Ribociclib and Letrozole in Treating Patients With Relapsed ER Positive Ovarian, Fallopian Tube, Primary Peritoneal, or Endometrial Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2 Trial of Ribociclib (LEE011) and Letrozole in ER Positive Relapsed Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Carcinomas, and Endometrial Cancers.

Conditions
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Estrogen Receptor Positive, Postmenopausal, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Recurrent Uterine Corpus Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Letrozole
* Drug: Ribociclib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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 and letrozole)<br>Patients receive ribociclib PO daily and letrozole PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Letrozole<br>* Given PO<br>* Other names: Femara;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 |
| --- | --- | --- |
| Percentage of Patients Alive and Free of Progression at 12 Weeks (PFS12) | The percentage of patients who are progression-free at 12 weeks (PFS12) is defined as patients who are alive and progression free at 12 weeks. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | At 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression free survival (PFS) is defined as the time from the date of registration to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | From registration to the first of either disease progression or death from any cause, assessed up to 2 years | 
| Overall Survival | Overall survival time is defined as the time from registration to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | From registration to death from any cause, assessed up to 2 years | 
| The Number of Patients With CA-125 Response | The number of patients with CA-125 response, defined as a 50% or greater reduction in baseline CA-125. | Up to 2 years | 
| The Number of Patients With Confirmed Response (Complete Response or Partial Response) | The number of patients with confirmed response (complete response or partial response) using Response Evaluation Criteria in Solid Tumors version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 2 years | 
| The Number of Treatment-related Grade 3 or Higher Adverse Events | The number of treatment-related Grade 3 or higher adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | Up to 30 days post-treatment |