A Phase II, Single-Arm Study of Ribociclib (LEE011), Everolimus, and Letrozole, in Patients with Advanced or Recurrent Endometrial Carcinoma
The goal of this clinical research study is to learn if the combination of everolimus, letrozole, and ribociclib can help to control recurrent (has returned after treatment) or progressive endometrial cancer. The safety of this drug combination will also be studied.
Disease Group: Malignant neoplasms of female genital organs
Treatment Agent: Everolimus,Letrozole,LEE011
Treatment Location: Only at MD Anderson
Primary Objective To determine the efficacy of Ribociclib (LEE011), Everolimus (RAD001) and letrozole in patients with recurrent or progressive endometrial carcinoma. Secondary Objectives To determine the median duration of progression-free survival (PFS) and overall survival (OS) in patients with recurrent or progressive endometrial adenocarcinoma treated with Ribociclib (LEE011), Everolimus (RAD001) and letrozole. To determine the frequency and severity of toxicities associated with Ribociclib (LEE011), everolimus (RAD001), and letrozole in this cohort of patients. To determine the presence of a CTNNB1 mutation is associated with response to Ribociclib (LEE011), everolimus (RAD001), and letrozole. Exploratory Objective To examine the pharmacokinetic and pharmacodynamic effects of Ribociclib in patients with recurrent or progressive endometrial carcinoma.
IRB Review and Approval Date: 08/18/2017
Recruitment Status: Open
Projected Accrual: N/A
1) Patient has signed the Informed Consent (ICF) prior to any screening
procedures being performed and is able to comply with protocol requirements.
2) Patients must have histologically-confirmed endometrial carcinoma (endometrioid and mixed endometrioid tumors, any grade).
3) Patients must have advanced or recurrent disease that is refractory to curative treatment based on imaging or clinical exam.
4) 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 or dose not have enough tissue, this does not prevent the patient from proceeding with the treatment.
5) 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.
6) Prior radiation therapy of any kind is allowed.
7) Prior treatment with letrozole is allowed.
8) All patients must have measurable disease per 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 (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.
9) 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
10) Patients must be off all other anti-tumor therapies (including immunologic or hormonal agents) for at least four weeks prior to study registration.
11) Age >/= 18 years
12) GOG performance status of 0 to 1
13) Patient has adequate bone marrow and organ function as defined by the following laboratory values at screening: a. Absolute neutrophil count >/=1.5 × 109/L b. Platelets >/=100 × 10^9/L c. Hemoglobin >/=9.0 g/dL d. Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication e. INR </=1.5 f. Serum creatinine </= 1.5 mg/dL or creatinine clearance >/=50 mL/min g. In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN. If the patient has liver metastases, ALT and AST <5 x ULN h. Total bilirubin < ULN; or total bilirubin </=3.0 x ULN or direct bilirubin </=1.5 x ULN in patients with well-documented Gilbert’s Syndrome.
14) Cont. from #13 i. 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.
15) Patient with available standard 12-lead ECG with the following parameters at screening (defined as the mean of the triplicate ECGs): a. QTcF interval at screening <450msec (using Fridericia’s correction). b. Resting heart rate 50-90bpm
1) Patients who have uterine sarcomas, carcinosarcomas, serous tumors
(any component) 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) Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 Grade </=1 (Exception to this criterion: patients with any grade of alopecia are allowed to enter the study).
4) 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).
5) Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.
6) Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
7) 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.
8) Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria: a. At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment. b. Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases.
9) Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
10) Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, may cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
11) Patient has a known history of HIV infection (testing not mandatory).
12) Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following: a.History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening. b. History of documented congestive heart failure (New York Heart Association functional classification III-IV). c.Documented cardiomyopathy. d. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening. e. clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
13) Cont. from #12. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: a. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia. b.Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication. c. Inability to determine the QT interval on screening (QTcF, using Fridericia’s correction). d. Systolic blood pressure (SBP) >160 mmHg or <90mmHg at screening.
14) Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study medication (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection associated with malabsorption)
15) Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug: a. Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges. b. That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5. c. Herbal preparations/medications, dietary supplements. d. Hormone replacement therapy, topical estrogens (including any intra-vaginal preparations), megestrol acetate and selective estrogen-receptor modulators (e.g. raloxifene)
16) Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.
17) Liver disease such as cirrhosis or severe hepatic impairment (Patient with a Child-Pugh score B or C). 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.
18) Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus).
19) Patients with a known hypersensitivity to ribociclib or everolimus or to its excipients.
20) History of noncompliance to medical regimens.
21) Patients unwilling to or unable to comply with the protocol.
Information and next steps
Malignant neoplasms of female genital organs
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