Clinical Trials /

A Phase II, Two-Arm Study of Everolimus and Letrozole, +/- Ribociclib (Lee011) in Patients With Advanced or Recurrent Endometrial Carcinoma

NCT03008408

Description:

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.

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II, Two-Arm Study of Everolimus and Letrozole, +/- Ribociclib (Lee011) in Patients With Advanced or Recurrent Endometrial Carcinoma
  • Official Title: A Phase II, Randomized Two-Arm Study of Everolimus and Letrozole, +/- Ribociclib (LEE011) in Patients With Advanced or Recurrent Endometrial Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2015-0961
  • SECONDARY ID: NCI-2018-01284
  • SECONDARY ID: 2015-0961
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03008408

Conditions

  • Recurrent Endometrial Carcinoma
  • Recurrent Endometrial Endometrioid Adenocarcinoma
  • Refractory Endometrial Carcinoma
  • Refractory Endometrial Endometrioid Adenocarcinoma
  • Stage III Uterine Corpus Cancer AJCC v8
  • Stage IIIA Uterine Corpus Cancer AJCC v8
  • Stage IIIB Uterine Corpus Cancer AJCC v8
  • Stage IIIC Uterine Corpus Cancer AJCC v8
  • Stage IIIC1 Uterine Corpus Cancer AJCC v8
  • Stage IIIC2 Uterine Corpus Cancer AJCC v8
  • Stage IV Uterine Corpus Cancer AJCC v8
  • Stage IVA Uterine Corpus Cancer AJCC v8
  • Stage IVB Uterine Corpus Cancer AJCC v8

Interventions

DrugSynonymsArms
Everolimus42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, ZortressArm I (ribociclib, everolimus, letrozole)
LetrozoleCGS 20267, FemaraArm I (ribociclib, everolimus, letrozole)
RibociclibKisqali, LEE-011, LEE011Arm I (ribociclib, everolimus, letrozole)

Purpose

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 used in chemotherapy, such as everolimus and letrozole, work in different ways to sop the growth of tumor cells, 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (ribociclib, everolimus, letrozole)ExperimentalPatients 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.
  • Everolimus
  • Letrozole
  • Ribociclib
Arm II (everolimus, letrozole)ExperimentalPatients 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.
  • Everolimus
  • Letrozole

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.

          -  Gynecologic Oncology Group (GOG) performance status of 0 to 1.

          -  Absolute neutrophil count >= 1.5 x 10^9/L (at screening).

          -  Platelets >= 100 x 10^9/L (at screening).

          -  Hemoglobin >= 9.0 g/dL (at screening).

          -  International normalized ratio (INR) =< 1.5 (at screening).

          -  Serum creatinine =< 1.5 mg/dL or creatinine clearance >=50 mL/min (at screening).

          -  Estimated glomerular filtration rate (eGFR) >= 30mL/min/1.73m^2 (at screening)
             according to the Modification of Diet in Renal Disease (MDRD) formula.

          -  In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate
             aminotransferase (AST) < 2.5 x upper limit of normal (ULN). If the patient has liver
             metastases, ALT and AST < 5 x ULN (at screening).

          -  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 (at screening).

          -  Fasting serum cholesterol =< 240 mg/dL or =< 7.75 mmol/L and fasting triglycerides =<
             2.5 x ULN (at screening).

               -  NOTE: In case one or both of these thresholds are exceeded, the patient can only
                  be included after initiation of appropriate lipid lowering medication.

          -  Patient with available standard 12-lead electrocardiography (ECG) with the following
             parameters at screening: a. Corrected QT interval by Fridericia's formula (QTcF)
             interval at screening < 450 msec (using Fridericia's correction). b. Resting heart
             rate 50-100 beats per minute (bpm).

        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.

          -  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
             curatively resected cervical cancer in situ.

          -  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.).

          -  Patient has a known history of human immunodeficiency virus (HIV) infection (testing
             not mandatory).

          -  Clinically significant, uncontrolled heart disease and/or cardiac repolarization
             abnormalities, including any of the following:

               -  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.

               -  History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV).

               -  Documented cardiomyopathy.

               -  Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
                  acquisition (MUGA) scan or echocardiogram (ECHO) at screening.

               -  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).

               -  Long QT syndrome or family history of idiopathic sudden death or congenital long
                  QT syndrome, or any of the following:

                    -  Risk factors for Torsades de Pointe (TdP) including uncorrected
                       hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or
                       history of clinically significant/symptomatic bradycardia.

                    -  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.

                    -  Inability to determine the QT interval on screening (QTcF, using
                       Fridericia's correction).

                    -  Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening.

          -  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).

          -  Patient is currently receiving any of the following medications and cannot be
             discontinued 7 days prior to starting study drug:

               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
                  hybrids, pummelos, star-fruit, and Seville oranges.

               -  That have a narrow therapeutic window and are predominantly metabolized through
                  CYP3A4/5.

               -  Herbal preparations/medications, dietary supplements.

               -  Hormone replacement therapy, topical estrogens (including any intra-vaginal
                  preparations), megestrol acetate and selective estrogen-receptor modulators (e.g.
                  raloxifene).

          -  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.

          -  Liver disease such as cirrhosis or severe hepatic impairment (patient with a
             Child-Pugh score B or C).

               -  Note: A detailed assessment of hepatitis B/C medical history and risk factors
                  must be done at screening for all patients. Hepatitis B virus (HBV)
                  deoxyribonucleic acid (DNA) and hepatitis C virus (HCV) ribonucleic acid (RNA)
                  polymerase chain reaction (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.

          -  Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus,
             temsirolimus, everolimus).

          -  Patients with a known hypersensitivity to ribociclib or everolimus or to its
             excipients.

          -  History of noncompliance to medical regimens.

          -  Patients unwilling to or unable to comply with the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical benefit rate (CBR)
Time Frame:At 8 weeks
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

July 13, 2020