Trial Outcomes & Findings for Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer (NCT NCT02311933)

NCT ID: NCT02311933

Last Updated: 2025-11-10

Results Overview

The primary endpoint is progression-free survival (PFS) defined as the time from randomization to documentation of local, regional or distant disease progression or death without progression of disease.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2

Target enrollment

81 participants

Primary outcome timeframe

Assessed up to 5 years

Results posted on

2025-11-10

Participant Flow

Participant milestones

Participant milestones
Measure	Arm I (Z-endoxifen Hydrochloride) Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm II (Tamoxifen Citrate) Patients receive 20 mg tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.
Overall Study STARTED	41	40
Overall Study COMPLETED	41	40
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Z-endoxifen Hydrochloride) n=41 Participants Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm II (Tamoxifen Citrate) n=40 Participants Patients receive 20 mg tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.	Total n=81 Participants Total of all reporting groups
Age, Continuous	64 years n=5 Participants	66 years n=20 Participants	65 years n=40 Participants
Sex: Female, Male Female	41 Participants n=5 Participants	40 Participants n=20 Participants	81 Participants n=40 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	3 Participants n=20 Participants	4 Participants n=40 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	39 Participants n=5 Participants	36 Participants n=20 Participants	75 Participants n=40 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=20 Participants	2 Participants n=40 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=20 Participants	2 Participants n=40 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	2 Participants n=20 Participants	5 Participants n=40 Participants
Race (NIH/OMB) White	36 Participants n=5 Participants	36 Participants n=20 Participants	72 Participants n=40 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=20 Participants	2 Participants n=40 Participants
Region of Enrollment United States	41 participants n=5 Participants	40 participants n=20 Participants	81 participants n=40 Participants

PRIMARY outcome

Timeframe: Assessed up to 5 years

Population: All patients registered who began protocol treatment and were eligible for assessment were included in this analysis. One patient in Arm I was ineligible, two patients in Arm II were ineligible and one patient in Arm II did not receive treatment.

Outcome measures

Outcome measures
Measure	Arm I (Z-endoxifen Hydrochloride) n=40 Participants Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm II (Tamoxifen Citrate) n=37 Participants Patients receive 20 mg tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.
Progression Free Survival (PFS)	130 days Interval 76.0 to 138.0	42 days Interval 24.0 to 129.0

SECONDARY outcome

Timeframe: Up to 5 years

For a given adverse event (AE), the proportion of patients on each treatment arm who report developing a grade 2-5 of this AE will be determined.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 5 years

Defined by Response Evaluation Criteria in Solid Tumors on 2 consecutive evaluations at least 6 weeks apart, divided by the total number of eligible patients who began study treatment. A 90% binomial confidence interval will be constructed for the true response rate.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: The time from registration to death due to any cause, assessed up to 5 years

The distribution of survival times will be estimated using the method of Kaplan-Meier.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Data will be returned as presence or absence of various DNA alterations, along with description of type and location of the alteration. The nature of alterations in each pathway and gene will be described in tabular format. Association of presence or absence of DNA alterations with PFS will be assessed overall, by pathway, and by gene via Cox regression with the goal of evaluating hazard ratio estimates and confidence intervals. Alterations will be considered together as well as by type. Model fit and stability evaluated, and exact methods used if needed. Performed for both arms and within arms.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Within each treatment arm, a point and interval estimate of the difference in tumor response rate between those with metastatic SRC3-positive disease and those with metastatic SRC3-negative disease will be constructed using the properties of the binomial distribution. Also, a point and interval estimate of the odds of disease progression among those with metastatic SRC3-positive disease relative to those with metastatic SRC3-negative disease will be ascertained from the parameter estimates of fitting a proportional hazard model to the progression data.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline to week 8 (after course 2)

For each of the markers of bone formation, the percent change after 2 courses of treatment from pre-treatment levels will be determined. A two-sided alpha = 0.01 z-test will be used to assess whether the percent change in a given bone absorption biomarkers differs with respect to treatment.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9

A population PK will be developed using the software program NONMEM, Version 7. The model will be parameterized in terms of AUC (the primary endpoint), as well as clearance and volume of distribution. Criteria for model selection will include the likelihood ratio test, shrinkage estimates, reasonableness of parameter estimates, as well as goodness-of-fit plots. Attempts will be made to identify the covariates that affect drug behavior or those that explain variability in this patient population.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9

Examined in an exploratory and hypothesis-generating fashion. Pharmacokinetic-pharmacodynamic (PD) relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Examined in an exploratory and hypothesis-generating fashion.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9

PK/PD relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.

Outcome measures

Outcome data not reported

Adverse Events

Arm I (Z-endoxifen Hydrochloride)

Serious events: 8 serious events

Other events: 34 other events

Deaths: 1 deaths

Arm II (Tamoxifen Citrate)

Serious events: 11 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Matthew P. Goetz, MD

Alliance for Clinical Trials in Oncology

Phone: : 507-284-2511

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Arm I (Z-endoxifen Hydrochloride) n=41 participants at risk Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm II (Tamoxifen Citrate) n=39 participants at risk Patients receive 20 mg tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.
Blood and lymphatic system disorders Anemia	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Cardiac disorders Aortic valve disease	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Cardiac disorders Cardiac disorders - Other, specify	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Cardiac disorders Heart failure	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Cardiac disorders Myocardial infarction	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Eye disorders Eye disorders - Other, specify	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Abdominal pain	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Ascites	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Colitis	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Diarrhea	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Dysphagia	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Nausea	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	7.7% 3/39 • Number of events 3 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Vomiting	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Chills	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Fatigue	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Fever	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Bladder infection	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Infections and infestations - Oth spec	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Lung infection	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Sepsis	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Urinary tract infection	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Injury, poisoning and procedural complications Wound complication	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Investigations Aspartate aminotransferase increased	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Investigations Creatinine increased	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Metabolism and nutrition disorders Anorexia	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Metabolism and nutrition disorders Dehydration	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Metabolism and nutrition disorders Hypercalcemia	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Metabolism and nutrition disorders Hyperglycemia	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Metabolism and nutrition disorders Hypophosphatemia	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 3 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Musculoskeletal and connective tissue disorders Muscle weakness upper limb	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, mal, uncpec - Oth spec	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Nervous system disorders Stroke	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Psychiatric disorders Delirium	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Renal and urinary disorders Acute kidney injury	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Renal and urinary disorders Urinary tract obstruction	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.4% 1/41 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Respiratory, thoracic and mediastinal disorders Pneumothorax	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.

Other adverse events
Measure	Arm I (Z-endoxifen Hydrochloride) n=41 participants at risk Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm II (Tamoxifen Citrate) n=39 participants at risk Patients receive 20 mg tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.
Blood and lymphatic system disorders Anemia	12.2% 5/41 • Number of events 6 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	10.3% 4/39 • Number of events 20 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Blood and lymphatic system disorders Blood and lymph sys disorders - Oth Spec	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 4 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Cardiac disorders Atrial fibrillation	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Cardiac disorders Sinus bradycardia	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Cardiac disorders Sinus tachycardia	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Eye disorders Blurred vision	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 8 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Eye disorders Dry eye	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 4 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Eye disorders Eye disorders - Other, specify	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Abdominal distension	4.9% 2/41 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Abdominal pain	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	7.7% 3/39 • Number of events 8 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Constipation	14.6% 6/41 • Number of events 13 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Diarrhea	2.4% 1/41 • Number of events 7 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Dyspepsia	12.2% 5/41 • Number of events 23 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	7.7% 3/39 • Number of events 8 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Gastroesophageal reflux disease	2.4% 1/41 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Gastrointestinal disorders - Oth spec	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Mucositis oral	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 4 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Nausea	12.2% 5/41 • Number of events 10 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	17.9% 7/39 • Number of events 11 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Oral dysesthesia	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Rectal hemorrhage	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Gastrointestinal disorders Vomiting	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Chills	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Edema limbs	4.9% 2/41 • Number of events 6 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Fatigue	39.0% 16/41 • Number of events 57 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	17.9% 7/39 • Number of events 48 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Fever	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Flu like symptoms	4.9% 2/41 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Gen disord and admin site conds-Oth spec	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
General disorders Pain	2.4% 1/41 • Number of events 5 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Immune system disorders Allergic reaction	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Bronchial infection	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Infections and infestations - Oth spec	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Otitis externa	2.4% 1/41 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	0.00% 0/39 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Tooth infection	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Upper respiratory infection	2.4% 1/41 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Urinary tract infection	2.4% 1/41 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	7.7% 3/39 • Number of events 6 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Vaginal infection	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Infections and infestations Vulval infection	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 1 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Injury, poisoning and procedural complications Fracture	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	2.6% 1/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Investigations Alanine aminotransferase increased	0.00% 0/41 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	5.1% 2/39 • Number of events 2 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Investigations Alkaline phosphatase increased	7.3% 3/41 • Number of events 11 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	7.7% 3/39 • Number of events 10 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
Investigations Aspartate aminotransferase increased	22.0% 9/41 • Number of events 26 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.	35.9% 14/39 • Number of events 57 • Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021. Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.