Clinical Trials /

Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer

NCT01857193

Description:

Dose Escalation part of the study: To estimate the MTD(s) and/ or RP2D of LEE011 in combination with everolimus + exemestane, and LEE011 in combination with exemestane, and to characterize the safety and tolerability of the combinations of everolimus + exemestane + LEE011 and LEE011 + exemestane in patients with ER+ HER2- advanced breast cancer Dose Expansion part of the study: To characterize the safety and tolerability of the triplet combination of LEE011 + everolimus + exemestane in patients naïve or refractory to CDK4/6 inhibitor based therapy, and the safety and tolerability of the doublet combination of LEE011 + exemestane in patients refractory to CDK4/6 inhibitor based therapy (except patients treated with prior LEE011 are not allowed in Group 3).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Phase Ib/II Trial of LEE011 With <span class="go-doc-concept go-doc-intervention">Everolimus (RAD001)</span> and <span class="go-doc-concept go-doc-intervention">Exemestane</span> in the Treatment of ER+ Her2- Advanced <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Phase Ib/II Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of ER+ Her2- Advanced Breast Cancer
  • Official Title: A Phase Ib/II Trial of LEE011 in Combination With Everolimus (RAD001) and Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive, Her2- Locally Advanced or Metastatic Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT01857193

    ORG ID: CLEE011X2106

    Trial Conditions

    Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    LEE011 L-R-E arm, L-E arm
    Exemestane L-R-E arm, L-E arm, R-E arm
    Everolimus L-R-E arm, R-E arm

    Trial Purpose

    To estimate the MTD(s) and/ or RP2D of LEE011 in combination with everolimus + exemestane,
    and LEE011 in combination with exemestane, and to characterize the safety and tolerability
    of the combinations of everolimus + exemestane LEE011 and LEE011 + exemestane in patients
    with ER+ HER2- advanced breast cancer

    Detailed Description

    The primary purpose of the phase Ib part of this study is to determine the maximum tolerated
    dose(s) (MTD(s)) and/or recommended phase II dose (RP2D) of LEE011 + everolimus + exemestane
    in patients with ER+ Her2- advanced breast cancer. This part of the study will also assess
    safety, tolerability, and PK of the LEE011 + exemestane, LEE011 + everolimus + exemestane
    combinations.

    The phase II part of the study will evaluate the triple combination of LEE011 + everolimus +
    exemestane and the double combination of LEE011 + exemestane in comparison to everolimus +
    exemestane. Safety, tolerability and PK (in a subset of patients) will also be assessed.

    Trial Arms

    Name Type Description Interventions
    L-R-E arm Experimental LEE011 + everolimus + exemestane triple combination LEE011, Exemestane, Everolimus
    L-E arm Experimental LEE011 + exemestane double combination LEE011, Exemestane
    R-E arm Active Comparator everolimus + exemestane double combination Exemestane, Everolimus

    Eligibility Criteria

    Inclusion Criteria:

    - Adult women ( 18 years of age) with metastatic or locally advanced breast cancer not
    amenable to curative treatment by surgery or radiotherapy

    - Histological or cytological confirmation of estrogen-receptor positive (ER+) breast
    cancer

    - A representative tumor specimen must be available for molecular testing. An archival
    tumor sample may be submitted; if one is not available, a newly obtained tumor
    specimen must be submitted instead

    - Postmenopausal women. Postmenopausal status is defined either by:

    - Age 18 with prior bilateral oophorectomy

    - Age 60 years

    - Age <60 years with amenorrhea for at least 12 months and both follicle-stimulating
    hormone (FSH) and estradiol levels are in postmenopausal range (according to the
    local laboratory)

    - Recurrence while on, or within 12 months of end of adjuvant treatment with letrozole
    or anastrozole, or

    - Progression while on, or within one month of end of letrozole or anastrozole
    treatment for locally advanced or metastatic breast cancer.

    - Patients must have:

    - Measurable disease*: At least one lesion that can be accurately measured in at
    least one dimension 20 mm with conventional imaging techniques or 10 mm with
    spiral CT or MRI or

    - Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable
    disease as defined above.

    - ECOG Performance Status 0-1.

    - Fasting serum cholesterol 300 mg/dl or 7.75 mmol/L and fasting triglycerides 2.5
    ULN. In case one or both of these thresholds are exceeded, the patient can only be
    included after initiation of statin therapy and when the above mentioned values have
    been achieved.

    - Exception for Phase Ib patients: measurable disease is not required

    Exclusion Criteria:

    - Her2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ
    hybridization positive).

    - Patients who received more than one chemotherapy line for advanced breast cancer.

    - Previous treatment with CDK4/6 inhibitors, exemestane or mTOR inhibitors*.

    - History of active or symptomatic brain or other CNS metastases.

    - Impaired cardiac function or clinically significant cardiac diseases, including any
    of the following:

    - Left ventricular ejection fraction (LVEF) < 45% or less than the institution lower
    limit of normal as determined by multiple gated acquisition scan (MUGA) or
    echocardiogram (ECHO)

    - Congenital long QT syndrome or family history of unexpected sudden cardiac death

    - QT corrected with Fredericia's (QTcF) >470 ms for females on screening ECG

    - Any other clinically significant heart disease such as angina pectoris, resting
    bradycardia, left bundle branch block, ventricular tachyarrhythmia, unstable atrial
    fibrillation, Right bundle branch block with left anterior hemiblock (bifascicular
    block), acute myocardial infarction or any heart disease that requires the use of a
    cardiac pacemaker or implantable cardioverter defibrillator 3 months prior to
    starting study drug.

    - Patients who are currently receiving treatment with agents that are known to cause
    QTc prolongation in humans.

    - Patients who are currently receiving treatment (within five days prior to
    randomization) with agents that are metabolized predominantly through CYP3A4 and that
    have a narrow therapeutic window. Agents that are known strong inducers or
    inhibitors CYP3A4 are prohibited (Refer to Appendix 4) * Exceptions for Phase Ib
    patients:

    1. Patients who received more than two prior lines of chemotherapy are eligible

    2. Patients who received CDK4/6 inhibitors, exemestane or mTOR inhibitors are
    eligible

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Incidence of dose limiting toxicity (DLT)- Phase Ib

    Progression Free Survival (PFS)- Phase II

    Secondary Outcome Measures

    Incidence of adverse drug reactions

    Incidence of serious adverse events

    Plasma concentration-time profiles - Phase Ib/II

    Overall Response Rate (ORR)- Phase Ib and Phase II

    Duration Of Response (DOR) - Phase Ib, Phase II

    Overall Survival (OS) - Phase II

    Plasma concentration-time profiles: AUCtau - Phase Ib/II

    Plasma concentration-time profiles - Cmin Phase Ib/II

    Plasma concentration-time profiles - Cmax Phase Ib/II

    Plasma concentration-time profiles - Tmax Phase Ib/II

    Plasma concentration-time profiles - Racc Phase Ib/II

    Disease Control Rate (DCR) - Phase Ib, Phase II

    Trial Keywords

    Open label; dose escalation; ER+; LEE011; CDK4/6; everolimus; advanced breast cancer; mTor; HR+; Her2-