Trial Outcomes & Findings for Dose Escalation Followed by Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer (NCT NCT00458237)

Last Updated: 2016-10-20

Results Overview

The MTD is determined by the number of patients who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached. Dose Limiting Toxicities (DLTs) were defined as follows (CTCAE v4.0): * Any grade 4 hematologic toxicity, excluding anemia. * Any grade 3 or 4 nonhematologic toxicity, except for nausea, vomiting, diarrhea, or hyperlipidemia that responds promptly (within 24 hours for nausea, vomiting, and diarrhea and within 1 week for hyperlipidemia) to appropriate treatment, and except for cardiac toxicity which will be assessed after 12 weeks of treatment. * Need to hold \>1 dose of trastuzumab or \> 7 doses of RAD001 within the first 3 weeks because of the presence of toxicity.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

11 participants

Primary outcome timeframe

Cycle One (first 21 days of treatment)

Results posted on

2016-10-20

Participant Flow

Patients enrolled from July 2007 through May 2009.

Participant milestones

Participant milestones
Measure	Phase I: Everolimus (Dose Level 1) and Trastuzumab Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 5 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase I: Everolimus (Dose Level 2) and Trastuzumab Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 10 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase II: Everolimus (Maximum Tolerated Dose) and Trastuzumab Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus at the MTD (10 mg) by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.
Overall Study STARTED	3	3	5
Overall Study COMPLETED	3	3	5
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Dose Escalation Followed by Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I: Everolimus (Dose Level 1) and Trastuzumab n=3 Participants Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 5 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase I: Everolimus (Dose Level 2) and Trastuzumab n=3 Participants Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 10 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase II: Everolimus (Maximum Tolerated Dose) and Trastuzumab n=5 Participants Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus at the MTD (10 mg) by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Total n=11 Participants Total of all reporting groups
Age, Continuous	53 years n=5 Participants	42 years n=7 Participants	42 years n=5 Participants	45 years n=4 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants	11 Participants n=4 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
Region of Enrollment United States	3 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants	11 participants n=4 Participants

PRIMARY outcome

Timeframe: Cycle One (first 21 days of treatment)

Population: The analysis dataset for the Phase I study is comprised of the two dose cohorts: Level 1 and 2.

Outcome measures

Outcome measures
Measure	Phase I: Everolimus (Dose Level 1) and Trastuzumab n=3 Participants Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 5 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase I: Everolimus (Dose Level 2) and Trastuzumab n=3 Participants Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 10 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.
Maximum Tolerated Dose (MTD)	0 participants with DLT	0 participants with DLT

SECONDARY outcome

Timeframe: Disease assessments occurred every 9 weeks (3 cycles) on treatment. Treatment continued until disease progression or unacceptable toxicity. Median duration of treatment was 2.4 months.

Population: The analysis dataset is comprised of patients treated at the MTD/dose level 2.

Best response on treatment was based on RECIST 1.0 criteria with overall clinical response defined as achieving stable disease (SD), partial response (PR) or complete response (CR). Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response. SD is neither CR/PR or progressive disease (PD). PD is at least a 20% increase in sum LD, takings as reference smallest sum LD since treatment started.

Outcome measures

Outcome measures
Measure	Phase I: Everolimus (Dose Level 1) and Trastuzumab n=3 Participants Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 5 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase I: Everolimus (Dose Level 2) and Trastuzumab n=5 Participants Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 10 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.
Clinical Response Rate	.67 proportion of participants Interval 0.14 to 0.98	.80 proportion of participants Interval 0.34 to 0.99

Adverse Events

Phase I: Everolimus (Dose Level 1) and Trastuzumab

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Phase I: Everolimus (Dose Level 2) and Trastuzumab

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Phase II: Everolimus (Maximum Tolerated Dose) and Trastuzumab

Serious events: 4 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I: Everolimus (Dose Level 1) and Trastuzumab n=3 participants at risk Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 5 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase I: Everolimus (Dose Level 2) and Trastuzumab n=3 participants at risk Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 10 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.	Phase II: Everolimus (Maximum Tolerated Dose) and Trastuzumab n=5 participants at risk Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus at the MTD (10 mg) by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.
General disorders Fatigue	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	20.0% 1/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Metabolism and nutrition disorders Hypokalemia	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	20.0% 1/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Investigations Leukocytes	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	20.0% 1/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Investigations Lymphopenia	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	33.3% 1/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Gastrointestinal disorders Muco/stomatitis (symptom) oral cavity	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	20.0% 1/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Investigations Neutrophils	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	20.0% 1/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Investigations Platelets	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	40.0% 2/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Vascular disorders Thrombosis/thrombus/embolism	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	40.0% 2/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.
Injury, poisoning and procedural complications Vascular access-Thrombosis/embolism	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	0.00% 0/3 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.	40.0% 2/5 • Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median duration of treatment was 2.4 months. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.

Other adverse events

Additional Information

Gerburg Wulf

Beth Israel Deaconess Medical Center

Phone: (617) 667-1910

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place