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Erlotinib and Everolimus in Treating Patients With Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00574366
Recruitment Status : Completed
First Posted : December 17, 2007
Last Update Posted : May 10, 2016
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Ingrid Mayer, MD, Vanderbilt-Ingram Cancer Center

Brief Summary:

RATIONALE: Erlotinib and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving erlotinib together with everolimus may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving erlotinib together with everolimus and to see how well it works in treating patients with metastatic breast cancer.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: erlotinib Drug: RAD001 Phase 1

Detailed Description:



  • To determine the safety of everolimus given in combination with erlotinib hydrochloride in patients with metastatic breast cancer (phase I).
  • To determine the antitumor activity of the combination (phase II).
  • Determine the rate of clinical benefit (complete response + partial response + stable disease for at least 6 months) in patients with metastatic breast cancer (phase II).


  • To determine the time to progression.
  • To determine PTEN, pAkt, pP70S6K1 and pEGFR in primary tumors at baseline.

OUTLINE: This is an open-label, dose escalation phase I study followed by an open-label phase II study.

  • Phase I: Patients receive escalating doses of oral everolimus and oral erlotinib hydrochloride once daily until the maximum tolerated dose (MTD) is determined. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. Once the MTD is reached, the recommended dose to be used in the phase II portion of the study is identified.
  • Phase II: Patients receive oral everolimus and oral erlotinib hydrochloride as in phase I at the recommended phase II dose determined in phase I.

Patients undergo tissue collection to evaluate tumor levels of PTEN, pAkt, pP70S6K1, and pEGFR at baseline in order to identify predictors of therapeutic response.

After completion of study treatment, patients are followed every 3 months for 2 years (from study entry), every 6 months for 3 years, and annually thereafter.

NOTE: Phase I completed. Investigator did not proceed with Phase II

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of an Oral MTOR Protein Kinase Inhibitor (Everolimus, RAD001) in Combination With an Oral EGFR Tyrosine Kinase Inhibitor (Erlotinib, Tarceva™) In Patients With Metastatic Breast Cancer
Study Start Date : December 2005
Actual Primary Completion Date : January 2009
Actual Study Completion Date : February 2009

Arm Intervention/treatment
Experimental: Erlotinib/RAD001 Ph I

Tarceva (OSI-774; erlotinib) Everolimus (RAD001)

Study did not progress to Phase II:

Experimental: Erlotinib/RAD001 Phase II Maximum tolerated dose of erlotinib (Tarceva,OSI-774) and RAD001 (Everolimus)

Drug: erlotinib


  • 1 Erlotinib 50 mg/d
  • 2 Erlotinib 50 mg/d

    • 1 Erlotinib 100 mg/d
    • 2 Erlotinib 100 mg/d
    • 3 Erlotinib 150 mg/d
    • 4 Erlotinib 150 mg/d
Other Name: Tarceva (OSI-774)

Drug: RAD001


minus 1: RAD001 2.5 mg/d

minus 2: RAD001 2.5 every other day

  1. RAD001 2.5 mg per day
  2. RAD001 5 mg per day
  3. RAD001 10 mg per day
  4. RAD001 10 mg per day
Other Name: everolimus

Primary Outcome Measures :
  1. To determine the maximum tolerated dose (MTD) of RAD001 given in combination with erlotinib (Phase I) [ Time Frame: at 4 weeks ]
    MTD will be the dose level at which fewer than 2 of 6 (or 33% of) patients experience dose limiting toxicity (DLT), starting at first 4 weeks.

  2. Anti-tumor activity of RAD001 in combination with erlotinib (Phase II) [ Time Frame: at 6 months ]
    Clinical benefit based upon number of patients with complete response (CR), partial response (PR), and stable disease (SD). Responses are determined by Response Evaluation in Solid Tumors (RECIST)criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions

Secondary Outcome Measures :
  1. Time to progression (Phase II) [ Time Frame: from study entry to disease progression ]
    Duration of time to progression of disease.

Other Outcome Measures:
  1. To determine PTEN, pAkt, pP70S6K1 and pEGFR in primary tumors at baseline. [ Time Frame: at day one ]
    Breast tissue paraffin-embedded blocks from patients's pre-treatment diagnostic surgery

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Histologically confirmed adenocarcinoma of the breast
  • Evaluable metastatic disease (no need for measurable disease)
  • Must have had anthracycline therapy in the adjuvant setting or failed anthracycline treatment in the metastatic setting

    • Total cumulative dose of lifetime exposure of doxorubicin not greater than 360 mg/m^2 or epirubicin not greater than 640 mg/m^2
  • Must have failed previous taxane (paclitaxel or docetaxel) therapy, defined as:

    • Taxane use in the adjuvant setting with metastatic relapse within 12 months of therapy
    • Progression on taxane therapy in the metastatic setting
    • Discontinuation of taxane therapy in the metastatic setting secondary to lack of resolution of ≥ grade 2 toxicity
  • No symptomatic brain metastases

    • Patients with a history of brain metastases are eligible provided they are clinically stable and not taking steroids or therapeutic anticonvulsants that are CYP3A4 modifiers
    • Patients with asymptomatic brain metastasis are eligible provided they are not on prophylactic anticonvulsants that are CYP3A4 modifiers
  • Hormone receptor status not specified


Inclusion criteria

  • Menopausal status not specified
  • ECOG performance status 0-1
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • SGOT and SGPT ≤ 2.5 times ULN
  • Albumin > 30 g/L
  • Creatinine ≤ 1.5 upper limit of normal
  • INR normal provided the patient is not on warfarin therapy
  • Not pregnant or nursing
  • Negative pregnancy test for premenopausal patients
  • Fertile patients must use effective barrier method contraception during and for 3 months after completion of study treatment
  • Patients must be disease-free of prior invasive cancers for > 5 years with the exception of basal cell or squamous cell cancer of the skin or cervical carcinoma in situ

Exclusion criteria

  • Serious or non-healing active wound, ulcer, or bone fracture
  • Known human immunodeficiency virus positivity
  • Uncontrolled intercurrent illness including, but not limited to, any of the following

    • Ongoing or active infection requiring parenteral antibiotics
    • Impairment of lung function (COPD, lung conditions requiring oxygen therapy)
    • Symptomatic congestive heart failure (New York Heart Association class III or IV heart disease)
    • Unstable angina pectoris or myocardial infarction within the past 6 months
    • Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg or diastolic blood pressure > 100 mm Hg, found on two consecutive measurements separated by a 1-week period despite adequate medical support)
    • Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment)
    • Uncontrolled diabetes
    • Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary


Inclusion criteria

  • See Disease Characteristics
  • Prior trastuzumab (Herceptin®) in the first-line treatment of metastatic breast cancer is required for patients who have HER2/neu overexpressing tumors
  • More than 6 months since prior cardiac angioplasty or stenting
  • Use of endocrine therapy (i.e., aromatase inhibitors, fulvestrant, tamoxifen or ovarian ablation) in the first-line treatment of metastatic breast cancer is required for patients who have estrogen receptor and or progesterone receptor expressing tumors

    • Concurrent endocrine therapy is not allowed
  • Patients may receive concurrent radiotherapy to painful bone metastases or areas of impending bone fracture as long as radiotherapy is initiated prior to study entry

    • Patients who have received prior radiotherapy must have recovered from toxicity induced by this treatment
  • More than 3 weeks since prior chemotherapy, biological or hormonal therapy while on protocol therapy.
  • No other concurrent antineoplastic or antitumor agents, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy

Exclusion criteria

  • More than 3 prior chemotherapy treatments in the metastatic setting

    • This restriction does not include endocrine therapies or single agent biologic therapies (i.e., trastuzumab [Herceptin®])
  • Use of steroids or immunosuppressants
  • Use of CYP3A4 modifiers
  • Concurrent therapy with trastuzumab (Herceptin®)
  • Use of growth support factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], recombinant erythropoietin) during the phase I portion of the study
  • Other concurrent investigational agents

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00574366

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United States, Tennessee
Vanderbilt-Ingram Cancer Center - Cool Springs
Nashville, Tennessee, United States, 37064
Vanderbilt-Ingram Cancer Center at Franklin
Nashville, Tennessee, United States, 37064
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232-6838
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
National Cancer Institute (NCI)
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Study Chair: Ingrid Mayer, MD Vanderbilt-Ingram Cancer Center

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Responsible Party: Ingrid Mayer, MD, Assistant Professor of Medicine; Clinical Director, Breast Cancer Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center Identifier: NCT00574366    
Obsolete Identifiers: NCT00179270
Other Study ID Numbers: VICC BRE 0523
First Posted: December 17, 2007    Key Record Dates
Last Update Posted: May 10, 2016
Last Verified: May 2016
Keywords provided by Ingrid Mayer, MD, Vanderbilt-Ingram Cancer Center:
recurrent breast cancer
stage IV breast cancer
male breast cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Erlotinib Hydrochloride
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action