Clinical Trials /

Study of Ribociclib (LEE011), Everolimus, and Letrozole, in Patients With Advanced or Recurrent Endometrial Carcinoma

NCT03008408

Description:

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. 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. Ribociclib is not FDA approved or commercially available. It is currently being used for research purposes only. The combination of everolimus, letrozole, and ribociclib to treat endometrial cancer is investigational. Up to 92 patients will have screening tests to learn if they are eligible to take part in this study. Up to 76 patients that are found eligible will be enrolled in this study. All will take part at MD Anderson.

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

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

Conditions

  • Malignant Neoplasms of Female Genital Organs
  • Endometrial Carcinoma

Interventions

DrugSynonymsArms
RibociclibLEEO11Phase I: Safety Lead-In - Ribociclib + Everolimus + Letrozole
EverolimusAfinitor, Zortress, RAD001Phase I: Safety Lead-In - Ribociclib + Everolimus + Letrozole
LetrozoleFemaraPhase I: Safety Lead-In - Ribociclib + Everolimus + Letrozole

Purpose

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. 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. Ribociclib is not FDA approved or commercially available. It is currently being used for research purposes only. The combination of everolimus, letrozole, and ribociclib to treat endometrial cancer is investigational. Up to 92 patients will have screening tests to learn if they are eligible to take part in this study. Up to 76 patients that are found eligible will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Drug Administration:

      Each study cycle is 28 days.

      Participant will take everolimus, letrozole and ribociclib by mouth and should be swallowed
      whole without opening, chewing, or crushing 1 time every day at the same time. Participant
      will take the dose in the morning with a full cup of water (about 8 ounces). Participant
      should fast (not eat or drink anything except water) for up to 2 hours before and after each
      dose of study drugs.

      When participant comes to clinic for a visit, participant should wait to take participant's
      drugs until the study team tells participant to take them.

      Length of Treatment:

      Participant may continue taking the study drugs for as long as the doctor thinks it is in
      participant's 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 participant is unable to
      follow study directions.

      Participation on the study will be over after follow-up.

      Study Visits:

      On Day 1 of Each Cycle:

        -  Participant will have a physical exam.

        -  Blood (about 2 tablespoons) and urine will be collected for routine tests.

        -  If the doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to check for
           hepatitis. If participant has had the hepatitis screening test during screening, it will
           not be repeated.

        -  On Day 1 of Cycles 2 and beyond, participant will have an EKG.

        -  On Day 1 of Cycle 3 and every 3 cycles after that (Cycles 6, 9, 12, and so on), part of
           the routine blood draw will be used to check the level of fat in participant's blood.

      On Day 15 of Cycle 1:

        -  Blood (about 3 ½ tablespoons) will be drawn for routine and pharmacodynamic PD testing.

        -  Participant will have three EKGs 5 minutes apart before the dose and then 2-4 hours
           after.

      On Day 15 of Cycle 2, participant will have an EKG before and then 2-4 hours after the dose.

      At the end of Cycles 2, 4, 6 and every 3 cycles after that (Cycles 9, 12, 15, and so on) (+/-
      7 days):

        -  Participant will have an MRI and/or CT scan. If participant has signs of disease in the
           chest chest disease, participant will have a CT scan of the chest.

        -  If the disease could be felt in the pelvis at the beginning of the study, participant
           will have a pelvic exam.

      End-of-Treatment Visit:

      Within 4 weeks after the last dose of study drugs:

        -  Participant will have a physical exam.

        -  Blood (about 2 tablespoons) and urine will be collected for routine tests.

        -  Participant will have an MRI and/or CT scan. If participant has signs of disease in the
           chest, participant will have a CT scan of the chest.

      Follow-Up:

      At 30 days after participant's last dose of study drugs and then every 3 months (+/- 1 month)
      after that, a member of the study staff will contact participant by phone or at a regularly
      scheduled clinic visit to ask how participant is doing and about any side effects participant
      may have had. These calls or visits should last about 5-10 minutes each time.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I: Safety Lead-In - Ribociclib + Everolimus + LetrozoleExperimentalSafety lead-in of 6 patients to confirm doses of combination therapy with Ribociclib, Everolimus and Letrozole. After safety lead-in 25 more participants enrolled if there are at least 12 patients with clinical benefit. Ribociclib 250 mg by mouth daily for 28 days. Everolimus 2.5 mg by mouth daily for 28 days. Letrozole 2.5 mg by mouth daily for 28 days.
  • Ribociclib
  • Everolimus
  • Letrozole
Phase II: Ribociclib + Everolimus + LetrozoleExperimentalPhase II: 25 participants to be enrolled in this phase. Ribociclib 250 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle. Everolimus 2.5 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle. Letrozole 2.5 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle. Participants may continue taking the study drugs for as long as the doctor thinks it is in their best interest.
  • Ribociclib
  • Everolimus
  • Letrozole

Eligibility Criteria

        Inclusion Criteria:

          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 if the patient meets the washout period of
             10 days.

          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 agents) for
             at least four weeks prior to study registration. Patients on hormonal agents require a
             washout for 10 days.

         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. INR </=1.5 e. Serum creatinine
             </= 1.5 mg/dL or creatinine clearance >/=50 mL/min f. 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 g. 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. h. i.h. 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.

         14. Patient with available standard 12-lead ECG with the following parameters at
             screening: a. QTcF interval at screening <450msec (using Fridericia's correction). b.
             Resting heart rate 50-100bpm

        Exclusion Criteria:

          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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity During Safety Lead-In With Ribociclib, Everolimus and Letrozole
Time Frame:28 days
Safety Issue:
Description:Dose Limiting Toxicity (DLT) defined as either hematologic or non-hematologic toxicity [assessed in accordance with the current version of NCI Common Terminology Criteria, CTCAE], occurring during cycle 1 of therapy.

Secondary Outcome Measures

Measure:Survival of Participants with Advanced or Recurrent Endometrial Carcinoma Using Ribociclib, Everolimus, and Letrozole
Time Frame:5 years
Safety Issue:
Description:Survival determined by measuring the time from study entry (1st treatment) to progression free survival (PFS) or death, overall survival (OS).

Details

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

Trial Keywords

  • Malignant neoplasms of female genital organs
  • Endometrial carcinoma
  • Advanced or Recurrent
  • Endometrioid and mixed endometrioid tumors
  • Ribociclib
  • LEE011
  • Everolimus
  • Afinitor
  • Zortress
  • RAD001
  • Letrozole
  • Femara

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