A Phase II, Single-Arm Study of RAD001 (Everolimus), Letrozole, and Metformin in Patients With Advanced or Recurrent Endometrial Carcinoma
Information source: M.D. Anderson Cancer Center
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Endometrial Cancer
Intervention: Metformin (Drug); Letrozole (Drug); Everolimus (Drug)
Phase: Phase 2
Status: Recruiting
Sponsored by: M.D. Anderson Cancer Center Official(s) and/or principal investigator(s): Pamela Soliman, MD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center
Overall contact: Pamela Soliman, MD, Phone: 713-745-2352
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.
Clinical Details
Official title: A Phase II, Single-Arm Study of RAD001 (Everolimus), Letrozole, and Metformin in Patients With Advanced or Recurrent Endometrial Carcinoma
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Clinical Benefit Rate (CBR)
Secondary outcome: Progression-Free Survival (PFS)
Detailed description:
Study Drug Administration:
If participant is found to be eligible to take part in this study and they are not already
taking metformin, they will take metformin before they begin the regular study cycles
(Cycles 1 and beyond). This will be called "Cycle 0." Participant will take metformin by
mouth 1 time a day on Days 1-4 of Cycle 0 and then 2 times a day (about 12 hours apart)
every day after that. Participant will take metformin for 7-10 days in Cycle 0 before Cycle
1 begins. If participant is already taking metformin, they will continue their regular
dose and start Day 1 of Cycle 1. If participant is already taking metformin but their dose
is less than 1000mg/day, their dose will be slowly raised up to the study dose over the
course of 7-10 days and then they will start Cycle 1. In Cycles 1 and beyond, all
participants will take all 3 drugs at a time. Participant should take metformin with food.
Starting in Cycle 1, participant will take everolimus 1 time a day by mouth at about the
same time every day. Participant should take it either consistently with food every day or
consistently without food every day.
Starting in Cycle 1, participant will take letrozole 1 time a day by mouth at about the same
time every day.
It is very important for participant to take the study drugs just as the study doctor tells
them. Participant should not skip any doses unless their study doctor tells them to skip
doses. If participant throws up after taking the study drugs, they should NOT take another
tablet that day. Participant should let their study doctor know that they got sick. If
participant forgets to take the study drugs one day, they should not take any extra doses
the next day. Participant should call their study doctor and ask for advice.
There are 4 weeks in each cycle (except Cycle 0).
Study Visits:
Every cycle (+/- 10 days):
- Participant will have a physical exam, including measurement of their vital signs and
weight. This will include a pelvic exam if the disease can be felt in the pelvis.
- Participant's performance status will be recorded.
- Participant will be asked about any side effects they may have had.
- Blood (about 2 tablespoons) will be drawn for routine tests.
- If the doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to check for
hepatitis.
After Cycles 2, 4, and 6 and then every 3 cycles after that (Cycles 9, 12, 15, and so on)
(+/- 10 days):
- Participant will have scans such as a CT scan and/or MRI to check the status of the
disease.
- If participant has chest disease, they will have a chest x-ray.
Length of Treatment:
Participant may continue taking the study drugs for as long as the doctor thinks it is in
their best interest. Participant will no longer be able to take the study drugs if the
disease gets worse, if intolerable side effects occur, or if they are unable to follow study
directions.
Patient's participation on the study will be over after the follow-up visits.
End-of-Treatment Visit:
After participant is finished taking the study drugs:
- Participant will have a physical exam, including a pelvic exam and measurement of their
vital signs and weight.
- Participant's performance status will be recorded.
- Participant will be asked about any side effects they may have had.
- Blood (about 2 tablespoons) will be drawn for routine tests.
- Participant will have scans such as a CT scan and/or MRI to check the status of the
disease.
- If participant has chest disease, they will have a chest x-ray.
Follow-Up Visits:
Participant will have follow-up visits as often as the doctor thinks is needed. At every
visit:
- Participant will have a physical exam, including measurement of their vital signs.
- Participant's performance status will be recorded.
- Participant will be asked about any side effects they may have had.
- If the doctor thinks it is needed, participant will have scans such as a CT scan and/or
MRI to check the status of the disease.
- If participant has chest disease, they will have a chest x-ray.
This is an investigational study. Everolimus is FDA approved and commercially available to
treat kidney, breast, and pancreatic cancers. Letrozole is FDA approved and commercially
available to treat breast cancer and ovarian cancer. Metformin is FDA approved and
commercially available to treat diabetes. The combination of everolimus, metformin, and
letrozole in this study to treat endometrial cancer is investigational.
Up to 64 participants will be enrolled in this study. Up to 59 may take part at MD
Anderson. Up to 5 participants per site may be enrolled at MD Anderson Cooper and
Spartanburg Regional Healthcare System and Harris Health System.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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:
creatinine clearance > 60 mL/min; 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, serous tumors 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
Locations and Contacts
Pamela Soliman, MD, Phone: 713-745-2352
Sacred Heart Health Systems, Pensacola, Florida 32504, United States; Recruiting
MD Anderson Cooper Cancer Center, Township, New Jersey 08043, United States; Recruiting
Spartanburg Regional Health Care System, Spartanburg, South Carolina 29303, United States; Recruiting
Lyndon B Johnson General Hospital, Houston, Texas 77026, United States; Recruiting
Memorial City Medical Center, Houston, Texas 77024, United States; Recruiting
The Woman's Hospital of Texas, Houston, Texas 77054, United States; Recruiting
University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Additional Information
University of Texas MD Anderson Cancer Center Website
Starting date: October 2013
Last updated: May 12, 2015
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