Estrogen Receptor Positive, Postmenopausal, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Recurrent Uterine Corpus Carcinoma
Conditions
Brief summary
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
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLetrozole
Given PO
DRUGRibociclib
Given PO
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Alive and Free of Progression at 12 Weeks (PFS12) | At 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From registration to death from any cause, assessed up to 2 years | 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. |
| Progression-free Survival | From registration to the first of either disease progression or death from any cause, assessed up to 2 years | 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. |
| The Number of Patients With CA-125 Response | Up to 2 years | The number of patients with CA-125 response, defined as a 50% or greater reduction in baseline CA-125. |
| The Number of Patients With Confirmed Response (Complete Response or Partial Response) | Up to 2 years | 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 |
| The Number of Treatment-related Grade 3 or Higher Adverse Events | Up to 30 days post-treatment | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Creation of Patient Derived Xenograft Models for Future Translational Experiments | 28 days following treatment initiation | Xenograft will be created on each patient. For patient derived xenograft experiments, response to therapy will be based on tumor volumes measured by ultrasound. Tumor growth curves will be plotted graphically and notated to indicate the outcome status of the originating patients. End of study tumor volumes will be correlated with outcome status of the originating patient as well. |
| Molecular Biomarkers Associated With a Response to Treatment With Letrozole and Ribociclib | Baseline | Whether response rates to letrozole and ribociclib in patient derived xenograft avatars correlate to responses noted in the patients will be determined. Fisher's Exact test will be used to measure the associations. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Ovarian Patients with ovarian, primary peritoneal, fallopian tube ACA receive ribociclib 400 mg PO daily and letrozole 2.5 mg PO daily on days 1-28. | 20 |
| Cohort B: Endometrial Patients with endometrial cancer receive ribociclib 400 mg PO daily and letrozole 2.5 mg PO daily on days 1-28. | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | Total | Cohort B: Endometrial | Cohort A: Ovarian |
|---|---|---|---|
| Age, Continuous | 64 years | 64.5 years | 61 years |
| ECOG Performance Score 0 | 23 Participants | 11 Participants | 12 Participants |
| ECOG Performance Score 1 | 13 Participants | 6 Participants | 7 Participants |
| ECOG Performance Score 2 | 4 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 20 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 38 Participants | 20 Participants | 18 Participants |
| Sex: Female, Male Female | 40 Participants | 20 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 20 | 10 / 20 |
| other Total, other adverse events | 18 / 20 | 19 / 20 |
| serious Total, serious adverse events | 6 / 20 | 10 / 20 |
Outcome results
Primary
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.
Time frame: At 12 weeks
Population: Per protocol analysis population: 19 evaluable patients per cohort
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Ovarian | Percentage of Patients Alive and Free of Progression at 12 Weeks (PFS12) | 52.6 percentage of patients |
| Cohort B: Endometrial | Percentage of Patients Alive and Free of Progression at 12 Weeks (PFS12) | 57.9 percentage of patients |
Secondary
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.
Time frame: From registration to death from any cause, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Ovarian | Overall Survival | 18.9 months |
| Cohort B: Endometrial | Overall Survival | 15.7 months |
p-value: 0.9127Log Rank
Secondary
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.
Time frame: From registration to the first of either disease progression or death from any cause, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Ovarian | Progression-free Survival | 2.8 months |
| Cohort B: Endometrial | Progression-free Survival | 5.4 months |
p-value: 0.5004Log Rank
Secondary
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.
Time frame: Up to 2 years
Population: Patients with CA-125 response data available with abnormal values at baseline are included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Ovarian | The Number of Patients With CA-125 Response | 4 Participants |
Secondary
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
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Ovarian | The Number of Patients With Confirmed Response (Complete Response or Partial Response) | 3 Participants |
| Cohort B: Endometrial | The Number of Patients With Confirmed Response (Complete Response or Partial Response) | 3 Participants |
Secondary
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
Time frame: Up to 30 days post-treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 3 : Febrile Neutropenia | 0 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 3 : Fatigue | 2 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 3 : Liver Enzymes | 3 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 4 : Lymphopenia | 1 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 3 : Lymphopenia | 5 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 3 : Leukopenia | 8 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 3 : Neutropenia | 6 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 4 : Leukopenia | 0 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 4 : Neutropenia | 0 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 4 : Febrile Neutropenia | 1 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 4 : Fatigue | 0 events |
| Cohort A: Ovarian | The Number of Treatment-related Grade 3 or Higher Adverse Events | Grade 4 : Liver Enzymes | 0 events |
Other Pre-specified
Creation of Patient Derived Xenograft Models for Future Translational Experiments
Xenograft will be created on each patient. For patient derived xenograft experiments, response to therapy will be based on tumor volumes measured by ultrasound. Tumor growth curves will be plotted graphically and notated to indicate the outcome status of the originating patients. End of study tumor volumes will be correlated with outcome status of the originating patient as well.
Time frame: 28 days following treatment initiation
Other Pre-specified
Molecular Biomarkers Associated With a Response to Treatment With Letrozole and Ribociclib
Whether response rates to letrozole and ribociclib in patient derived xenograft avatars correlate to responses noted in the patients will be determined. Fisher's Exact test will be used to measure the associations.
Time frame: Baseline