Breast CancerPhase 1/2NCT02520063
Combination of Letrozole, Everolimus and TRC105 in Postmenopausal Women With Hormone-Receptor Positive and Her2 Negative Breast Cancer
A Phase 1/2 study testing Letrozole, Everolimus and TRC105 in people with Breast Cancer, run by University of Alabama at Birmingham at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 19 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Letrozole, Everolimus and TRC105
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Feb 2015to 1 Dec 2022
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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%).
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- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Alabama at Birmingham
Birmingham, Alabama, 35294
About this study
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
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.
Read the 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.
- Conditions
- Breast Cancer
- Being tested
- Letrozole, Everolimus, TRC105
- Keywords
- hormone-receptor positive breast cancer, Her2 negative breast cancer, neoadjuvant, everolimus, TRC105, letrozole
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LetrozoleDrug
Also called Femara
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.
EverolimusDrug
Also called Afinitor
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.
TRC105Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| Phase I Cohort 1 | Experimental | 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 Receives: Drug: Letrozole; Drug: Everolimus; Drug: TRC105 |
| Phase I Cohort 2 | Experimental | 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 Receives: Drug: Letrozole; Drug: Everolimus; Drug: TRC105 |
| Phase I Cohort -1 | Experimental | 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 Receives: Drug: Letrozole; Drug: Everolimus; Drug: TRC105 |
| Phase II | Experimental | 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. Receives: Drug: Letrozole; Drug: Everolimus; Drug: TRC105 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Who Experienced Dose-limiting Toxicities
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:
- A grade 3 or 4 non-hematologic toxicity except anorexia, alopecia, nausea (which is not refractory to antiemetics), fatigue, and fever without neutropenia;
- Failure to recover to baseline (except alopecia) after delaying the next dose by more than 14 days;
- Grade 3 or 4 neutropenia complicated by fever >38.5°C or infection, or grade 4 neutropenia of ≥7 days duration; or
- 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.
Measured: 4 weeks
Secondary outcomes (10)
Rates of Pathologic Complete Remission (pCR)
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.
Measured: 24 weeks up to time of surgery
C Max - Letrozole
Maximum serum concentration of Letrozole.
Measured: Day 1 and Day 29
Tumor Proliferation Changes
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.
Measured: 24 weeks (pretreatment to time of definitive surgery)
T Max - Letrozole
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.
Measured: Day 1
AUC - Letrozole
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.
Measured: Day 1 and Day 29
T 1/2 - Letrozole
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.
Measured: Day 1
C Max - Everolimus
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.
Measured: Day 1 and Day 29
T Max Everolimus
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.
Measured: Day 1
AUC - Everolimus
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).
Measured: Day 1 and Day 29
T 1/2 - Everolimus
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).
Measured: day 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Aug 2015 (estimated)
- Study start1 Feb 2015
- Primary completion1 Dec 2022
- Study completion1 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by University of Alabama at BirminghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alabama at Birmingham
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals, Tracon Pharmaceuticals Inc.
- Responsible party
- Principal investigator, Christos Vaklavas, MD, University of Utah
- Investigators
- Erica Stringer-Reasor, M.D., Principal investigator, University of Alabama at BirminghamErica Stringer-Reasor, MD, Principal investigator, University of Alabama at Birmingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02520063
- Sponsor's protocol ID
- F150701004 (UAB 1514)
- Other IDs
- UAB1514
- Status last verified
- Feb 2026
- First submitted
- 30 Jul 2015
- Last updated
- 6 Feb 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Vaklavas C, Stringer-Reasor EM, Elkhanany AM, Ryan KJ, Li Y, Theuer CP, Acosta EP, Wei S, Yang ES, Grizzle WE, Forero-Torres A. A phase I/II study of preoperative letrozole, everolimus, and carotuximab in stage 2 and 3 hormone receptor-positive and Her2-negative breast cancer. Breast Cancer Res Treat. 2023 Apr;198(2):217-229. doi: 10.1007/s10549-023-06864-9. Epub 2023 Feb 3.
PubMed 36735117