

I. Identify molecular biomarkers associated with a response to treatment with letrozole and ribociclib (LEE011) (in patients with relapsed ovarian carcinomas and endometrial cancers).

II. Develop patient derived xenograft (PDX) avatars on tumors from participants for possible future translational study evaluating a potential correlation between responses in the PDX model to patients' responses.

OUTLINE:

Patients receive ribociclib orally (PO) daily and letrozole PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 2 years.

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent document
• Post-menopausal
• Histologically confirmed recurrent ovarian, fallopian tube or primary peritoneal carcinoma or endometrial cancer in post-menopausal women; NOTE: pure clear cell and pure mucinous carcinomas are ineligible; platinum sensitive, platinum resistant and platinum refractory disease are eligible; no limitations in the number of prior regimens
• Patient has disease amenable to biopsy and is agreeable to undergo a biopsy; NOTE: under unusual circumstances, submission of ascites material may be acceptable if a biopsy is not possible; this exception will require approval by one of the study principal investigators
• Willing to provide tissue samples for ER and retinoblastoma (RB) staining
• Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) criteria
• Tumors must stain positive for estrogen receptor (>= 10%) by immunohistochemistry (IHC)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 9.0 g/dL
• Total bilirubin =< 1 x upper limit of normal (ULN); or total bilirubin =< 3.0 x ULN with direct bilirubin =< 1.5 x ULN in patients with well-documented Gilbert's syndrome
• Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (=< 5 x ULN in patients with liver metastasis)
• International normalized ratio (INR) =< 2
• Creatinine =< 1.5 mg/dL
• Potassium =< ULN (or corrected to =< ULN with supplements prior to registration)
• Total calcium (corrected for serum calcium) =< ULN (or corrected to =< ULN with supplements prior to registration)
• Magnesium =< ULN (or corrected to =< ULN with supplements prior to registration)
• Sodium =< ULN (or corrected to =< ULN with supplements prior to registration)
• Phosphorus =< ULN (or corrected to =< ULN with supplements prior to registration)
• Ability to swallow study medication
• Provide informed written consent
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Willing to provide tissue samples for correlative research purposes

Exclusion Criteria:

• Patients who have central nervous system (CNS) involvement unless they meet ALL of the following criteria:

  • >= 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

• 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.)

• Clinically significant, uncontrolled heart disease or cardiac repolarization abnormalities and/or recent events 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
  • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
  • Documented cardiomyopathy
  • Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
  • Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third-degree AV block) long QT syndrome or family history of long QT syndrome
  • Idiopathic sudden death or congenital long QT syndrome
  • 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 (corrected QT interval [QTcF], using Fridericia's correction)
  • Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening
  • Bradycardia (heart rate < 50 at rest), by electrocardiogram (ECG) or pulse, at screening
  • Tachycardia (heart rate > 110 at rest), by ECG or pulse at screening

• Inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 450 msec (using Fridericia's correction); NOTE: all as determined by screening ECG

• 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 cytochrome P450 family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges or that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5 or herbal preparations/medications or dietary supplements

• Patient is currently receiving or has received systemic corticosteroids within =< 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: 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 received radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom >= 30% of the bone marrow was irradiated

• Patient has had major surgery =< 14 days prior to registration or has not recovered from major side effects (tumor biopsy is not considered as major surgery)

• Known to be human immunodeficiency virus (HIV) positive (testing not mandatory)

• Patient has a known hypersensitivity to any of the excipients of ribociclib

• Patient is currently receiving warfarin or other Coumarin-derived anticoagulant for treatment, prophylaxis or otherwise; NOTE: therapy with apixaban, dabigatran, heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed

• Participation in a prior investigational study within 30 days prior to enrollment or =< 5 half-lives of the investigational product, whichever is longer

• Patient has not recovered from all toxicities related to prior anticancer therapies to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade < 3 (exception to this criterion: patients with any grade of alopecia or neuropathy are allowed to enter the study)

• Patient with a Child-Pugh score B or C

• 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 significant small bowel resection)

• Prior therapy with ribociclib or an aromatase inhibitor (letrozole, anastrozole or exemestane)

• Patient has received systemic chemotherapy =< 3 weeks prior to registration