Clinical Trials /

Study of Efficacy of Ribociclib After Progression on CDK4/6 Inhibition in Patients With HR+ HER2- Advanced Breast Cancer

NCT02632045

Description:

This is a randomized trial for patients with metastatic hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have progressed on an aromatase inhibitor plus a CDK4/6 inhibitor (either palbociclib or ribociclib) to either fulvestrant alone or fulvestrant with ribociclib (LEE-011). The purpose of the trial is to determine whether there is continued benefit for patients to remain on a CDK4/6 inhibitor at the time of switching anti-estrogen therapy. As ribociclib and palbociclib have a similar toxicity and drug profile and mechanism of action, we feel that it is appropriate for patients to receive either drug with an aromatase inhibitor prior to randomization.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Study of Efficacy of Ribociclib After Progression on <span class="go-doc-concept go-doc-biomarker">CDK4</span>/6 Inhibition in Patients With HR+ H2N- Advanced Breast Cancer

Title

  • Brief Title: Study of Efficacy of Ribociclib After Progression on CDK4/6 Inhibition in Patients With HR+ H2N- Advanced Breast Cancer
  • Official Title: A Randomized Phase II Trial of Fulvestrant With or Without Ribociclib After Progression on Aromatase Inhibition Plus Cyclin-dependent Kinase 4/6 Inhibition in Patients With Unresectable or Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02632045

    ORG ID: AAAP9506

    Trial Conditions

    Metastatic Breast Cancer

    Breast Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    LEE-011 ribociclib LEE-011/Fulvestrant
    Fulvestrant Faslodex LEE-011/Fulvestrant, Placebo/Fulvestrant
    Placebo No other name Placebo/Fulvestrant

    Trial Purpose

    This is a randomize trial for patients with metastatic HR-positive HER2-negative breast
    cancer who have progressed on an aromatase inhibitor plus a CDK4/6 inhibitor (either
    palbociclib or ribociclib) to either fulvestrant alone or fulvestrant with ribociclib. The
    purpose of the trial is to determine whether there is continued benefit for patients to
    remain on a CDK4/6 inhibitor at the time of switching anti-estrogen therapy. As ribociclib
    and palbociclib have a similar toxicity and drug profile and mechanism of action, we feel
    that it is appropriate for patients to receive either drug with an aromatase inhibitor prior
    to randomization.

    Detailed Description

    Despite advances in early detection and therapeutic options, unresectable or metastatic
    breast cancer remains incurable and is one of the leading causes of cancer-related
    mortality. Breast cancer is a molecularly heterogeneous disease. This study will be
    evaluating estrogen receptor (ER) expression positivity and/or progesterone receptor (PgR)
    positivity of breast cancer with the absence of over-expression or amplification of HER2.

    Inhibitors of the cyclin dependent kinases 4 and 6 (CDK4/6) have been developed and
    demonstrated impressive activity in patients with ER-positive HER2-negative breast cancer
    with marked improvements in progression free survival. This question is asking whether CDK
    4/6 inhibition should be continued with hormone therapy in patients who will be switching
    their hormone therapy in the metastatic breast cancer setting.

    Trial Arms

    Name Type Description Interventions
    LEE-011/Fulvestrant Experimental LEE-011 is administered orally, 600mg, daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks. LEE-011, Fulvestrant
    Placebo/Fulvestrant Placebo Comparator Placebo is administered orally, 600mg daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks. Fulvestrant, Placebo

    Eligibility Criteria

    Inclusion Criteria:

    1. Men or women at least 18 years of age with histologically or cytologically confirmed
    adenocarcinoma of the breast with unresectable or metastatic disease.

    2. Most recent tumor biopsy or surgical resection specimen must be either ER positive,
    PgR positive, or both, as defined by immunohistochemistry (IHC) 1% (as per the
    ASCO-CAP guidelines).

    3. HER2-negative breast cancer defined as a negative in situ hybridization test or an
    IHC status of 0, 1+ or 2+. If IHC is 2+ (i.e. indeterminate), a negative in situ
    hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. (as
    per the ASCO-CAP guidelines).

    4. Postmenopausal status or receiving ovarian ablation with a GnRH agonist such as
    goserelin. Postmenopausal status is defined by any one of the following criteria:

    - Prior bilateral oophorectomy.

    - Age 60 years.

    - Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
    tamoxifen, toremifene, or ovarian suppression) and FSH, LH, and estradiol in the
    postmenopausal range per local normal.

    If the patient does not meet criteria for postmenopausal status but is receiving
    ovarian ablation therapy with a gonadotropin-releasing hormone (GnRH) agonist such as
    goserelin, the patient is eligible for this study, provided that the GnRH agonist is
    started at least 2 weeks prior to C1D1 of anti-estrogen therapy.

    5. Have evidence of measurable or unmeasurable disease.

    6. Eastern Cooperative Group (ECOG) performance status of 0 or 1.

    7. Scenario 1: No prior cdk 4/6 inhibitor. If patient has not previously received
    letrozole, letrozole will be supplied by Novartis. If previously progressed on
    letrozole, another aromatase inhibitor that the patient has not previously received
    is allowed, per standard of care (anastrazole or exemestane, not supplied by study).
    Ribociclib will be supplied by Novartis. If patient has previously received
    letrozole, anastrazole, and exemestane, (s)he is not eligible. No prior fulvestrant
    allowed.

    8. Scenario 2: the patient must have received an aromatase inhibitor plus palbociclib as
    standard of care or received a CDK4/6 inhibitor (palbociclib or ribociclib) as part
    of a clinical trial, and demonstrated evidence of disease progression. If the patient
    was enrolled in a randomized clinical trial involving ribociclib or palbociclib (such
    as the MONALEESA or PALOMA series of trials), then it must be known after study
    discontinuation and unblinding that the patient received the investigational drug and
    not placebo. Documentation of progression and duration of response on aromatase
    inhibitor plus CDK 4/6 inhibitor should be provided whenever possible. No prior
    fulvestrant allowed.

    9. Adequate baseline laboratory studies (hematologic and chemistry), including the
    following parameters:

    - Absolute neutrophil count 1500 per microliter, Platelets 75,000 per
    microliter, Hemoglobin level 8.0 gm/dL on screening complete blood count

    - Potassium, sodium, total calcium (corrected for serum albumin), magnesium, and
    phosphorus within normal limits of the central laboratory (Screening values can
    be rechecked after electrolyte repletion and before the first dose of study
    medication, if necessary.)

    - Serum creatinine level 1.5 mg/dL or estimated glomerular filtration rate > 50
    mL/min.

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

    - Total bilirubin 1.5 x ULN. (In patients with well documented Gilbert's
    Syndrome, total bilirubin 3 ULN with direct bilirubin within normal range.)

    - INR 1.5

    10. Subject must be capable of understanding and participating in the informed consent
    process.

    11. Must be able to swallow ribociclib and letrozole

    Exclusion Criteria:

    1. Prior fulvestrant use.

    2. Patient has a known hypersensitivity to any of the excipients of ribociclib,
    letrozole or fulvestrant

    3. Active central nervous system (CNS) disease. History of CNS metastases or cord
    compression is allowable if the patient has been clinically stable for at least 4
    weeks since completion of definitive treatment and is off systemic steroids. In the
    case of brain metastases, the patient must have stable or improved imaging at least 4
    weeks after completion of definitive treatment. If there is evidence of active
    leptomeningeal disease, the patient is ineligible.

    4. Identified as having visceral crisis, lymphangitic spread, or leptomeningeal
    carcinomatosis. Visceral crisis is not the mere presence of visceral metastases but
    implies severe organ dysfunction as assessed by symptoms and signs, laboratory
    studies, and rapid progression of the disease.

    5. Received more than 1 prior systemic chemotherapy in the unresectable or metastatic
    setting. If the patient received 1 prior systemic chemotherapy, the patient is
    eligible. To clarify, this prior line can be single agent or combination (example,
    carboplatin/gemcitabine given concurrently). Patients do not need to have
    demonstrated disease progression on chemotherapy to be eligible. Having received
    prior targeted therapies for breast cancer (such as everolimus or experimental
    agents) does not affect eligibility for this study, with the exception of patients
    who have received the investigational CDK4/6 inhibitor abemaciclib (LY2835219). If
    the patient has previously received abemaciclib, the patient is not eligible for this
    study.

    6. Completion of major surgery or radiation within 14 days prior to starting
    investigational drug or has not recovered from major side effects.

    7. Residual acute toxic effects of prior anti-cancer therapy that have not resolved to
    CTCAE v.4 Grade 1 (except alopecia or other grade II or above toxicities not
    considered a safety risk for the patient at investigator's discretion).

    8. Presence of a concurrent malignancy or malignancy diagnosed within 5 years of
    randomization, with the exception of basal or squamous cell carcinoma,
    non-melanomatous skin cancer, curatively resected cervical cancer, localized prostate
    cancer treated with curative intent, and stage I colorectal cancer treated with
    curative resection,

    9. 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).

    10. Patient has a known history of HIV infection (testing not mandatory)

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

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

    - Documented cardiomyopathy

    - Patient has a known Left Ventricular Fraction (LVEF) <50% as determined by
    Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).

    - Long QT syndrome or family history of long QT syndrome or family history of
    idiopathic sudden death or congenital long QT syndrome, or any of the following:
    i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia
    or hypomagnesaemia, history of cardiac failure, or history of clinically
    significant/symptomatic bradycardia ii. Concomitant medications(s) with a known
    risk to prolong the QT interval and/or known to cause Torsades de Pointe that
    cannot be discontinued or replaced by safe alternative medication (e.g. within 5
    half-lives or 7 days prior to starting study drug) iii. Inability to determine
    the QTc interval

    - 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)

    12. Corrected QT interval (QTc) > 480 msec on screening electrocardiogram. If QTc
    prolongation is felt to be related to electrolyte imbalance, an EKG can be repeated
    after correction of electrolytes.

    13. The presence of any other concurrent severe and/or uncontrolled medical condition
    that would, in the investigator or treating physician's judgment, cause unacceptable
    safety risks, contraindicate patient participation in the clinical study or
    compromise compliance with the protocol. This includes uncontrolled infections that
    could potentially be exacerbated by anti-neoplastic treatment, active untreated or
    uncontrolled fungal bacterial or viral infections, etc.

    14. Currently receiving treatment with known strong inducers or inhibitors of cytochrome
    p450 enzymes CYP3A4/5 medications that have a narrow therapeutic window and are
    predominately metabolized through CYP3A4/5 or herbal preparations/medications,
    dietary supplements, which cannot be discontinued at least one week prior to
    receiving investigational drug. Anti-retrovirals, anti-microbials, and
    anti-arrhythmics are the most common medications that interact with these enzymes.
    Section 5: Pharmaceutical Information and Appendix B for more information and a list
    of drugs that should not be used concurrently with ribociclib. In addition, this
    includes grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.

    15. Patients who are receiving any other investigational agents concurrently or have
    received investigational agents within 14 days or 5 half-lives of the compound or
    active metabolites, whichever is longer before the first dose of the study treatment.

    16. Subject is pregnant or nursing. Serum or urine Beta-HCG must be checked in all pre-
    and peri-menopausal patients. (Fulvestrant is pregnancy category D and CDK4/6
    inhibitors have demonstrated teratogenicity/fetotoxicity in animal studies.)

    17. The effects of ribocicilb on the developing human fetus are unknown. For this reason
    and because the effects of chemotherapy are known to be teratogenic, women of
    child-bearing potential and men must agree to use adequate contraception (hormonal or
    barrier method of birth control; abstinence) prior to study entry and for the
    duration of study participation. Should a woman become pregnant or suspect she is
    pregnant while she or her partner is participating in this study, she should inform
    her treating physician immediately. Men treated or enrolled on this protocol must
    also agree to use adequate contraception prior to the study, for the duration of
    study participation, and 3 weeks after completion of ribociclib administration.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Percent progression-free at 24 weeks

    Secondary Outcome Measures

    Overall Response Rate in the fulvestrant/ribociclib group

    Trial Keywords

    Breast Neoplasms

    Breast Cancer

    Breast Carcinoma

    Breast tumors

    Cancer of the Breast