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

Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02520063
• Other study ID #: F150701004 (UAB 1514)
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 1, 2016
• Est. completion date: December 2022

Study information

• Verified date: December 2023
• Source: University of Alabama at Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: December 2022
• Est. primary completion date: December 1, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 19 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Letrozole
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.
• Everolimus
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.
• TRC105
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.

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama

Sponsors (3)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	Novartis Pharmaceuticals, Tracon Pharmaceuticals Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	C Max	Maximum serum concentration of the interaction between TRC105 and everolimus	collections over 24 hours on Day 1 and Day 25
Secondary	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
Secondary	T Max	Time of maximum serum concentration of the interaction between TRC105 and everolimus	collections over 24 hours on Day 1 and Day 25
Secondary	AUC	Area under the serum concentration versus time curve	collections over 24 hours on Day 1 and Day 25
Secondary	T 1/2	Terminal half-life of the interaction between TRC105 and everolimus	collections over 24 hours on Day 1 and Day 25