Breast Cancer
Conditions
Keywords
Breast Cancer
Brief summary
This phase II trial studies how well everolimus with or without trastuzumab works in treating patients with breast cancer that has not responded to hormone therapy and has spread from where it started to other places in the body. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving everolimus and adding trastuzumab at the time of disease progression may be an effective treatment for breast cancer.
Detailed description
Breast cancer is the most common type of invasive cancer in women, with more than 1 million cases and almost 600,000 deaths occurring worldwide annually. Breast cancer that has spread to other parts of the body (metastasized) is usually not curable. Patients with a type of metastatic breast cancer that has hormone receptors on the surface of the cancer cells are usually treated with the drug tamoxifen, which interferes with the function of these hormone receptors. However, the average survival time for these patients remains at around 36 months. In patients who no longer respond to tamoxifen (hormone-refractory breast cancer), the cancer drug trastuzumab (Herceptin), which acts on a protein called human epidermal growth factor receptor 2 (HER2), may have some activity. In addition, studies suggest that the drug everolimus, which acts on a pathway within cancer cells that is important for growth of the tumor, may make the cancer cells more sensitive to treatment with trastuzumab. Thus, the two drugs may act together to increase their anti-cancer potential.
Interventions
DRUGEverolimus
BIOLOGICALTrastuzumab
Sponsors
Genentech, Inc.
Novartis Pharmaceuticals
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 one line of endocrine therapy in the metastatic setting * Candidate for hormonal therapy (ER and/or progestin receptor \[PR\]-positive at primary diagnosis and at metastatic diagnosis where tissue is available) * HER2/neu-negative breast cancer by standard criteria (immunohistochemistry \[IHC\] \< 3+ or fluorescence in situ hybridization \[FISH\]-negative if IHC 3+) at primary diagnosis * Must have a biopsy in the metastatic setting with HER2 expression of 1+ or 2+ by IHC * If biopsy of metastatic lesion is performed prior to study entry, HER2 expression by IHC must be 1+ or 2+ * Histologically confirmed, measurable or evaluable disease; if disease is measurable, Response Evaluation Criteria In Solid Tumors (RECIST) criteria should be used * Life expectancy \> 6 months * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Adequate bone marrow function as indicated by the following: * Absolute neutrophil count (ANC) \> 1500/µL * Platelets ≥ 100,000/µL * 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 * International normalized ratio (INR) ≤ 1.3 (or ≤ 3 on anticoagulants) * Aspartate aminotransferase (AST) or alanine aminotransferase (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 mammalian target of rapamycin (mTOR) inhibitor within 12 months of study entry (when cancer was not definitely hormone refractory) * HER2 0 or 3+ by IHC on pre-treatment biopsy of metastatic lesion (if performed) * Active infection * Uncontrolled central nervous system metastases * Life-threatening, visceral 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 arrhythmias * 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 hepatitis * A known history of HIV seropositivity * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (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 everolimus) * 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 cytochrome P450, family 3, subfamily A (CYP3A)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Until First Progression | Every 3 to 4 weeks after study start, until progression or death, assessed up to 5 years | Median PFS will be calculated based on time to first progression or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) in Patients Who Crossed Over | Every 3 to 4 weeks after study start, until progression or death, assessed up to 5 years | Median PFS will be calculated based on time to first progression or death. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at Winship Cancer Institute of Emory University, Emory University Hospital Midtown, and Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Pre-assignment details
70 participants were enrolled. Nine were found to be ineligible. Three declined to participate and were not treated.
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab Patients receive trastuzumab IV over 30 minutes once every 3 weeks and continue to receive their most recent hormone therapy. Patients achieving disease progression receive everolimus PO daily in combination with trastuzumab and hormone therapy. | 24 |
| Everolimus Patients receive everolimus PO daily and continue their most recent hormone therapy. Patients achieving disease progression receive trastuzumab IV over 30-90 minutes once every 3 weeks in combination with everolimus and hormone therapy. | 30 |
| Trastuzumab and Everolimus (ARM REMOVED) Patients receive trastuzumab IV over 30 minutes once every 3 weeks and everolimus PO daily while continuing to receive their most recent hormone therapy. | 4 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 0 |
| Overall Study | Protocol revised to remove arm | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Trastuzumab | Everolimus | Trastuzumab and Everolimus (ARM REMOVED) | Total |
|---|---|---|---|---|
| Age, Customized Age range 30-39 | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Age, Customized Age range 40-49 | 2 Participants | 5 Participants | 0 Participants | 7 Participants |
| Age, Customized Age range 50-59 | 9 Participants | 8 Participants | 0 Participants | 17 Participants |
| Age, Customized Age range 60-69 | 4 Participants | 9 Participants | 4 Participants | 17 Participants |
| Age, Customized Age range 70-79 | 7 Participants | 7 Participants | 0 Participants | 14 Participants |
| Age, Customized Age range 81-89 | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 26 Participants | 4 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 3 Participants | 1 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 15 Participants | 24 Participants | 2 Participants | 41 Participants |
| Region of Enrollment United States | 24 participants | 30 participants | 4 participants | 0 participants |
| Sex: Female, Male Female | 23 Participants | 30 Participants | 4 Participants | 57 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 24 | 8 / 30 | 3 / 4 |
| other Total, other adverse events | 0 / 24 | 12 / 30 | 0 / 4 |
| serious Total, serious adverse events | 1 / 24 | 6 / 30 | 0 / 4 |
Outcome results
Primary
Progression-free Survival (PFS) Until First Progression
Median PFS will be calculated based on time to first progression or death.
Time frame: Every 3 to 4 weeks after study start, until progression or death, assessed up to 5 years
Population: Four patients were treated with both trastuzumab \& everolimus up front. These patients were not included in the data analysis because this arm was later discontinued.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab | Progression-free Survival (PFS) Until First Progression | 2.0 months |
| Everolimus | Progression-free Survival (PFS) Until First Progression | 5.7 months |
Secondary
Progression-free Survival (PFS) in Patients Who Crossed Over
Median PFS will be calculated based on time to first progression or death.
Time frame: Every 3 to 4 weeks after study start, until progression or death, assessed up to 5 years
Population: Among 48 patients with disease progression, everolimus was added to 16 patients treated by trastuzumab, and trastuzumab was added to 12 patients treated by everolimus.~Four patients were treated with both trastuzumab \& everolimus up front. These patients were not included in the data analysis because this arm was later discontinued.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab | Progression-free Survival (PFS) in Patients Who Crossed Over | 6.3 months |
| Everolimus | Progression-free Survival (PFS) in Patients Who Crossed Over | 3.1 months |