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Randomized Phase II Trial of Trastuzumab or EVEROLIMUS in Hormone-refractory Metastatic Breast Cancer

Phase 2
18 Years
Open (Enrolling)
Breast Cancer

Thank you

Trial Information

Randomized Phase II Trial of Trastuzumab or EVEROLIMUS in Hormone-refractory Metastatic Breast Cancer

The purpose of this study is to investigate if trastuzumab or everolimus alone or in
combination are effective for metastatic breast cancers that are no longer controlled with (
are resistant to) hormonal therapies, and express small to moderate amounts of HER2/neu.
There is no standard of care for disease once it becomes resistant to hormonal therapy, and
many patients are treated with chemotherapy. Trastuzumab alone or trastuzumab in
combination with everolimus, have not been previously used to treat breast cancers than are
resistant to hormonal therapies and have small to moderate amounts of HER2/neu. Everolimus
alone has been demonstrated to improve outcome for patients with hormone-resistant
metastatic breast cancer that is resident to hormonal agents.

In this study participants will be randomized 50:50 to receive trastuzumab alone or
everolimus alone alone with the most recent hormonal agent they have taken. At the time of
disease progression, patients randomized to receive trastuzumab will start everolimus, and
patients randomized to everolimus will receive trastuzumab, so that all patients ultimately
receive both agents. Trastuzumab is widely used to treat all stages of breast cancer, and is
currently approved for the treatment of early and advanced breast cancer that have very high
amounts of HER2/neu. Everolimus, when given with hormonal therapy, has been demonstrated to
improve outcome for patients with hormone-resistant metastatic breast cancer. Patients will
continue on the most recent hormonal therapy they received prior to entering this study.

It is hoped that trastuzumab alone, everolimus alone, or trastuzumab in combination with
everolimus, may cause your tumor to stop growing or possibly to cause your tumor to shrink.
This assessment will be based on measuring changes in the size of your tumor. You will be
requested to have a biopsy of one of your metastatic areas prior to study entry to measure
the amount of HER2/neu protein in your tumor.

Inclusion Criteria:

Patients will be included in the study based on the following criteria:

- Hormone-refractory metastatic breast cancer defined as disease progression within 6
months from starting most recent hormonal therapy

- At least 2 prior endocrine therapies, including in the adjuvant setting. Patients
must have had at least one hormonal agent in the metastatic setting

- Candidate for hormonal therapy (ER and/or PR-positive at primary diagnosis and at
metastatic diagnosis where tissue is available)

- HER2/neu-negative breast cancer by standard criteria (FISH-negative and IHC <3+) at
primary diagnosis

- If biopsy of metastatic lesion is performed prior to study entry, HER2 expression by
IHC must be 1+ or 2+.

- Histologically confirmed, measurable disease

- Life expectancy > 6 months

- Age >18 years

- ECOG performance status

- Adequate bone marrow function as indicated by the following:

ANC >1500/uL Platelets ≥100,000/uL Hemoglobin >10 g/dL

- Adequate renal function, as indicated by creatinine ≤1.5x upper limit of normal (ULN)

- Adequate liver function, as indicated by bilirubin ≤1.5x ULN

- INR ≤ 1.3 (or ≤ 3 on anticoagulants)

- AST or ALT <2x ULN unless related to primary disease.

- Signed informed consent

- Adequate birth control

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5
x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can
only be included after initiation of appropriate lipid lowering medication.

Exclusion Criteria:

Patients will be excluded from the study based on the following criteria:

- Prior treatment with trastuzumab or other HER2-directed therapies or with an mTOR
inhibitor within 12 months of study entry (when cancer was not definitely hormone
refractory) (25)

- HER2 0 or 3+ by IHC on pre-treatment biopsy of metastatic lesion (if performed)

- Active infection

- Uncontrolled central nervous system metastases

- Pregnant or lactating women

- Prior chemotherapy within the last 4 weeks

- Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator
lesion (unless objective disease recurrence or progression within the radiation
portal has been documented since completion of radiation).

- Concomitant malignancies or previous malignancies within the last 5 years, with the
exception of adequately treated basal or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix.

- History of significant cardiac disease, cardiac risk factors or uncontrolled

- Ejection fraction <50% or below the lower limit of the institutional normal range,
whichever is lower

- Hypersensitivity to trial medications

- Emotional limitations

- Prior treatment with any investigational drug within the preceding 4 weeks Patients
receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent

- uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

- liver disease such as cirrhosis, chronic active hepatitis or chronic persistent

- A known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

- Patients with an active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. If barrier
contraceptives are being used, these must be continued throughout the trial by both
sexes. Hormonal contraceptives are not acceptable as a sole method of contraception.
(Women of childbearing potential must have a negative urine or serum pregnancy test
within 7 days prior to administration of RAD001)

- Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus).

- Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs,
resulting in dyspnea at rest

- Taking any of the following agents:

- chronic treatment with systemic steroids or another immunosuppressive agent

- live vaccines

- drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rate

Outcome Time Frame:

Every 8 to 12 weeks

Safety Issue:


Principal Investigator

Ruth O'Regan, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Emory University Winship Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

May 2009

Completion Date:

October 2014

Related Keywords:

  • Breast Cancer
  • Breast Cancer
  • Breast Neoplasms



Emory University Winship Cancer InstituteAtlanta, Georgia  30322