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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01797523
Recruitment Status : Active, not recruiting
First Posted : February 22, 2013
Last Update Posted : January 27, 2020
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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.

Condition or disease Intervention/treatment Phase
Endometrial Cancer Drug: Metformin Drug: Letrozole Drug: Everolimus Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Single-Arm Study of RAD001 (Everolimus), Letrozole, and Metformin in Patients With Advanced or Recurrent Endometrial Carcinoma
Actual Study Start Date : October 7, 2013
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Letrozole + Metformin + RAD001

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
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.

Drug: Letrozole
2.5 mg tablet by mouth once daily in a 28 day cycle.
Other Name: Femara

Drug: Everolimus
10 mg by mouth once daily in a 28 day cycle.
Other Names:
  • Afinitor
  • Zortress
  • RAD001

Primary Outcome Measures :
  1. Clinical Benefit Rate (CBR) [ Time Frame: 8 weeks ]
    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).

Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: 6 months ]
    Survival determined by measuring the time from study entry (1st treatment) to progression (PFS) or death (OS). Progression-free survival (PFS) and overall survival (OS) estimated with the Kaplan-Meier product-limit estimator.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 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
  2. 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
  3. Prior radiation therapy of any kind is allowed
  4. 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
  5. 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.
  6. Patients must be off all other anti-tumor therapies (including immunologic or hormonal agents) for at least four weeks prior to study registration.
  7. Age >/= 18 years
  8. GOG performance status </= 2
  9. Adequate bone marrow function as shown by: ANC >/= 1.5 x 10^9/L, Platelets >/= 100 x 10^9/L, Hb >9 g/dL
  10. 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
  11. Signed informed consent
  12. Prior treatment with letrozole is allowed.

Exclusion Criteria:

  1. Patients who have uterine sarcomas, carcinosarcomas, any serous histology or pure clear cell carcinomas
  2. 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.)
  3. 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
  4. Prior treatment with any investigational drug within the preceding 4 weeks
  5. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed
  6. 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.
  7. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  8. Other malignancies within the past 3 years except for basal or squamous cell carcinomas of the skin.
  9. 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
  10. 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
  11. 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)
  12. Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus).
  13. Patients with a known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients
  14. History of noncompliance to medical regimens
  15. Patients unwilling to or unable to comply with the protocol.
  16. Patients with isolated recurrences (vaginal, pelvic, or paraaortic) that are amenable to potentially curative treatment with radiation therapy or surgery.
  17. 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 IV contrast to minimize risk of lactic acidosis.
  18. Patients who have hypoglycemia with a value of </= 50 mg/dL

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01797523

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United States, Florida
Sacred Heart Health Systems
Pensacola, Florida, United States, 32504
United States, New Jersey
MD Anderson Cooper Cancer Center
Voorhees, New Jersey, United States, 08043
United States, Texas
Memorial City Medical Center
Houston, Texas, United States, 77024
Lyndon B Johnson General Hospital
Houston, Texas, United States, 77026
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
The Woman's Hospital of Texas
Houston, Texas, United States, 77054
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
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Principal Investigator: Pamela Soliman, MD M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT01797523    
Other Study ID Numbers: 2012-0543
NCI-2013-00960 ( Registry Identifier: NCI CTRP )
First Posted: February 22, 2013    Key Record Dates
Last Update Posted: January 27, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by M.D. Anderson Cancer Center:
Endometrial cancer
Advanced or Recurrent Endometrial Carcinoma
Additional relevant MeSH terms:
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Endometrial Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Genital Diseases, Female
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists