Trial Outcomes & Findings for A Phase II Study of Rapamycin and Trastuzumab for Patients With HER-2 Receptor Positive Metastatic Breast Cancer (NCT NCT00411788)

Last Updated: 2016-09-21

Results Overview

To determine the clinical activity of oral daily rapamycin administered in combination with weekly intravenous trastuzumab in patients with HER2 overexpressing advanced breast cancer, the primary outcome is to determine the proportion of patients who are progression-free at 16 weeks, defined by complete response (CR), partial response (PR), or stable disease (SD).who are progression free at 16 weeks, defined by complete response (CR), partial response (PR), or stable disease (SD). Response objectives assessed using response evaluation criteria (RECIST) 1.0 This primary outcome was reworded from its original format when results were entered.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

11 participants

Primary outcome timeframe

16 weeks

Results posted on

2016-09-21

Participant Flow

Participant milestones

Participant milestones
Measure	Rapamycin and Trastuzumab Patients received oral rapamycin/sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Overall Study STARTED	11
Overall Study COMPLETED	9
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Rapamycin and Trastuzumab Patients received oral rapamycin/sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Overall Study Protocol Violation	1
Overall Study Adverse Event	1

Baseline Characteristics

A Phase II Study of Rapamycin and Trastuzumab for Patients With HER-2 Receptor Positive Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rapamycin and Trastuzumab n=11 Participants Patients received oral rapamycin/sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Age, Continuous	57 years n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: 16 weeks

Population: Nine patients were evaluable for response assessment. Two patients withdrew from study before first response assessment (one for noncompliance and the other for toxicity).

Outcome measures

Outcome measures
Measure	Sirolimus and Trastuzumab n=9 Participants Patients received oral sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Proportion of Patients Who Are Progression-free (CR, PR and Stable Disease)	4 participants

SECONDARY outcome

Timeframe: study completion up to 58 weeks

ORR was determined according to RECIST criteria, duration of response, and time to progression in patients with HER2 overexpressing advanced breast cancer receiving trastuzumab and rapamycin. The objective response rate (ORR) by response evaluation criteria (RECIST) 1.0, duration of response, safety, and pharmacodynamic endpoints. This secondary outcome measure was reworded from its original submission when results were entered.

Outcome measures

Outcome measures
Measure	Sirolimus and Trastuzumab n=9 Participants Patients received oral sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Objective Response Rate (ORR)	1 participants

SECONDARY outcome

Timeframe: study completion up to 58 weeks

Population: Safety population consisting of 9 of 11 patients that received treatment following first dose.

This safety measure was used to determine the number of patients treated with the combination of trastuzumab and rapamycin with cardiac dysfunction. This secondary outcome measure was reworded from its original version when results were entered.

Outcome measures

Outcome measures
Measure	Sirolimus and Trastuzumab n=9 Participants Patients received oral sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Incidence of Cardiac Dysfunction	1 participants

SECONDARY outcome

Timeframe: Upon completion of study

These data were not collected and analyzed as described here in the initial protocol submission.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: study completion

Population: This outcome measure was not collected nor analyzed due to study closure and low sample size.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Upon completion of study

Population: This outcome measure was not collected nor analyzed due to study closure and low sample size.

Outcome measures

Outcome data not reported

Adverse Events

Sirolimus and Trastuzumab

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Sirolimus and Trastuzumab n=9 participants at risk Patients received oral sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Endocrine disorders Hyperglycemia	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Cardiac disorders Cardiac Dysfunction	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).

Other adverse events

Other adverse events
Measure	Sirolimus and Trastuzumab n=9 participants at risk Patients received oral sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.
Blood and lymphatic system disorders Leukopenia	55.6% 5/9 • Number of events 5 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Blood and lymphatic system disorders Neutropenia	33.3% 3/9 • Number of events 3 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Blood and lymphatic system disorders Anemia	88.9% 8/9 • Number of events 8 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Blood and lymphatic system disorders Thrombocytopenia	44.4% 4/9 • Number of events 4 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Skin and subcutaneous tissue disorders Nail Changes	22.2% 2/9 • Number of events 2 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Gastrointestinal disorders Nausea	33.3% 3/9 • Number of events 3 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
General disorders Fatigue	22.2% 2/9 • Number of events 2 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Gastrointestinal disorders Dyspepsia	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Infections and infestations Mucositis	55.6% 5/9 • Number of events 5 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
General disorders Xerostomia	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
General disorders Dysgeusia	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Respiratory, thoracic and mediastinal disorders Hemorrhage, pulmonary/upper respiratory	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Respiratory, thoracic and mediastinal disorders Pneumonitis	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Skin and subcutaneous tissue disorders Rash	22.2% 2/9 • Number of events 2 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Metabolism and nutrition disorders Anorexia	11.1% 1/9 • Number of events 1 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Blood and lymphatic system disorders Hypertriglyceridemia	22.2% 2/9 • Number of events 2 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Endocrine disorders Hyperglycemia	22.2% 2/9 • Number of events 2 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).
Endocrine disorders AST/ALT	44.4% 4/9 • Number of events 4 • Adverse events were collected in aggregate through the end of the study (up to 58 weeks).

Additional Information

Abu-Khalaf, Maysa

Yale University

Phone: (203) 785-4095

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place