Trial Outcomes & Findings for Combination of Letrozole, Everolimus and TRC105 in Postmenopausal Women With Hormone-Receptor Positive and Her2 Negative Breast Cancer (NCT NCT02520063)

Results Overview

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.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE1/PHASE2

Target enrollment

15 participants

Primary outcome timeframe

4 weeks

Results posted on

2024-12-27

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I Cohort 1 Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 2 Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase II Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
Overall Study STARTED	6	4	5
Overall Study COMPLETED	5	3	5
Overall Study NOT COMPLETED	1	1	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I Cohort 1 n=6 Participants 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 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.	Phase I Cohort 2 n=4 Participants 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 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.	Phase I Cohort -1 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 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.	Phase II n=5 Participants 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. 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.	Total n=15 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants	13 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	2 Participants n=21 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants	15 Participants n=21 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race/Ethnicity, Customized White	5 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants	13 Participants n=21 Participants
Race/Ethnicity, Customized Black	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants

PRIMARY outcome

Timeframe: 4 weeks

Population: There were no patients enrolled in the phase 1 cohort -1 portion of the protocol due to lack of toxicities in phase 1 cohort 1 and 2.

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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=4 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
Number of Participants Who Experienced Dose-limiting Toxicities	0 participants	1 participants	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=4 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 n=5 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
Rates of Pathologic Complete Remission (pCR)	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1 and Day 29

Maximum serum concentration of Letrozole.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=4 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 n=5 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
C Max - Letrozole Day 1	45.3 ng/ml Geometric Coefficient of Variation 31.5	41.2 ng/ml Geometric Coefficient of Variation 28.6	33.3 ng/ml Geometric Coefficient of Variation 43.8
C Max - Letrozole Day 29	211 ng/ml Geometric Coefficient of Variation 32.7	292 ng/ml Geometric Coefficient of Variation 53.1	168 ng/ml Geometric Coefficient of Variation 73.5

SECONDARY outcome

Timeframe: 24 weeks (pretreatment to time of definitive surgery)

Population: There were no patients enrolled in Phase 1 Cohort -1 due to the lack of toxicities in Phase 1 Cohort 1 and Phase I Cohort 2. Additionally, one patient in Phase 1 Cohort 1, one patient in Phase 1 cohort 2, and two patients in Phase 2 were not evaluable for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=5 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=3 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 n=3 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
Tumor Proliferation Changes	-96.7 percent change in the of Ki67(+) cells Interval -100.0 to -83.3	14 percent change in the of Ki67(+) cells Interval -100.0 to 240.0	-77.8 percent change in the of Ki67(+) cells Interval -100.0 to -38.5

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=4 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 n=5 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
T Max - Letrozole	3 Hours Interval 2.0 to 24.0	1.5 Hours Interval 1.0 to 2.0	2 Hours Interval 1.0 to 4.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=4 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 n=5 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
AUC - Letrozole Day 1	639 ng*hrs/ml Geometric Coefficient of Variation 34	532 ng*hrs/ml Geometric Coefficient of Variation 17.1	408 ng*hrs/ml Geometric Coefficient of Variation 28.5
AUC - Letrozole Day 29	3500 ng*hrs/ml Geometric Coefficient of Variation 41.7	2500 ng*hrs/ml Geometric Coefficient of Variation 205	1400 ng*hrs/ml Geometric Coefficient of Variation 195

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=4 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 n=5 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
T 1/2 - Letrozole	15.5 Hours Geometric Coefficient of Variation 4.26	24.7 Hours Geometric Coefficient of Variation 2.34	31.7 Hours Geometric Coefficient of Variation 11.4

SECONDARY outcome

Timeframe: Day 1 and Day 29

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=9 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
C Max - Everolimus day 1	1.56 ng/mL Geometric Coefficient of Variation 51.5	3.7 ng/mL Geometric Coefficient of Variation 55.5	—
C Max - Everolimus day 29	2.63 ng/mL Geometric Coefficient of Variation 27.9	5.38 ng/mL Geometric Coefficient of Variation 86.7	—

SECONDARY outcome

Timeframe: Day 1

Population: Phase 1 Cohort 1, and combined Phase 1 Cohort 2 and Phase 2 (since patients received the same dose of everolimus) at 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.

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=9 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
T Max Everolimus	2 hours Interval 1.0 to 6.0	1 hours Interval 1.0 to 4.0	—

SECONDARY outcome

Timeframe: Day 1 and Day 29

Population: 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)

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).

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=9 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
AUC - Everolimus Day 1	15.4 ng*hrs/mL Geometric Coefficient of Variation 41.9	20.9 ng*hrs/mL Geometric Coefficient of Variation 50.4	—
AUC - Everolimus Day 29	22.5 ng*hrs/mL Geometric Coefficient of Variation 39.3	32.1 ng*hrs/mL Geometric Coefficient of Variation 153	—

SECONDARY outcome

Timeframe: day 1

Population: 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).

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).

Outcome measures

Outcome measures
Measure	Phase I Cohort 2 n=6 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 10 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort 1 n=9 Participants Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 15 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).	Phase I Cohort -1 Letrozole: 2.5 mg was given orally once each day until one day before surgery. Everolimus: 5 mg was administered as an oral pill once daily until four weeks prior to surgery (24 weeks). TRC105: 10 mg/kg was given intravenously every two weeks and continued until four weeks prior to surgery (24 weeks).
T 1/2 - Everolimus	13.4 hours Geometric Coefficient of Variation 1.64	11.8 hours Geometric Coefficient of Variation 7.86	—

Adverse Events

Phase I Cohort 1

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Phase I Cohort 2

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Phase I Cohort -1

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Phase II

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I Cohort 1 n=6 participants at risk 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 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.	Phase I Cohort 2 n=4 participants at risk 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 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.	Phase I Cohort -1 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 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.	Phase II n=5 participants at risk 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. 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.
Nervous system disorders headache	16.7% 1/6 • Number of events 1 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.	0.00% 0/4 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.	— 0/0 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.	0.00% 0/5 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.

Other adverse events

Other adverse events
Measure	Phase I Cohort 1 n=6 participants at risk 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 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.	Phase I Cohort 2 n=4 participants at risk 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 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.	Phase I Cohort -1 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 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.	Phase II n=5 participants at risk 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. 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.
Nervous system disorders headache	100.0% 6/6 • Number of events 6 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.	100.0% 4/4 • Number of events 4 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.	— 0/0 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.	0.00% 0/5 • 6 months There were no patients enrolled in the phase 1 cohort -1 section due to lack of adverse events in phase 1 cohorts 1 and 2.

Additional Information

Erica Stringer-Reasor

UAB

Phone: 2059759375

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place