Trial Outcomes & Findings for Effect of Trastuzumab on Disease Free Survival in Early Stage HER2-Negative Breast Cancer Patients With ERBB2 Expressing Disseminated Tumor Cells (NCT NCT01779050)

Last Updated: 2022-11-01

Results Overview

-Disease recurrence is defined as the documented appearance of local (breast, chest wall, axillary, supraclavicular nodes) or distant disease.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

7 participants

Primary outcome timeframe

Up to 3 years after completion of treatment (estimated to be 4 years)

Results posted on

2022-11-01

Participant Flow

Participant milestones

Participant milestones
Measure	Arm I (Definitive Therapy) Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel	Arm II (Definitive Therapy, Trastuzumab) Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity.
Overall Study STARTED	4	3
Overall Study COMPLETED	3	3
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm I (Definitive Therapy) Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel	Arm II (Definitive Therapy, Trastuzumab) Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity.
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

Effect of Trastuzumab on Disease Free Survival in Early Stage HER2-Negative Breast Cancer Patients With ERBB2 Expressing Disseminated Tumor Cells

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Definitive Therapy) n=4 Participants Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel	Arm II (Definitive Therapy, Trastuzumab) n=3 Participants Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity.	Total n=7 Participants Total of all reporting groups
Age, Continuous	63.5 years n=5 Participants	58 years n=7 Participants	63 years n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 3 years after completion of treatment (estimated to be 4 years)

Population: One participant in Arm 1 was not evaluable as they withdrew before receiving any treatment.

-Disease recurrence is defined as the documented appearance of local (breast, chest wall, axillary, supraclavicular nodes) or distant disease.

Outcome measures

Outcome measures
Measure	Arm I (Definitive Therapy) n=3 Participants Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel	Arm II (Definitive Therapy, Trastuzumab) n=3 Participants Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity.
Number of Participants With Disease Recurrence	1 Participants	0 Participants

PRIMARY outcome

Timeframe: Up to 3 years after completion of treatment (estimated to be 4 years)

Population: One participant in Arm 1 was not evaluable as they withdrew before receiving any treatment.

Outcome measures

Outcome measures
Measure	Arm I (Definitive Therapy) n=3 Participants Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel	Arm II (Definitive Therapy, Trastuzumab) n=3 Participants Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity.
Death Rate	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Before treatment and after treatment (estimated to be 6-18 months)

Population: Data was not collected.

Bone marrow disseminated tumor cells (DTCs) are evaluated by RT-PCR performed on specimens collected 6-18 months apart (one before and one after therapy). The proportion of samples turned negative after therapy will be calculated. Samples will be considered negative for ERBB2-expression if expression from bone marrow collected from each iliac crest is less than 2 standard deviations above the ERBB2-level in pooled normal bone marrow specimens.

Outcome measures

Outcome data not reported

Adverse Events

Arm I (Definitive Therapy)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 1 deaths

Arm II (Definitive Therapy, Trastuzumab)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Rebecca Aft, M.D., Ph.D.

Washington University School of Medicine

Phone: 314-747-0063

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Arm I (Definitive Therapy) n=3 participants at risk Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel	Arm II (Definitive Therapy, Trastuzumab) n=3 participants at risk Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: * doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel * docetaxel plus cyclophosphamide * single-agent paclitaxel * docetaxel plus carboplatin * fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity.
Cardiac disorders Decreased LVEF-asymptomatic	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Endocrine disorders Hyperthyroidism	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Gastrointestinal disorders Constipation	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Gastrointestinal disorders Diarrhea	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Gastrointestinal disorders Dry mouth	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Gastrointestinal disorders Hemorrhoidal hemorrhage	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Gastrointestinal disorders Nausea	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Gastrointestinal disorders Vomiting	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
General disorders Edema limbs	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
General disorders Fatigue	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
General disorders Fever	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Infections and infestations Nasal mucosal infection	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Infections and infestations Shingles	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Infections and infestations Upper respiratory infection	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Infections and infestations Urinary tract infection	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Injury, poisoning and procedural complications Bruising to arms and legs	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Investigations Hemoglobin increased	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Investigations Neutropenia	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Metabolism and nutrition disorders Dehydration	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Musculoskeletal and connective tissue disorders Arthralgia	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Musculoskeletal and connective tissue disorders Pain-left side	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Nervous system disorders Headache	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Nervous system disorders Lethargy	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Nervous system disorders Neuropathy - sensory	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Nervous system disorders Tremors	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Psychiatric disorders Amnesia	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Psychiatric disorders Anxiety	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Psychiatric disorders Depression	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Psychiatric disorders Insomnia	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Reproductive system and breast disorders Breast enlargement (post-radiation change)	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Reproductive system and breast disorders Menorrhagia	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Respiratory, thoracic and mediastinal disorders Cough	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Respiratory, thoracic and mediastinal disorders Laryngeal inflammation	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Respiratory, thoracic and mediastinal disorders Weeping rash beneath breast	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Skin and subcutaneous tissue disorders Alopecia	100.0% 3/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Skin and subcutaneous tissue disorders Atrophy	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Skin and subcutaneous tissue disorders Hyperhydrosis	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	33.3% 1/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.
Skin and subcutaneous tissue disorders Left pointer finger laceration	0.00% 0/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.	66.7% 2/3 • -Adverse events were collected from the time informed consent was obtained and initiation of study procedures and ended 30 days following the last day of study treatment or study discontinuation/termination, whichever was earlier. Median length of follow-up for adverse event data was 272 days (full range 135 days-395 days). -All-cause mortality was assessed for up to 4 years.