A Phase II, Single-Arm Study of RAD001 (Everolimus), Letrozole, and Metformin in Patients With Advanced or Recurrent Endometrial Carcinoma

NCT01797523 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: 2012-0543NCI-2013-00960
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 6

Brief Summary

The goal of this clinical research study is to learn if the combination of everolimus, letrozole, and metformin can help to control recurrent or progressive endometrial cancer. The safety of this drug combination will also be studied. Everolimus is designed to block a protein inside cancer cells that is involved in cancer growth. Letrozole is designed to block a protein from making estrogen. This may interfere with the growth of cancer cells. Metformin is commonly used to control blood sugar levels in patients with diabetes. It is designed to lower insulin levels, which may slow or stop the growth of endometrial cancer cells.

Conditions

Endometrial Cancer

Keywords

Endometrial cancer; Advanced or Recurrent Endometrial Carcinoma; Metformin; Letrozole; Femara; Everolimus; Afinitor; Zortress; RAD001

Outcome Measures

Primary Outcomes (1)

• Clinical Benefit Rate (CBR)

  Clinical benefit rate (CBR) determined by combining the complete response rate, partial response rate, and stable disease rate. Response evaluated by repeat imaging (CT or MRI) using RECIST 1.1 at the completion of the second cycle (8 weeks + 7 days of treatment).

  8 weeks

Secondary Outcomes (1)

• Progression-Free Survival (PFS)

  6 months

Study Arms (1)

Letrozole + Metformin + RAD001

EXPERIMENTAL

Patients have a 7-10 day lead in period where they take Metformin alone. The starting dose of Metformin 500 mg by mouth daily for 4 days and then increased to 500 mg by mouth twice a day. Everolimus and Letrozole added and considered the start of Cycle #1. Everolimus administered by mouth as once daily dose of 10 mg. Letrozole 2.5 mg tablet by mouth once daily. The oral dose of Everolimus should be taken together with the daily dose of Letrozole 2.5mg.

Drug: Metformin; Drug: Letrozole; Drug: Everolimus

Interventions

Metformin DRUG

500 mg by mouth daily for 4 days on Days 1 - 4 of Cycle 0 and then 2 times a day (about 12 hours apart) every day after that. Metformin taken for 7 - 10 days in Cycle 0 before Cycle 1 begins.

Letrozole + Metformin + RAD001

Letrozole DRUG

2.5 mg tablet by mouth once daily in a 28 day cycle.

Also known as: Femara

Letrozole + Metformin + RAD001

Everolimus DRUG

10 mg by mouth once daily in a 28 day cycle.

Also known as: Afinitor, Zortress, RAD001

Letrozole + Metformin + RAD001

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 RECIST 1.1 defined as at least one target lesion that can be accurately measured in at least one dimension (\>/=10mm 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 (CT or 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 total 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.
• Age \>/= 18 years
• GOG performance status \</= 2
• Adequate bone marrow function as shown by: ANC \>/= 1.5 x 10\^9/L, Platelets \>/= 100 x 10\^9/L, Hb \>9 g/dL
• Adequate liver function as shown by: a. serum bilirubin \</= 1.5 x ULN b. ALT and AST \</= 2.5x ULN (\</= 5x ULN in patients with liver metastases); Adequate renal function:serum creatinine \< 1.4mg/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.

You may not qualify if:

• 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, 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: a. Symptomatic congestive heart failure of New York heart Association Class III or IV; b. 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; c. Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air; d. Active (acute or chronic) or uncontrolled severe infections
• CONTINUED FROM 10 - e. 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. HBV DNA and HCV RNA 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; f. A known history of HIV seropositivity; g. 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); h. 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 an 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.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Novartis: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (6)

Sacred Heart Health Systems

Pensacola, Florida, 32504, United States

Location

MD Anderson Cooper Cancer Center

Voorhees Township, New Jersey, 08043, United States

Location

Memorial City Medical Center

Houston, Texas, 77024, United States

Location

Lyndon B Johnson General Hospital

Houston, Texas, 77026, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

The Woman's Hospital of Texas

Houston, Texas, 77054, United States

Location

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Endometrial Neoplasms

Interventions

Metformin; Letrozole; Everolimus

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sirolimus; Macrolides; Lactones

Study Officials

• Pamela Soliman, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2013
• First Posted: February 22, 2013
• Study Start: October 7, 2013
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): October 31, 2027
• Last Updated: November 6, 2025

Record last verified: 2025-11

Locations

US (6)