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

Phase 1

Active, not recruiting

Conditions: Breast Cancer

Interventions: Drug: Letrozole
Drug: Everolimus
Drug: TRC105

Registration Number: NCT02520063

Lead Sponsor: University of Alabama at Birmingham

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: Female

Target Recruitment: 15

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I Cohort 1	Letrozole	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
Phase I Cohort 1	Everolimus	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
Phase I Cohort 1	TRC105	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
Phase I Cohort 2	TRC105	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
Phase I Cohort -1	Everolimus	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
Phase I Cohort -1	TRC105	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
Phase II	TRC105	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.
Phase I Cohort 2	Letrozole	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
Phase I Cohort 2	Everolimus	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
Phase I Cohort -1	Letrozole	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
Phase II	Letrozole	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.
Phase II	Everolimus	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Dose-limiting Toxicities	4 weeks	This outcome will report the number of patients who experienced a dose-limiting Toxicity (DLT) in Phase I Cohort 1, Phase I Cohort 2, and Phase I Cohort -1. A DLT was defined as: 1. A grade 3 or 4 non-hematologic toxicity except anorexia, alopecia, nausea (which is not refractory to antiemetics), fatigue, and fever without neutropenia; 2. Failure to recover to baseline (except alopecia) after delaying the next dose by more than 14 days; 3. Grade 3 or 4 neutropenia complicated by fever \>38.5°C or infection, or grade 4 neutropenia of ≥7 days duration; or 4. Grade 4 thrombocytopenia, or grade 3 thrombocytopenia complicated by hemorrhage. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 out of the first 3 or 1 out of a total of 6 patients experience DLT during the first cycle of therapy; this dose level will be the recommended phase 2 dose (RP2D) in the Phase II Group.

Secondary Outcome Measures

Name	Time	Method
Rates of Pathologic Complete Remission (pCR)	24 weeks up to time of surgery	The 2-dimensional size of the surgically excised residual tumor was measured and compared to the radiographic size of the tumor at baseline. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions and reduction in short axis of any pathological lymph nodes to \<10 mm; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
C Max - Letrozole	Day 1 and Day 29	Maximum serum concentration of Letrozole.
Tumor Proliferation Changes	24 weeks (pretreatment to time of definitive surgery)	This outcome will report the change in tumor cell proliferation. This was measured by the change in the percentage of Ki67 positive cells from pretreatment to surgery (up to 24 weeks): (%Ki67(+) cells pretreatment - %Ki67(+) cells posttreatment)/(%Ki67(+) cells pretreatment) \* 100 Ki67 is a protein found in cells that are dividing. The Ki-67 assessment was performed by the clinical histology laboratory using a validated assay. The results were evaluated by a board-certified pathologist, who estimated the proportion of cancer cells stained for Ki-67. The individual tissue sections were analyzed blindly and at the completion of the assay, results were correlated per case as to changes in Ki-67 with the investigational therapy.
T Max - Letrozole	Day 1	T Max is the time to the maximum serum concentration of a drug in the blood. This outcome will report the T Max of Letrozole at Day 1 in Phase 1 Cohort 1, Phase 1 Cohort 2, and Phase 2. All patients in the trial received the same dose of letrozole.
AUC - Letrozole	Day 1 and Day 29	This outcome will report the area under the serum concentration of letrozole versus time curve (AUC-L). AUC-L is the integral of the concentration of letrozole in the blood as a function of time. AUC-L measures how much letrozole reaches the bloodstream in a period of time after a dose is given. This is useful in dose determination and assessing drug interactions. This outcome was assessed on Day 1 and on Day 29 for Phase I Cohort I, Phase I Cohort 2, and Phase 2.
T 1/2 - Letrozole	Day 1	T ½ is the half-life of a drug in the blood. This is the time it takes for the concentration of the drug in the blood to be reduced by half. This outcome will report the T 1/2 of Letrozole.
C Max - Everolimus	Day 1 and Day 29	Cmax is the maximum serum concentration of a drug in the blood. This outcome will report the Cmax of Everolimus in Phase 1 Cohort 1 and Phase 1 Cohort 2 combined with Phase 2 (since the dose of everolimus was the same in these cohorts) at Day 1 and Day 29.
T Max Everolimus	Day 1	T Max is the time to the maximum serum concentration of a drug in the blood. This outcome will report the T Max of Everolimus in Phase 1 Cohort 1, and combined Phase 1 Cohort 2 and Phase 2 (since patients received the same dose of everolimus) at Day 1.
AUC - Everolimus	Day 1 and Day 29	This outcome will report the area under the serum concentration everolimus of versus the time curve (AUC-E). AUC-E is the integral of the concentration of everolimus in the blood as a function of time. AUC-E measures how much everolimus reaches the bloodstream in a period of time after a dose is given. This is useful in dose determination and assessing drug interactions. This outcome was assessed on Day 1 and on Day 29 for Phase I Cohort I, and combined Phase I Cohort 2 and Phase 2 (since patients in Phase I cohort 2 and Phase 2 received the same dose of everolimus).
T 1/2 - Everolimus	day 1	T ½ is the half-life of a drug in the blood. This is the time it takes for the concentration of the drug in the blood to be reduced by half. This outcome will report the T 1/2 of Everolimus in Phase 1 Cohort 1 and combined Phase 1 Cohort 2 and Phase 2 at Day 1 (since patients in Phase 1 Cohort 2 and Phase 2 at Day 1 received the same dose of everolimus).