Clinical Trials /

An Open-Label, Phase Ib/II Clinical Trial Of Cdk 4/6 Inhibitor, Ribociclib (Lee011), In Combination With Trastuzumab Or T-Dm1 For Advanced/Metastatic Her2-Positive Breast Cancer.

NCT02657343

Description:

Participants that have breast cancer that has spread to other parts of the body, is positive for a protein called HER2, and has not responded to standard treatment. This research study is a way of gaining new knowledge about the combination of Ribociclib with other drugs as a possible treatment for this diagnosis.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

An Open-Label, Phase Ib/II Clinical Trial Of Cdk 4/6 Inhibitor, <span class="go-doc-concept go-doc-intervention">Ribociclib</span> (Lee011), In Combination With <span class="go-doc-concept go-doc-intervention">Trastuzumab</span> Or <span class="go-doc-concept go-doc-intervention">T-Dm1</span> For Advanced/Metastatic Her2-Positive Breast Cancer.

Title

  • Brief Title: An Open-Label, Phase Ib/II Clinical Trial Of Cdk 4/6 Inhibitor, Ribociclib (Lee011), In Combination With Trastuzumab Or T-Dm1 For Advanced/Metastatic Her2-Positive Breast Cancer.
  • Official Title: An Open-Label, Phase Ib/II Clinical Trial Of Cdk 4/6 Inhibitor, Ribociclib (Lee011), In Combination With Trastuzumab Or T-Dm1 For Advanced/Metastatic Her2-Positive Breast Cancer.
  • Clinical Trial IDs

    NCT ID: NCT02657343

    ORG ID: 15-530

    NCI ID: CLEE011XUS20T

    Trial Conditions

    Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Ribociclib LEE-011 Cohort A, Cohort B
    T-DM1 Kadcyla Cohort A
    Trastuzumab Herceptin Cohort B

    Trial Purpose

    Participants that have breast cancer that has spread to other parts of the body, is positive
    for a protein called HER2, and has not responded to standard treatment. This research study
    is a way of gaining new knowledge about the combination of Ribociclib with other drugs as a
    possible treatment for this diagnosis.

    Detailed Description

    This research study is a Phase I clinical trial, which tests the safety of an
    investigational intervention and also tries to define the appropriate dose of the
    investigational intervention to use for further studies.

    Ribociclib is a drug that is designed to block certain proteins called Cyclin-Dependent
    Kinases (CDKs) that are required for cells to divide. These proteins may also control the
    ability of certain cancers to grow.

    In this research study, we are looking for the safe and tolerated dose of ribociclib that
    can be given in combination with trastuzumab emtansine (T-DM1). T-DM1 is a standard
    treatment for patients with HER2-positive breast cancer.

    The FDA (the U.S. Food and Drug Administration) has not approved Ribociclib as a treatment
    for any disease.

    Trial Arms

    Name Type Description Interventions
    Cohort A Experimental Ribociclib will be given orally once day (day 5-18) at a pre-determine dose for two weeks of a 21 day cycle. T-DM1 will be given as IV infusions on Day 1 of a 3 week cycle at a pre-determined dose over pre-determined period of time. Ribociclib, T-DM1
    Cohort B Experimental Ribociclib will be given orally once day continuously for a 21-day cycle of treatment (except at Dose Level -2, when Ribociclib is given Days 1-14 of a 21 day cycle). Trastuzumab will be given as IV infusions over a pre-determined period of time and dose. Ribociclib, Trastuzumab

    Eligibility Criteria

    Inclusion Criteria:

    - Participants must have histologically confirmed invasive breast cancer, with locally
    advanced or metastatic disease. Patients without pathologic confirmation of
    metastatic disease should have unequivocal evidence of metastasis from physical
    examination or radiologic evaluation.

    - The primary tumor, and/or metastasis must have been tested for ER, PR and HER 2, and
    be HER2 positive as defined by the 2013 ASCO-CAP guidelines.

    - Measureable disease by RECIST 1.1 (at least one lesion that can be accurately
    measured in at least one dimension > 20mm with conventional imaging techniques or >
    10mm with spiral CT or MRI) or evaluable disease. Bone lesions (blastic, lytic, or
    mixed) in the absence of measurable disease as defined above are also acceptable.

    - Prior treatment

    - Cohort A:

    - Prior treatment with at least one regimen containing Trastuzumab and taxane.

    - No prior treatment with T-DM1 that was discontinued due to disease progression
    or toxicity.

    - No more than 4 prior lines of therapy in the metastatic setting.

    - Cohort B:

    - Must have received prior Trastuzumab, pertuzumab, and T-DM1 in neo-adjuvant,
    adjuvant, or metastatic setting.

    - No limit on prior lines of therapies.

    - Age 18 years.

    - ECOG performance status 0-2 (see Appendix A)

    - Participants must have adequate organ and bone marrow function as defined below:

    - Absolute neutrophil count 1.5 x 109/L

    - Platelets 100 x 109/L

    - Hemoglobin 9 g/dL

    - Total bilirubin < 1.5xULN; or total bilirubin 3.0 x ULN or direct bilirubin
    1.5 x ULN in patients with well-documented Gilbert's Syndrome.

    - Serum creatinine 1.5 mg/dL or calculated GFR 50mL/min

    - ALT/AST <2.5x ULN; if liver metastases, ALT/AST 5.0x ULN

    - INR 1.5

    - 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

    - Biopsies:

    - Cohort B: all patients with disease that is deemed by the treating investigator
    as safely accessible to biopsy are required to undergo research biopsies as
    outlined in this protocol.

    Cohort A: Such biopsies are optional.

    - A negative serum pregnancy test 72 hours before starting study treatment for
    premenopausal women and for women < 1 year after the onset of menopause.

    - Ability to understand and the willingness to sign a written informed consent
    document.

    - Participants must be able to swallow Ribociclib capsules.

    - Patients must have at screening a standard 12-lead ECG with mean values that meet the
    following parameters:

    - QtcF interval at screening < 450msec (using Friderica's correction)

    - Resting heart rate of 50-90bpm

    Exclusion Criteria:

    - Participants who have had chemotherapy within 14 days prior registration or those who
    have 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). There is no washout period required for
    Trastuzumab.

    - Participants who have received radiotherapy 2 weeks prior to starting study drug,
    and who have not recovered to grade 1 or better from related side effects of such
    therapy (except alopecia and neuropathy) and/or in whom 25% of the bone marrow was
    irradiated.

    - Participants who have previously received a CDK 4/6 inhibitor.

    - Participants with central nervous system (CNS) involvement unless they meet ALL of
    the following criteria:

    - At least 4 weeks from prior therapy completion (including radiation and/or
    surgery) to starting the study treatment

    - Clinically stable CNS tumor at the time of screening and not receiving steroids
    and/or enzyme-inducing anti-epileptic medications for brain metastases.

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to ribociclib, T-DM1 (Cohort A) and/or Trastuzumab (Cohort B).

    - In general, the use of any concomitant medication deemed necessary for the care of
    the patient is permitted in this study, except as specifically prohibited below.
    Combination administration of study drugs could result in drug-drug interactions
    (DDI) that could potentially lead to reduced activity or enhanced toxicity of the
    concomitant medication and/or Ribociclib.

    - Patient is currently receiving any of the following medications and cannot
    discontinue use within 7 days prior to starting study drug (see (Tables 1 and 2,
    Appendix B for details):

    - Known strong inducers or inhibitors of CYP3A4/5, including grapefruit,
    grapefruit hybrids, pummelos, star-fruit, and Seville oranges

    - That have a narrow therapeutic window and are predominantly metabolized through
    CYP3A4/5

    - Herbal preparations/medications, dietary supplements.

    - The list provided here (and in Tables 1 and 2, Appendix B) is not comprehensive and
    is only meant to be used as a guide. The list is based on the Oncology Clinical
    Pharmacology Drug-Drug Interaction Database (release date: 29 Oct 2012), which was
    compiled from the Indiana University School of Medicine's P450 Drug Interaction
    Table.

    - http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA
    Draft Guidance for Industry, Drug Interaction Studies - Study Design, Data Analysis,
    and Implications for Dosing and Labeling (February 2012)
    (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf), and the University of Washington's Drug Interaction Database (http://www.druginteractioninfo.org/). For current lists of medications that may cause QT prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds website (https://crediblemeds.org/).

    - Participants who have any other concurrent severe and/or uncontrolled medical
    condition that would, in the investigator's judgment, cause unacceptable safety
    risks, contraindicate patient participation in the clinical trial or compromise
    compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis,
    active untreated or uncontrolled fungal, bacterial or viral infections, etc.).

    - Participants who have had major surgery within 2 weeks prior to starting study drug
    or has not recovered from major side effects (tumor biopsy is not considered as major
    surgery).

    - Participants who have clinically significant, uncontrolled heart disease and/or
    cardiac repolarization abnormalities including any of the following:

    - 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

    - History of documented congestive heart failure (New York Heart Association
    functional classification III-IV)

    - 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

    - Documented cardiomyopathy

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

    - Long QT syndrome or family history of idiopathic sudden death or congenital long
    QT syndrome, or any of the following

    - Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia
    or hypomagnesemia, history of cardiac failure, or history of clinically
    significant/symptomatic bradycardia.

    - Inability to determine the QT interval on screening (QTcF, using
    Fridericia's correction)

    - Systolic blood pressure (SBP)>160 mmHg or <90 mmHg at screening

    - Known history of HIV-positivity.

    - Active Hepatitis B and/or Hepatitis C Infection

    - Known impairment of gastrointestinal (GI) function or GI disease that may
    significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative
    diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
    bowel resection).

    - Concurrent malignancy or a 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. Participants
    with malignancies less than 3 years prior to registration may be considered eligible
    after discussion with the principle investigator.

    - Participants who are currently receiving or have received systemic corticosteroids 2
    weeks prior to starting study drug, or who have not fully recovered from side effects
    of such treatment. The following uses of corticosteroids are permitted: single doses,
    topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways
    diseases), eye drops or local injections (e.g., intra-articular).

    - 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.

    - Participation in a prior investigational study within 30 days prior to enrollment or
    within 5 half-lives of the investigational product, whichever is longer.

    - Patient with a Child-Pugh score B or C.

    - Participants who have a history of non-compliance to medical therapies.

    - Pregnant women are excluded from this study because Ribociclib has the potential for
    teratogenic or abortifacient effects. Because there is an unknown but potential risk
    for adverse events in nursing infants secondary to treatment of the mother with
    Ribociclib, breastfeeding should be discontinued if the mother is treated with
    Ribociclib. These risks also apply to Trasutuzumab used in this study. Pregnancy is
    defined as the state of a female after conception and until the termination of
    gestation, confirmed by a postitive hCG laboratory test (>5 mIU/mL).

    - 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. Highly
    effective contraception methods include:

    - Total abstinence when this is in line with the preferred and usual lifestyle of
    the patient.

    - Female sterilization (have had surgical bilateral oophorectomy with or without
    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

    - Male sterilization (at least 6 months prior to screening). For female patients
    on the study, the vasectomized male partner should be the sole partner for that
    patient

    - Combination of the two following

    - Placement of an intrauterine device (IUD) or intrauterine system (IUS)

    - Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
    cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal
    suppository.

    - Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
    methods) and withdrawal are not acceptable methods of contraception 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.

    - Sexually active males unless they use a condom during intercourse while taking the
    drug and for 4 months after stopping treatment and should not father a child in this
    period. A condom is required to be used also by vasectomized men in order to prevent
    delivery of the drug via seminal fluid.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (Mtd) And/Or Recommended Phase2 Dose (RP2D)

    Clinical Benefit Rate (CBR) By RECIST

    Secondary Outcome Measures

    Plasma Concentrations Of Ribociclib

    Objective Response Rate (ORR)

    Progression-Free Survival (PFS)

    Overall Survival (OS)

    Frequencies Of Biomarkers

    Frequencies of Adverse Events

    Trial Keywords

    Breast Cancer With Positive HER2