Combination of Letrozole, Everolimus and TRC105 in Postmenopausal Women With Hormone-Receptor Positive and Her2 Negative Breast Cancer

Study Overview
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Brief Summary
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This study will test how well a new combination of three drugs (Letrozole, Everolimus, and TRC105) is tolerated and how well it works in Stage 2 and 3 breast cancer when given prior to definitive surgery. Letrozole blocks the estrogen receptor expressed by many breast cancers while everolimus blocks signals that drive cancer cells to grow. TRC105 is an investigational drug that blocks the formation and growth of blood vessels that feed the cancer and promote its growth. The goal of this study is to investigate the safety and efficacy of this multitargeted approach in breast cancer.

Detailed Description
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In postmenopausal women with hormone receptor-positive and Her2 negative non-metastatic breast cancer, downstaging or the achievement of a complete pathologic remission before definitive surgery has been associated with the lowest risk of recurrence of breast cancer. In order to achieve a better response in these patients in the preoperative setting, this study combines 3 potentially synergistic agents. Letrozole blocks the synthesis of estrogens and, in doing so, deprives the tumor from hormones which drive its growth. Everolimus is a drug that blocks growth factor signaling which is essential for tumor cells to maintain their growth and proliferation. Everolimus has already been shown to work very well in this subtype of breast cancer in the recurrent and metastatic setting. TRC105 is an investigational agent that prevents the formation and growth of new blood vessels that support tumors by providing oxygen and nutrients. The study has 2 components. First the investigators will determine the ideal in terms of tolerance combination of doses of the 3 agents. Once the ideal regimen is determined, more patients will be treated with the investigational combination. During this second stage, the investigators will get a preliminary idea of how effective the investigational therapy is. Further studies will need to be done to confirm the efficacy of the investigational combination.

Official Title
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A Phase I/II Study of Preoperative (Neoadjuvant) Combination of Letrozole (Femara), Everolimus (Afinitor), and TRC105 in Postmenopausal Women With Newly Diagnosed Local or Locally Advanced Potentially Resectable Hormone-Receptor Positive and Her2 Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Letrozole
* Drug: Everolimus
* Drug: TRC105


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recent diagnosis of hormone receptor positive and HER2 negative breast cancer. Stage 2 and 3 hormone receptor positive and HER2 negative breast cancer (stage T2-4 but not inflammatory, N0-2, M0). Histological grade I, II or III according to the modified Bloom Richardson scale. No prior treatment specific for breast cancer. Postmenopausal status as defined by the National Comprehensive Cancer Network. ECOG performance status < 2 (Karnofsky > 60%). Must have signed study-specific informed consent. Liver Function Tests < 2.5 times the upper normal limit (UNL). ANC ≥ 1,500/mm3, platelets ≥ 100,000/mm3, Hemoglobin ≥ 10g%. Renal function: serum creatinine < 1.5 institutional UNL or creatinine clearance > 40 cc/min. Exclusion Criteria: Inflammatory breast cancer. Pre- and peri-menopausal state. Pregnancy. Metastatic disease. HER2 positive breast cancer by immunohistochemistry or FISH. Triple negative breast cancer (hormone receptor and Her2 negative). Disease that cannot be followed by imaging studies.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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Female

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: Phase I Cohort 1<br>Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks | Drug: Letrozole<br>* A dose of 2.5 mg of letrozole will be given orally once each day until one day before surgery. This drug is commercially available and is not provided by the study.<br>* Other names: Femara;Drug: Everolimus<br>* The dose of everolimus will be escalated from 5 mg to 10 mg daily depending upon the cohort in Phase I. It is administered as an oral pill to be taken once daily up until four weeks prior to surgery.<br>* Other names: Afinitor;Drug: TRC105<br>* The dose for TRC105 is either 15 or 10 mg/kg to be given intravenously every two weeks and continued until four weeks prior to surgery.<br>|
| Experimental: Phase I Cohort 2<br>Letrozole 2.5 mg PO daily until surgery, everolimus 10 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks | Drug: Letrozole<br>* A dose of 2.5 mg of letrozole will be given orally once each day until one day before surgery. This drug is commercially available and is not provided by the study.<br>* Other names: Femara;Drug: Everolimus<br>* The dose of everolimus will be escalated from 5 mg to 10 mg daily depending upon the cohort in Phase I. It is administered as an oral pill to be taken once daily up until four weeks prior to surgery.<br>* Other names: Afinitor;Drug: TRC105<br>* The dose for TRC105 is either 15 or 10 mg/kg to be given intravenously every two weeks and continued until four weeks prior to surgery.<br>|
| Experimental: Phase I Cohort -1<br>Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 10 mg/kg IV q 2 weeks for 24 weeks | Drug: Letrozole<br>* A dose of 2.5 mg of letrozole will be given orally once each day until one day before surgery. This drug is commercially available and is not provided by the study.<br>* Other names: Femara;Drug: Everolimus<br>* The dose of everolimus will be escalated from 5 mg to 10 mg daily depending upon the cohort in Phase I. It is administered as an oral pill to be taken once daily up until four weeks prior to surgery.<br>* Other names: Afinitor;Drug: TRC105<br>* The dose for TRC105 is either 15 or 10 mg/kg to be given intravenously every two weeks and continued until four weeks prior to surgery.<br>|
| Experimental: Phase II<br>Letrozole 2.5 mg PO daily until surgery, everolimus 5 or 10 mg PO daily for 24 weeks, and TRC105 15 or 10 mg/kg IV q 2 weeks for 24 weeks. Dose and regimen to be determined based on data from the phase I component. | Drug: Letrozole<br>* A dose of 2.5 mg of letrozole will be given orally once each day until one day before surgery. This drug is commercially available and is not provided by the study.<br>* Other names: Femara;Drug: Everolimus<br>* The dose of everolimus will be escalated from 5 mg to 10 mg daily depending upon the cohort in Phase I. It is administered as an oral pill to be taken once daily up until four weeks prior to surgery.<br>* Other names: Afinitor;Drug: TRC105<br>* The dose for TRC105 is either 15 or 10 mg/kg to be given intravenously every two weeks and continued until four weeks prior to surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose-limiting Toxicities | Evaluate the number of participants who had a dose limiting toxicity with the combination of letrozole with everolimus and TRC105 per treatment arm | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of Pathologic Complete Remission (pCR) | The 2-dimensional size of the surgically excised residual tumor will be measure and compared to the radiographic size of the tumor at baseline. | 24 weeks up to time of surgery | 
| C Max | Maximum serum concentration of the interaction between TRC105 and everolimus | collections over 24 hours on Day 1 and Day 25 | 
| Tumor Proliferation Changes | Determine the changes in tumor cell proliferation by means of changes in Ki67 expression and changes in serum concentration of markers of angiogenesis | 24 weeks up to time of surgery | 
| T Max | Time of maximum serum concentration of the interaction between TRC105 and everolimus | collections over 24 hours on Day 1 and Day 25 | 
| AUC | Area under the serum concentration versus time curve | collections over 24 hours on Day 1 and Day 25 | 
| T 1/2 | Terminal half-life of the interaction between TRC105 and everolimus | collections over 24 hours on Day 1 and Day 25 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hormone-receptor positive breast cancer, Her2 negative breast cancer, neoadjuvant, everolimus, TRC105, letrozole