Clinical Trials /

A Trial of Ribocilcib (LEE011) and Weekly Paclitaxel in Patients With Rb+ Advanced Breast Cancer

NCT02599363

Description:

This is a Phase I study to assess the safety and MTD of paclitaxel + ribociclib (LEE011) in patients with Rb+, advanced breast cancer. Dose escalation will be performed using standard 3 + 3 dosing strategy. The starting dose of ribociclib (LEE011) is 200 mg once daily; dose escalation proceeds in 200 mg increments up to a maximum of 600 mg. Dose-limiting toxicities (DLT) will be based upon first-cycle toxicity.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

A Trial of Ribocilcib (<span class="go-doc-concept go-doc-intervention">LEE011</span>) and Weekly <span class="go-doc-concept go-doc-intervention">Paclitaxel</span> in Patients With Rb+ Advanced Breast Cancer

Title

  • Brief Title: A Trial of Ribocilcib (LEE011) and Weekly Paclitaxel in Patients With Rb+ Advanced Breast Cancer
  • Official Title: A Phase I Trial of Ribocilcib (LEE011) and Weekly Paclitaxel in Patients With Rb+ Advanced Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02599363

    ORG ID: UPCC 06115

    Trial Conditions

    Advanced Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Ribociclib (LEE011)
    Paclitaxel

    Trial Purpose

    This is a Phase I study to assess the safety and MTD of paclitaxel + ribociclib (LEE011) in
    patients with Rb+, advanced breast cancer. Dose escalation will be performed using standard
    3 + 3 dosing strategy. The starting dose of ribociclib (LEE011) is 200 mg once daily; dose
    escalation proceeds in 200 mg increments up to a maximum of 600 mg. Dose-limiting toxicities
    (DLT) will be based upon first-cycle toxicity.

    Detailed Description

    Trial Arms

    Name Type Description Interventions

    Eligibility Criteria

    Inclusion Criteria:

    - Patient must have histologically or cytologically confirmed breast cancer that is now
    metastatic; any ER, PR or HER2 status is allowed.

    - Biopsy confirming metastatic breast cancer and Retinoblastoma protein (Rb) positivity
    by immunohistochemistry prior to enrolling on this protocol is required.

    - Biopsy must be obtained immediately before study enrollment; no intervening
    treatments are allowed.

    - Patient must have measurable disease defined by RECIST 1.1 criteria.

    - Age 18 years

    - Patient must have received 3 prior cytotoxic regimens in the metastatic setting.

    - Performance status of 0-1 on the ECOG Performance Scale.

    - The subject must have adequate organ function, defined as follows

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

    - In the absence of liver metastases, alanine aminotransferase (AST) and aspartate
    aminotransferase (ALT) < 2.5 x ULN. If the patient has liver metastases, ALT and
    AST < 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.

    - For subjects without extensive bone metastases: alkaline phosphatase levels <
    2.5 x ULN

    - 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

    - INR 1.5 unless on warfarin in which case INR <3.0 is acceptable.

    - The subject must have adequate marrow function, defined as follows

    - Leukocytes Absolute neutrophil count (ANC) 1500/mm3

    - Platelets 100,000/mm3, and

    - Hemoglobin 9 g/dL

    - The subject must be able to swallow ribociclib (LEE011)

    Exclusion Criteria

    - Patient is currently participating or has participated in a study with an
    investigational compound or device within 30 days of Study Day 1 or within 5
    half-lives of the investigational product, whichever is longer, with the exception of
    a prior CDK 4/6 inhibitor.

    - Patient has had prior toxicity from a CDK 4/6 inhibitor necessitating discontinuation
    of the drug. Patient may have had prior treatment with a cdk 4/6 inhibitor in the
    adjuvant or metastatic setting.

    - Patient who has had chemotherapy or exposure to a CDK 4/6 inhibitor within 3 weeks (6
    weeks for nitrosoureas, mitomycin C or bevacizumab) who has not recovered from the
    adverse events due to previous agents administered more than 4 weeks prior to Study
    Day 1. Hormonal therapy must be discontinued at least 24 hours prior to starting
    study treatment.

    - Patient is unable to have a biopsy of a metastatic site for Rb testing, because the
    biopsy is felt to be too invasive or risky by the treating physician.

    - Patient has not received available therapies that confer clinical benefit.

    - Patient has known active CNS metastases and/or carcinomatous meningitis. However,
    patients with CNS metastases (including brain metastases) are eligible for the study
    provided they are clinically stable and have met 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.

    - Patient has known hypersensitivity to any of the excipients of ribociclib

    - The subject has uncontrolled intercurrent illness including, but not limited to:

    - Ongoing or active infection

    - Diabetes mellitus

    - Symptomatic congestive heart failure (see 5.2.14), unstable angina pectoris,
    stroke or myocardial infarction within 12 months of screening

    - Patient has baseline neuropathy of grade 2.

    - Patients who have known allergic reactions to paclitaxel or IV contrast dye despite
    standard prophylaxis.

    - The subject is known to be positive for the human immunodeficiency virus (HIV). Note:
    baseline HIV screening is not required

    - The subject is unable or unwilling to abide by the study protocol or cooperate fully
    with the investigator or designee.

    - 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.

    - Patient is not able to swallow oral medication and/or 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).

    - Patient has 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 study or compromise compliance
    with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active
    untreated or uncontrolled fungal, bacterial or viral infections, etc.).

    - Patient has active cardiac disease or a history of cardiac dysfunction 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 12 months prior to screening

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

    - Documented cardiomyopathy

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

    - History of ventricular, supraventricular, nodal arrhythmias, or any other cardiac
    arrhythmias, long QT Syndrome or conduction abnormality within 12 months of screening

    - Congenital long QT syndrome or family history of long QT syndrome

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

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

    - On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable
    or not interpretable) or QTcF > 450 msec (using Fridericia's correction). All as
    determined by screening ECG (mean of triplicate ECGs)

    - Patient is currently receiving any of the following medications and cannot be
    discontinued 7 days prior to starting study drug (see Table 6.2 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

    - That have a known risk to prolong the QT interval or induce Torsades de Pointes

    - Patient is currently receiving or has received systemic corticosteroids 2 weeks
    prior to starting study drug, or has not fully recovered from side effects of such
    treatment. The following uses of corticosteroids are permitted: single doses, topical
    application (e.g., for rash), inhaled sprays (e.g., for obstructive airway 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 therapeutic study within 30 days prior to
    enrollment or within 5 half-lives of the investigational product, whichever is
    longer.

    - Patient who has received radiotherapy 4 weeks or limited field radiation for
    palliation 2 weeks prior to starting study drug, and who has not recovered to grade
    1 or better from related side effects of such therapy (exceptions include alopecia)
    and/or in whom 25% of the bone marrow was irradiated.

    - Patient has had major surgery within 14 days prior to starting study drug or has not
    recovered from major side effects (all surgical wounds must be fully healed). For the
    purpose of this criterion, a major surgical procedure is defined as one requiring the
    administration of general anesthesia (tumor biopsy is not considered as major
    surgery).

    - 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
    degree of alopecia are allowed to enter the study).

    - Patient with a Child-Pugh score B or C

    - Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
    female after conception and until the termination of gestation, confirmed by a
    positive hCG laboratory test.

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

    - 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

    - Combination of any two of the following (a+b or a+c or b+c) Use of oral, injected or
    implanted hormonal methods of contraception or other forms of hormonal contraception
    that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or
    transdermal hormone contraception 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

    - In case of use of oral contraception, women should have been stable on the same pill
    before taking study treatment.

    - Note: Oral contraceptives are allowed but should be used in conjunction with a
    barrier method of contraception due to unknown effect of drug-drug interaction.

    - 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of Adverse Events

    Secondary Outcome Measures

    Trial Keywords