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.
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)
