Everolimus, Letrozole, and Metformin Hydrochloride in Treating Patients with Advanced or Recurrent Endometrial Cancer

Status: Closed to Accrual

Description

This phase II trial studies how well everolimus, letrozole, and metformin hydrochloride work in treating patients with endometrial cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment or has come back. Everolimus, letrozole, and metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving everolimus with letrozole and metformin hydrochloride may be an effective treatment for endometrial cancer.

Eligibility Criteria

Inclusion Criteria

  • Patients must have histologically-confirmed advanced or recurrent endometrial carcinoma (endometrioid and mixed tumors, any grade) that is refractory to curative therapy or established treatments
  • Patients must have had no more than two prior chemotherapeutic regimens for recurrent management of endometrial carcinoma; chemotherapy administered in conjunction with primary radiation as a radio-sensitizer is not counted as a prior treatment for recurrent or advanced disease
  • Prior radiation therapy of any kind is allowed
  • All patients must have measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) defined as at least one target lesion that can be accurately measured in at least one dimension (>= 10 mm longest dimension to be recorded; lymph nodes must be >= 15 mm per short axis); each lesion must be > 20 mm when measured by palpation or conventional imaging techniques (computed tomography [CT] or magnetic resonance imaging [MRI]-based on primary physician preference) or > 10 mm with spiral CT scan; measurable lesions must be at least 2 times the slice thickness in millimeters; tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented; ascites and pleural effusions are not considered measurable disease; if the measurable disease is confined to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology
  • Patients must not be of child-bearing potential; patients are considered not of child-bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal for greater than 12 months; patients in whom ovaries are present and were not previously menopausal at the time of hysterectomy, should have a serum estradiol < 10 pm/mL to confirm ovarian senescence
  • Patients must be off all other anti-tumor therapies (including immunologic or hormonal agents) for at least four weeks prior to study registration
  • Gynecologic Oncology Group (GOG) performance status =< 2
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Hemoglobin (Hb) > 9 g/dL
  • Serum bilirubin =< 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN in patients with liver metastases)
  • Serum creatinine < 1.4 mg/dL (per manufacturer, metformin is contraindicated in the presence of renal dysfunction defined as a serum creatinine > 1.4 mg/dL in females and in patients with abnormal clearance)
  • Fasting serum cholesterol =< 240 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
  • Signed informed consent
  • Prior treatment with letrozole is allowed

Exclusion Criteria

  • Patients who have uterine sarcomas, carcinosarcomas, any serous histology or pure clear cell carcinomas
  • Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
  • Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
  • Prior treatment with any investigational drug within the preceding 4 weeks
  • Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
  • Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period; close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette–Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
  • Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  • Other malignancies within the past 3 years except for basal or squamous cell carcinomas of the skin
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: symptomatic congestive heart failure of New York Heart Association class III or IV; unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease; severely impaired lung function as defined as spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or oxygen (O2) saturation that is 88% or less at rest on room air; active (acute or chronic) or uncontrolled severe infections; liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C); note: a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection; a known history of human immunodeficiency virus (HIV) seropositivity; impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection); patients with an active, bleeding diathesis
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes; (women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus)
  • Patients who have received prior treatment with a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus, temsirolimus, everolimus)
  • Patients with a known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients
  • History of noncompliance to medical regimens
  • Patients unwilling to or unable to comply with the protocol
  • Patients with isolated recurrences (vaginal, pelvic, or para-aortic) that are amenable to potentially curative treatment with radiation therapy or surgery
  • Patients with acute or chronic metabolic acidosis, lactic acidosis, or ketoacidosis; Note: during the study, metformin must be discontinued for 24 hours before and 48 hours after imaging involving intravenous (IV) contrast to minimize risk of lactic acidosis
  • Patients who have hypoglycemia with a value of =< 50 mg/dL

Locations & Contacts

See trial information on ClinicalTrials.gov for a list of participating sites.

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the efficacy of RAD001 (everolimus) in combination with letrozole and metformin (metformin hydrochloride) in patients with recurrent or progressive endometrial carcinoma.

SECONDARY OBJECTIVES:

I. To determine the median duration of progression-free survival and overall survival in patients with recurrent or progressive endometrial adenocarcinoma treated with RAD001, letrozole, and metformin.

II. To determine the frequency and severity of toxicities associated with RAD001, letrozole, and metformin in this cohort of patients.

III. To determine the effects of RAD001, letrozole, and metformin on tissue deoxyribonucleic acid (DNA) biomarkers of women with endometrial cancer and to determine response to treatment based on phosphatase and tensin homolog (PTEN) expression and/or v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and other mutation status.

OUTLINE:

Patients may receive metformin orally (PO) once daily (QD) for 7-10 days. Beginning in course 1, patients receive everolimus PO QD, letrozole PO QD, and metformin hydrochloride PO twice daily (BID) for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Pamela Therese Soliman

Trial IDs

Primary ID 2012-0543
Secondary IDs NCI-2013-00960, RAD001CUS195T
Clinicaltrials.gov ID NCT01797523