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

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ClinicalTrials.gov Identifier: NCT03008408
Recruitment Status : Recruiting
First Posted : January 2, 2017
Last Update Posted : November 6, 2018
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Malignant Neoplasms of Female Genital Organs Endometrial Carcinoma Drug: Ribociclib Drug: Everolimus Drug: Letrozole Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Single-Arm Study of Ribociclib (LEE011), Everolimus, and Letrozole, in Patients With Advanced or Recurrent Endometrial Carcinoma
Actual Study Start Date : August 18, 2017
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase I: Safety Lead-In - Ribociclib + Everolimus + Letrozole

Safety 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.

Drug: Ribociclib

Phase I Safety Lead-In: Ribociclib 250 mg by mouth daily for 28 days.

Phase II: Ribociclib 250 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle.

Other Name: LEEO11

Drug: Everolimus

Phase I Safety Lead-In: Everolimus 2.5 mg by mouth daily for 28 days.

Phase II: Everolimus 2.5 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle.

Other Names:
  • Afinitor
  • Zortress
  • RAD001

Drug: Letrozole

Phase I Safety Lead-In: Letrozole 2.5 mg by mouth daily for 28 days.

Phase II: Letrozole 2.5 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle.

Other Name: Femara

Experimental: Phase II: Ribociclib + Everolimus + Letrozole

Phase 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.

Drug: Ribociclib

Phase I Safety Lead-In: Ribociclib 250 mg by mouth daily for 28 days.

Phase II: Ribociclib 250 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle.

Other Name: LEEO11

Drug: Everolimus

Phase I Safety Lead-In: Everolimus 2.5 mg by mouth daily for 28 days.

Phase II: Everolimus 2.5 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle.

Other Names:
  • Afinitor
  • Zortress
  • RAD001

Drug: Letrozole

Phase I Safety Lead-In: Letrozole 2.5 mg by mouth daily for 28 days.

Phase II: Letrozole 2.5 mg (or dose determined by Safety Lead-In) by mouth daily for a 28 day cycle.

Other Name: Femara




Primary Outcome Measures :
  1. Dose Limiting Toxicity During Safety Lead-In With Ribociclib, Everolimus and Letrozole [ Time Frame: 28 days ]
    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.

  2. Clinical Benefit Rate (CBR) of Ribociclib, Everolimus, and Letrozole, in Participants with Advanced or Recurrent Endometrial Carcinoma [ Time Frame: 8 weeks ]
    Clinical benefit rate (CBR) determined by combining the complete response rate, partial response rate, and stable disease rate. Response evaluated by repeat imaging (CT or MRI) using RECIST 1.1 at the completion of the second cycle.


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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03008408


Contacts
Contact: Ljiljana Milojevic 713-792-8578 lmilojev@mdanderson.org
Contact: June Ellis, RN,BSN 713-745-1774 jhellis@mdanderson.org

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact       lmilojev@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Novartis
Investigators
Principal Investigator: Pamela Soliman, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03008408     History of Changes
Other Study ID Numbers: 2015-0961
NCI-2018-01284 ( Registry Identifier: NCI CTRP )
First Posted: January 2, 2017    Key Record Dates
Last Update Posted: November 6, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Malignant neoplasms of female genital organs
Endometrial carcinoma
Advanced or Recurrent
Endometrioid and mixed endometrioid tumors
Ribociclib
LEE011
Everolimus
Afinitor
Zortress
RAD001
Letrozole
Femara

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Endometrial Neoplasms
Genital Neoplasms, Female
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Uterine Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Genital Diseases, Female
Letrozole
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists