Everolimus and Letrozole in Treating Patients With Recurrent Hormone Receptor Positive Ovarian, Fallopian Tube, or Primary Peritoneal Cavity Cancer

Study Overview
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Brief Summary
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This pilot, phase II trial studies how well everolimus and letrozole work in treating patients with hormone receptor positive ovarian, fallopian tube, or primary peritoneal cavity cancer that has come back. Everolimus and letrozole may stop the growth of tumor cells by blocking some the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. Demonstrate that the combination of letrozole and everolimus leads to a higher percentage of patients who are free of progression at 12 weeks (PFS 12) as compared with that observed in a previously reported phase 2 trial of letrozole alone for relapsed ovarian carcinomas. SECONDARY OBJECTIVES: I. Cancer antigen (CA)-125 response, 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 everolimus in patients with relapsed ovarian carcinomas. II. Develop and determine if response rates to letrozole and everolimus in patient derived xenograft (PDX) avatars correlate to responses noted in the patients. OUTLINE: Patients receive everolimus orally (PO) once daily (QD) and letrozole PO QD 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 6 months for 2 years.

Official Title
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A Phase 2 Trial of Letrozole and Everolimus in Relapsed Hormone Receptor Positive Ovarian, Fallopian Tube or Primary Peritoneal Carcinomas

Conditions
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Ovarian Endometrioid Adenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Cystadenocarcinoma, Ovarian Serous Surface Papillary Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Ovarian Germ Cell Tumor, Recurrent Primary Peritoneal Carcinoma, Undifferentiated Ovarian Carcinoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed estrogen receptor positive (greater than 10%) recurrent ovarian, fallopian tube or primary peritoneal carcinoma in post-menopausal women; note: pure clear cell and pure mucinous carcinomas are ineligible; both 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 will require approval by one of the study principal investigators Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Absolute neutrophil count (ANC) >= 1500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin > 9.0 g/dL Total serum bilirubin =< 2 mg/dL Aspartate transaminase (AST) =< 2.5 x upper limit of normal (ULN) (=< 5 x ULN in patients with liver metastasis) International normalized ratio (INR) =< 2 Creatinine =< 1.5 x ULN Fasting serum cholesterol =< 300 mg/dL or =< 7.75 mmol/L and fasting triglycerides =< 2.5 x ULN; in case of any of these thresholds be exceeded, the patient can only be included after initiation of appropriate lipid lowering medications 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: Any of the following Pregnant women Nursing women Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including but not limited to any of the following that would limit compliance with study requirements: Ongoing or active severe infection Liver disease such as cirrhosis Decompensated liver disease Symptomatic congestive heart failure (New York heart Association class III or IV) Unstable angina pectoris, serious uncontrolled cardiac arrhythmia, myocardial infarction =< 6 months prior to registration Known severely impaired lung function (spirometry and diffusing capacity of the lung for carbon monoxide [DLCO] 50% or less of normal and oxygen [O2] saturation 88% or less at rest on room air) Active bleeding diathesis Psychiatric illness Known to be human immunodeficiency virus (HIV) positive Receiving any other investigational agent =< 4 weeks prior to registration which would be considered as treatment for the primary neoplasm Other active malignancy =< 3 years prior to registration; exceptions: non-melanotic skin cancer or carcinoma-in-situ of the cervix, uterus or breast; note: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer Patients currently receiving anticancer therapies or who have received anticancer therapies =< 4 weeks prior to registration (including chemotherapy, radiation therapy, antibody based therapy, etc.) Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus Uncontrolled diabetes mellitus as defined by hemoglobin (Hb)A1c > 8% despite adequate therapy; note: patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary Chronic treatment with corticosteroids or other immunosuppressive agents; note: topical or inhaled corticosteroids are allowed Patients who have received live attenuated vaccines =< 1 week prior to registration and during the study; note: patient should also avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines History of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study Prior therapy with everolimus or an aromatase inhibitor Known brain metastasis Active and chronic viral hepatitis (i.e. quantifiable serum hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive hepatitis B virus surface antigen [HBsAg], or quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA] in serum)

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 (everolimus and letrozole)<br>Patients receive everolimus PO QD and letrozole PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Everolimus<br>* Given PO<br>* Other names: RAD001;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Letrozole<br>* Given PO<br>* Other names: Femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Alive and Progression Free Survival at 12 Weeks | The percentage of PFS12 successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the exact binomial method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Disease progression in evaluable patients will be defined as one or more of the following: Any new disease and/or clear progression of evaluable disease; OR 2 fold elevation in CA-125 from its lowest level (either initial level or nadir, whichever is lowest, since study enrollment) combined with CA-125 elevation confirmed by re-assay at any time. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CA-125 Response | CA-125 response: The key secondary endpoint of the study will be a CA-125 response, defined as a 50% or greater reduction in baseline CA-125. The null hypothesis will be set at CA-125 response rate of 8.3%, based on the response of single agent letrozole, as reported by Bowman et al (7). The treatment of letrozole and everolimus will be considered promising, based on CA-125, if the observed CA-125 response rate is 30% or more. | Up to 2 years | 
| Confirmed Response Rate, Estimated Using RECIST 1.1 Criteria | A confirmed tumor response is defined to be either a complete response or partial response noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. A complete response (CR) in evaluable patients will be defined as: Disappearance of any sign of (evaluable) disease, AND Normalization of CA-125; if CA-125 normalizes, it should be confirmed at any time. A partial response (PR) in evaluable patients will be defined as: Decrement in CA-125 by >50%, and Improvement in any additional evaluable disease (if present) as assessed by the enrolling physician. | Up to 24 weeks | 
| Number of Participants Experiencing Adverse Events | The number of patients with adverse events.The maximum grade for each type of adverse event (AE) will be recorded for each patient, and frequency tables will be reviewed to determine AE patterns. These tables are reported in the adverse events section of this report. | Up to 30 days post-treatment | 
| Overall Suravival(OS) | OS will be estimated using the method of Kaplan-Meier. | Time from registration to death from any cause, assessed up to 2 years | 
| Progression Free Survival (PFS) | PFS will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Disease progression in evaluable patients will be defined as one or more of the following: Any new disease and/or clear progression of evaluable disease; OR 2 fold elevation in CA-125 from its lowest level (either initial level or nadir, whichever is lowest, since study enrollment) combined with CA-125 elevation confirmed by re-assay at any time. | Time from registration to the first of either disease progression or death from any cause, assessed up to 2 years |