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, Ribociclib, With Adjuvant Endocrine Therapy 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 + 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 study with endocrine therapy and CDK 4/6 inhibitor (ribociclib) for
      early breast cancer. There is no placebo in this study. The study has two components -
      pre-screening with ctDNA to detect minimal residual disease (pre-screening), and treatment
      with ribociclib in combination with endocrine therapy (main portion).

      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 evaluating efficacy of ribociclib in patients
      who have MRD based on ctDNA.

      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 + Endocrine RxExperimentalRibociclib will be administered. Endocrine therapy will be administered.
  • Ribociclib
Endocrine RxActive ComparatorEndocrine therapy will be administered.

    Eligibility Criteria

            Inclusion Criteria:
              -  Participants must have biopsy proven localized ER+ (≥ 10%), HER2 negative, invasive
                 breast cancer, with pathological stage (including post-neoadjuvant therapy) T1c-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.
              -  Detectable ctDNA (separate pre-screening consent)
              -  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.
              -  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 (till date of trial consent). Prior use of
                 any AI, including letrozole, anastrozole or exemestane, or tamoxifen is allowed.
              -  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.
              -  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:ctDNA clearance
    Time Frame:12 Months
    Safety Issue:
    Description:tumor ctDNA response after 12 cycles of adjuvant ribociclib in combination with endocrine therapy vs endocrine therapy alone in patients with localized post-menopausal breast cancer and elevated ctDNA.

    Secondary Outcome Measures

    Measure:Comparison of Adverse Events
    Time Frame:2 years
    Safety Issue:
    Description:compare the adverse effects, as assessed by CTCAE grading, in patients treated with endocrine therapy within 5 years versus those on endocrine therapy > 5 years
    Measure:Number of participants who have a switch in endocrine therapy
    Time Frame:2 years
    Safety Issue:
    Description:determine how many patients have switch in endocrine therapy
    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:Recruiting
    Lead Sponsor:Massachusetts General Hospital

    Trial Keywords

    • Breast Cancer

    Last Updated

    May 14, 2021