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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

Phase 1
18 Years
Not Enrolling
Breast Cancer

Thank you

Trial Information

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



- 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

Inclusion Criteria


- 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

- 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

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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the maximum tolerated dose (MTD) of RAD001 given in combination with erlotinib (Phase I)

Outcome Description:

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.

Outcome Time Frame:

at 4 weeks

Safety Issue:


Principal Investigator

Ingrid Mayer, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

December 2005

Completion Date:

February 2009

Related Keywords:

  • Breast Cancer
  • recurrent breast cancer
  • stage IV breast cancer
  • male breast cancer
  • Breast Neoplasms



Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Vanderbilt-Ingram Cancer Center - Cool SpringsNashville, Tennessee  37064
Vanderbilt-Ingram Cancer Center at FranklinNashville, Tennessee  37064