A Phase II, Randomized Two-Arm Study of Everolimus and Letrozole, +/- Ribociclib (LEE011) in Patients With Advanced or Recurrent Endometrial Carcinoma
Overview
- Phase
- Phase 2
- Intervention
- Everolimus
- Conditions
- Recurrent Endometrial Carcinoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 90
- Locations
- 2
- Primary Endpoint
- Clinical benefit rate (CBR)
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase II trial studies how well everolimus and letrozole with or without ribociclib work in treating participants with endometrial cancer that has spread to other areas of the body or has come back. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs such as everolimus and letrozole have been shown to be effective at stopping tumor growth either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib, everolimus, and letrozole may work better than everolimus and letrozole in treating participants with endometrial cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To determine if the addition of ribociclib (LEE011) to everolimus and letrozole improves progression free survival in patients with advanced or recurrent endometrial carcinoma. SECONDARY OBJECTIVES: I. To determine clinical benefit and the median duration of progression-free survival (PFS) and overall survival (OS) in patients with advanced or recurrent endometrial carcinoma treated with ribociclib (LEE011), everolimus and letrozole versus everolimus and letrozole alone. II. To determine the frequency and severity of toxicities associated with ribociclib (LEE011), everolimus (RAD001), and letrozole in this cohort of patients. III. To determine the presence of a CTNNB1 mutation is associated with response to ribociclib (LEE011), everolimus (RAD001), and letrozole. IV. To determine if liquid biopsies at baseline and 8 weeks correlate with presence of a tissue mutation or response to therapy. EXPLORATORY OBJECTIVE: I. To examine the pharmacokinetic and pharmacodynamic effects of ribociclib in patients with advanced or recurrent endometrial carcinoma. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive ribociclib orally (PO) once daily (QD), everolimus PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive everolimus PO QD and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 days and then every 3 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient has signed the informed consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements.
- •Patients must have histologically-confirmed endometrial carcinoma (endometrioid and mixed endometrioid tumors, any grade).
- •Patients must have advanced or recurrent disease that is refractory to curative treatment based on imaging or clinical exam.
- •Patient must consent to allow for a baseline tumor biopsy. Tumor material from biopsies done before the screening period are acceptable if the biopsy was performed within 3 months prior to the planned treatment start and no other systemic cancer therapy was administered in the interim. If a biopsy is performed and the specimen is considered non-diagnostic, does not have enough tissue, or the biopsy is deemed infeasible to perform, this does not prevent the patient from proceeding with the treatment
- •Patients must have had no more than two prior chemotherapeutic regimens for recurrent 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.
- •Prior treatment with letrozole is allowed if the patient meets the washout period of 10 days.
- •All patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 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 pregnant, breastfeeding or 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 (if patient is uncertain of amenorrhea for 12 months, a pregnancy test will be done to confirm pregnancy status). 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 agents) for at least four weeks prior to study registration. Patients on hormonal agents require a washout for 10 days.
Exclusion Criteria
- •Patients who have uterine sarcomas, carcinosarcomas, serous tumors (any component) 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.)
- •Patient has not recovered from all toxicities related to prior anticancer therapies to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade =\< 1 (exception to this criterion: patients with grade 1 taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk for the patient as per investigator's discretion are allowed to enter the study).
- •Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
- •Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational product (whichever is longer) or participation in any other type of medical research judged not to be scientifically or medically compatible with this study.
- •Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical, short duration (\< 5 days) of systemic corticosteroids, eye drops, local injections, 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.
- •Patients with central nervous system (CNS) involvement unless they meet all of the following criteria:
- •At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment.
- •Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases.
Arms & Interventions
Arm I (ribociclib, everolimus, letrozole)
Patients receive ribociclib PO QD, everolimus PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Everolimus
Arm I (ribociclib, everolimus, letrozole)
Patients receive ribociclib PO QD, everolimus PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Letrozole
Arm I (ribociclib, everolimus, letrozole)
Patients receive ribociclib PO QD, everolimus PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Ribociclib
Arm II (everolimus, letrozole)
Patients receive everolimus PO QD and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Everolimus
Arm II (everolimus, letrozole)
Patients receive everolimus PO QD and letrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Letrozole
Outcomes
Primary Outcomes
Clinical benefit rate (CBR)
Time Frame: At 8 weeks
Per Response Evaluation Criteria in Solid Tumors version 1.1. This will be determined by combining the complete response rate, partial response rate, and stable disease rate. Response will be evaluated by repeat imaging (computed tomography or magnetic resonance imaging). Fisher's exact test will be used to compare patients with/without CTNNB1 mutation with respect to CBR.