Clinical Trials /

CDK 4/6 Inhibitor, Ribociclib, With Adjuvant Endocrine Therapy for ER-positive Breast Cancer



This research study is studying a drug as a possible treatment for ER-positive Breast Cancer The drug involved in this study is: -Ribociclib

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: CDK 4/6 Inhibitor, LEE011 (Ribociclib), in Combination With Adjuvant Endocrine Therapy at Varying Duration for ER-positive Breast Cancer
  • Official Title: Phase II Study of CDK 4/6 Inhibitor, LEE011 (Ribociclib), in Combination With Adjuvant Endocrine Therapy at Varying Duration for ER-positive Breast Cancer (LEADER).

Clinical Trial IDs

  • ORG STUDY ID: 17-232
  • NCT ID: NCT03285412


  • Breast Cancer


RibociclibKisqaliRibociclib Intermittent + Endocrine Rx


This research study is studying a drug as a possible treatment for ER-positive Breast Cancer The drug involved in this study is: -Ribociclib

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug to learn whether the drug works in treating a
      specific disease. "Investigational" means that the drug is being studied.

      This research study is a Pilot Study of two different doses, which is the first time
      investigators are examining this study drug at the different dosage, for early breast cancer.

      The FDA (the U.S. Food and Drug Administration) has approved ribociclib in combination with
      aromatase inhibitors as a treatment option for advanced/metastatic (stage IV) breast cancer.

      In this research study, The investigators are comparing the safety and efficacy of ribociclib
      given at two different doses given on different schedules during a period of 28 days.

      Ribociclib is a drug designed to block certain proteins called cyclin-dependent protein
      kinases 4 and 6 (CDK4/6). These proteins are needed for cells to divide and may also control
      the ability of certain cancers to grow. The investigators believe that ribociclib may stop
      the participant cancer cells from growing and dividing by blocking these CDK4/6 proteins.

Trial Arms

Ribociclib Intermittent + Endocrine RxExperimentalRibociclib will be administered for 21 days on a 28 days cycle Endocrine therapy will be administered daily
  • Ribociclib
Ribociclib Continuous + Endocrine RxExperimentalRibociclib will be administered daily on a 28 days cycle Endocrine therapy will be administered daily
  • Ribociclib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have biopsy proven localized ER+ (≥ 10%), HER2 negative, grade 2 or
             3 invasive breast cancer, with pathological stage (including post-neoadjuvant therapy)
             T2-T4c, any N, M0, by AJCC 7th edition staging. Invasive breast cancer must be ER+ in
             ≥10% of the cells and HER2 negative (IHC 0 or 1+ and/or FISH negative with a ratio <2)
             by ASCO/CAP guidelines. For IHC 2+, the tumor must be FISH negative with a ratio <2.
             PR status must be performed. ER, PR and HER2 measurements should be performed
             according to institutional (local) guidelines, in a CLIA-approved setting. Evaluation
             for metastatic disease is not required in the absence of symptoms. Patients must have
             completed definitive surgery for breast cancer.

          -  No prior history of other malignancies within past 5 year (besides breast cancer as
             per 3.1.1). Individuals with the following cancers are eligible if diagnosed and
             treated within the past 5 years: ductal carcinoma in situ of the breast, cervical
             cancer in situ, and basal cell or squamous cell carcinoma of the skin. No concurrent
             malignancy or other serious medical condition as deemed by the investigator. Patients
             with history of contralateral breast cancer are not eligible.

          -  Participants may or may not have received (neo)adjuvant chemotherapy, but must be at
             least 30 days after last dose of chemotherapy and/or biological therapy, with no more
             than grade 1 residual toxicity at the time of screening.

          -  Participants may or may not have received adjuvant radiotherapy, but must be at least
             30 days after last dose radiotherapy, with no more than grade 1 residual toxicity at
             the time of screening.

          -  Pre- and postmenopausal women are eligible. Premenopausal women must have a negative
             serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female
             patients who are: age ≥ 60 years; or age < 60 with intact uterus and amenorrhea for 12
             consecutive months or more AND estrogen (estradiol) levels within postmenopausal
             range; or status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal

          -  QTc (Fredericia's formula) < 470ms.

          -  Must be ≥ 18 years of age.

          -  No history of prior CDK 4/6 inhibitor use.

          -  ECOG performance status 0-1 (Karnofsky ≥70%, see Appendix A)

          -  Patients may enroll within 10 years of breast cancer diagnosis, as long as there is a
             plan for at least 1 more year of adjuvant endocrine therapy.

          -  Ability to understand and the willingness to sign a written informed consent document.
             Patient must sign the Informed Consent (ICF) prior to any screening procedures being
             performed and is able to comply with protocol requirements.

          -  Participants must have been on adjuvant endocrine therapy, either tamoxifen or
             aromatase inhibitor (AI), for at least 6 months without any significant adverse events
             leading to drug interruption for more than 1 month, and must not have had any change
             in endocrine therapy in the past 6 months. Ongoing use of any AI, including letrozole,
             anastrozole or exemestane, or tamoxifen is allowed. Concurrent GNRH agonist is

          -  Patient has adequate bone marrow and organ function as defined by the following
             laboratory values at screening:

               -  Absolute neutrophil count ≥1.5 × 109/L

               -  Platelets ≥100 × 109/L

               -  Hemoglobin ≥9.0 g/dL

               -  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

               -  Serum creatinine <1.5 mg/dL or creatinine clearance ≥50 mL/min

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN.

               -  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.

               -  Fasting plasma glucose <140 mg/dL / 7.7 mmol/L..

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier.

          -  Participants who are receiving any other investigational agents. History of prior
             PI3K, mTOR or CDK 4/6 inhibitor use for breast cancer.

          -  Participants with known brain metastases, or any other metastases from cancer.

          -  Participants receiving any medications or substances that are inhibitors or inducers
             of CYP3A4 are ineligible. Because the lists of these agents are constantly changing,
             it is important to regularly consult a frequently-updated list such as
   ; medical reference texts such as
             the Physicians' Desk Reference may also provide this information. As part of the
             enrollment/informed consent procedures, the patient will be counseled on the risk of
             interactions with other agents, and what to do if new medications need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal

          -  Uncontrolled inter-current illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements. Patient has impairment of gastrointestinal (GI) function or GI
             disease that may significantly alter the absorption of the study drugs (e.g.,
             ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome,
             or small bowel resection).

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

               -  History of angina pectoris, symptomatic pericarditis, coronary artery bypass
                  graft (CABG) or myocardial infarction within 6 months prior to study entry.

               -  Documented cardiomyopathy.

               -  Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated
                  acquisition (MUGA) scan or echocardiogram (ECHO) detected during screening.

               -  History of cardiac failure, significant/symptomatic bradycardia, Long QT
                  syndrome, family history of idiopathic sudden death or congenital long QT
                  syndrome or any of the following:

               -  Known risk to prolong the QT interval or induce Torsade's de Pointes.

               -  Uncorrected hypomagnesemia or hypokalemia.

               -  Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg.

               -  Bradycardia (heart rate <50 at rest), by ECG or pulse.

               -  On screening, inability to determine the QTcF interval on the ECG (i.e.:
                  unreadable or not interpretable) or QTcF >450 screening ECG (based on a mean of 3

          -  History of hypersensitivity to ribociclib or any of its components.

          -  HIV-positive participants on combination antiretroviral therapy are ineligible. These
             participants are at increased risk of lethal infections when treated with
             marrow-suppressive therapy. Appropriate studies will be undertaken in participants
             receiving combination antiretroviral therapy when indicated.

          -  Pregnant women are excluded from this study because the safety of ribociclib is not
             established in pregnant women. For this reason and because CDK4/6 agents as well as
             other therapeutic agents used in this trial are known to be teratogenic, women of
             child-bearing potential (WOCBP) and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of treatment, and for at least 3 months after the completion of
             treatment. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she must inform her treating physician immediately. Prior
             to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy
             during trial participation and the potential risk factors for an unintentional
             pregnancy. In addition, men enrolled on this study should understand the risks to any
             sexual partner of childbearing potential. All WOCBP must have a negative pregnancy
             test within 72 hours prior to receiving the first dose of the investigational
             agent(s). Registration may occur prior to this pregnancy test. If the pregnancy test
             is positive, the patient must not receive protocol treatment and must not be enrolled
             in the study. WOCBP is defined as follows: Any female who has experienced menarche and
             who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal
             ligation, or a bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea
             > 12 consecutive months, or women on hormone replacement therapy (HRT) with documented
             plasma follicle-stimulating hormone (FSH) level > 35 mIU/ml). Even women who are using
             oral, implanted, or injectable contraceptive hormones or mechanical products
             (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or
             where partner is sterile (e.g. vasectomy), should be considered to be a WOCBP.

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             throughout the study and for 8 weeks after study drug discontinuation. Women are
             considered post-menopausal and not of child bearing potential if they have had 12
             months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.
             age appropriate, history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
             In the case of oophorectomy alone, only when the reproductive status of the woman has
             been confirmed by follow up hormone level assessment is she considered not of child
             bearing potential. Highly effective contraception methods include:

               -  Total abstinence when this is in line with the preferred and usual lifestyle of
                  the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
                  taking study treatment. In case of oophorectomy alone, only when the reproductive
                  status of the woman has been confirmed by follow up hormone level assessment

               -  Use of oral, injected or implanted hormonal methods of contraception or placement
                  of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
                  hormonal contraception that have comparable efficacy (failure rate <1%), for
                  example hormone vaginal ring or transdermal hormone contraception.

               -  In case of use of oral contraception, women should have been stable on the same
                  pill for a minimum of 3 months before taking study treatment. Note: While oral
                  contraceptives are allowed, they should be used in conjunction with a barrier
                  method of contraception due to unknown effect of drug-drug interaction
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants That Complete 12 Months of Treatment
Time Frame:12 Months
Safety Issue:
Description:The study treatment will be considered safe and reasonably well tolerated if more than 2/3 (66%) of participants complete 12 months of Ribociclib treatment (with ≥75% of intended doses). Failure to complete 12 months of the study treatment may be the result of dose delays, dose reductions, death, or withdrawal from the study. Participants may be held off Ribociclib due to the occurrence of adverse events. Adverse events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE version 4). If these adverse events resolve to grade 1 within 7 days or less, Ribociclib will be resumed at the same dose as previously given. If the toxicities require more than 7 days to return to grade 1, Ribociclib will be reduced by one dose level. A maximum of two dose level reductions will be allowed on the trial before the participant is removed. Ribociclib can be held for a maximum of two cycles (56 days) before the participant will be discontinued from the clinical trial.

Secondary Outcome Measures

Measure:Comparison of Adverse Events Among Participants Treated With Endocrine therapy for ≤ 5 Years to Participants Treated With Endocrine Therapy for > 5 Years
Time Frame:2 years
Safety Issue:
Description:Summary of the cumulative incidence of adverse events as assessed using Common Terminology Criteria for Adverse Events (CTCAE 4) among participants treated with endocrine therapy for ≤ 5 years compared to participants treated with endocrine therapy for > 5 years.
Measure:Number of participants who have a switch in endocrine therapy
Time Frame:2 years
Safety Issue:
Description:The number of participants who switch to a different endocrine therapy during study treatment.
Measure:Disease-free survival (DFS)
Time Frame:2 years
Safety Issue:
Description:Disease-Free Survival (PFS) is defined as the time from randomization (or registration) to evidence of disease recurrence or death due to any cause. Participants alive without disease recurrence are censored at date of last evaluation.


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Breast Cancer

Last Updated

September 14, 2017