Dose Escalation Followed by Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this research study is to determine the safety of RAD001 and the highest dose of this drug that can be given to people with HER2-positive metastatic breast cancer safely in combination with trastuzumab. RAD001 has been used in patients with severe rheumatoid arthritis, in recipients of solid-organ transplants, healthy volunteers and experiments with animals, and information from those other research studies suggest that this RAD001 may help to stop cancer cells from growing abnormally.

Detailed Description
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Since we are looking for the dose of RAD001 that can be given safely in combination with trastuzumab, not everyone will receive the same amount of RAD001. Small groups of participants will be enrolled at a certain dose of RAD001 and if they tolerate the medications well, the next small group will receive a higher dose. This will continue until the optimal dose of RAD001 that can be given in combination with trastuzumab is found. Blood will be drawn on days 1, 2, 8, and 15 of the first cycle of treatment and then once at every 4 cycles for everolimus pharmacokinetics analysis. There is an optional tissue biopsy component to this study asking for 2 biopsies performed pre-treatment and after the cycle one. We will keep track of the participants medical condition for the next three years by calling them on the telephone twice a year to see how they are doing. OBJECTIVES: Primary - To assess the safety and tolerability of RAD001 in combination with trastuzumab in HER2-positive metastatic breast cancer Secondary To evaluate the activity of RAD001 plus trastuzumab, as defined by objective response rate, in patients with progression on a trastuzumab-containing regimen To evaluate changes in signaling molecules in response to trastuzumab and RAD001 in circulating tumor cells and tumor tissue To evaluate the pharmacokinetics of RAD001 in combination with trastuzumab. STATISTICAL DESIGN: This Phase I study followed a standard 3+3 dose escalation design with two dose levels of everolimus in combination with trastuzumab to be evaluated. The DLT observation period was cycle one (first 21 days of treatment). There is a 20 patient expansion cohort treated at the MTD. The regimen would be considered promising if at least 2 objective responses are observed out of 20 treated patients. If the true but unknown response rate is 15% then the probability of observing at least 2 responses is 82% but if the true rate is 5% this probability reduces to 26%.

Official Title
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A Brief Dose Escalation Followed by a Phase 2 Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Everolimus
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed invasive breast cancer, with stage IV disease Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as greater than or equal to 20mm with conventional techniques or as greater than or equal to 10mm with spiral CT scan. Primary tumor or metastasis must overexpress HER2 Patient must have received 1-2 prior chemotherapeutic regiments for metastatic breast cancer and must have been off treatment for at least three weeks. Patient must have received and progressed on at least 1 prior trastuzumab-containing regimen, but not more than 2, in the metastatic setting. Patients may have received prior radiation therapy Patients may have received hormonal therapy in the adjuvant or metastatic setting 18 years of age or older Life expectancy of greater than 6 months Normal organ and marrow function as defined in the protocol Left ventricular ejection fraction (LVEF) greater than or equal to the institutional lower limit of normal Exclusion Criteria: Treatment with any investigational drug within 4 weeks Long-term treatment, over 3 months, with a systemic steroid or another immunosuppressive agent Other malignancies within the past 3 years, except for adequately treated carcinoma of teh cervix or basal-or squamous-cell carcinoma of the skin Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 An active, bleeding diathesis or an oral anti-vitamin K medication Prior treatment with an mTOR inhibitor History of non-compliance with medical regimens Unwillingness or inability to comply with the protocol Major surgery within 2 weeks before study entry Patients with active brain metastases or leptomeningeal carcinomatosis Patients who have experienced grade 1 or grade 2 hypersensitivity reactions to prior trastuzumab therapy are eligible ONLY IF these reactions did not prevent further administration Severe and/or uncontrolled intercurrent medical condition, psychiatric illness or a social situation that could limit their ability to comply with the study requirements. Pregnant or breast-feeding women HIV positive patients Known hypersensitivity to RAD001 (everolimus) or other rapamycins

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ph I: Everolimus L1 + Trastuzumab<br>Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg [8 mg/kg loading dose] IV once every three weeks and take everolimus 5 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity. | Drug: Everolimus<br>* Everolimus is being administered orally 7 days per week.<br>* Other names: RAD001;Drug: Trastuzumab<br>* Trastuzumab is being administered at a dose of 6 mg/kg intravenously once every 21 days.<br>* Other names: Herceptin;|
| Experimental: Ph I: Everolimus L2 + Trastuzumab<br>Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg [8 mg/kg loading dose] IV once every three weeks and take everolimus 10 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity. | Drug: Everolimus<br>* Everolimus is being administered orally 7 days per week.<br>* Other names: RAD001;Drug: Trastuzumab<br>* Trastuzumab is being administered at a dose of 6 mg/kg intravenously once every 21 days.<br>* Other names: Herceptin;|
| Experimental: PhII: Everolimus MTD + Trastuzumab<br>Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg [8 mg/kg loading dose] IV once every three weeks and take everolimus at the MTD by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity. | Drug: Everolimus<br>* Everolimus is being administered orally 7 days per week.<br>* Other names: RAD001;Drug: Trastuzumab<br>* Trastuzumab is being administered at a dose of 6 mg/kg intravenously once every 21 days.<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The MTD is determined by the number of patients who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached. Dose Limiting Toxicities (DLTs) were defined as follows (CTCAE v4.0): Any grade 4 hematologic toxicity, excluding anemia. Any grade 3 or 4 nonhematologic toxicity, except for nausea, vomiting, diarrhea, or hyperlipidemia that responds promptly (within 24 hours for nausea, vomiting, and diarrhea and within 1 week for hyperlipidemia) to appropriate treatment, and except for cardiac toxicity which will be assessed after 12 weeks of treatment. Need to hold >1 dose of trastuzumab or > 7 doses of RAD001 within the first 3 weeks because of the presence of toxicity. | Cycle One (first 21 days of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate | Best response on treatment was based on RECIST 1.0 criteria with overall clinical response defined as achieving stable disease (SD), partial response (PR) or complete response (CR). Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response. SD is neither CR/PR or progressive disease (PD). PD is at least a 20% increase in sum LD, takings as reference smallest sum LD since treatment started. | Disease assessments occurred every 9 weeks (3 cycles) on treatment. Treatment continued until disease progression or unacceptable toxicity. Median duration of treatment was 2.4 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2 positive, metastatic breast cancer, RAD001, Herceptin