Trial Outcomes & Findings for Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer (NCT NCT03939897)

Last Updated: 2025-09-24

Results Overview

DLT will be determined based on the incidence, intensity and duration of adverse events (AEs) that are related to the drug combinations and occur within 28 days of drug administration. The severity of AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. AEs will be summarized by counts and percentages, overall as well as by dose levels and by patient characteristics.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE1

Target enrollment

24 participants

Primary outcome timeframe

Up to 28 days from drug administration

Results posted on

2025-09-24

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Overall Study STARTED	7	3	7	7
Overall Study COMPLETED	7	3	7	7
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Total n=24 Participants Total of all reporting groups
Age, Continuous	58 years n=5 Participants	62 years n=7 Participants	56 years n=5 Participants	63 years n=4 Participants	59 years n=21 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	7 Participants n=4 Participants	23 Participants n=21 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants	7 Participants n=4 Participants	23 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 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	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants	5 Participants n=4 Participants	19 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Region of Enrollment United States	7 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants	7 participants n=4 Participants	24 participants n=21 Participants

PRIMARY outcome

Timeframe: Up to 28 days from drug administration

Population: 1 subject in Phase I Part A Dose Level 1 was not evaluable due to copanlisib not being held per protocol. 1 subject in Phase I Part B Dose Level 1b and 1 subject in Phase I Part B Dose Level 2b were not evaluable as they had cycle 1 dosing errors.

Outcome measures

Outcome measures
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=6 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=6 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=6 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Dose-limiting Toxicity (DLT)	1 Participants	2 Participants	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Time from randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 4 years

Radiographic disease recurrence/progression will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be estimated by the Kaplan-Meier (KM) product limit method and survival difference will be compared between the two arms by stratified log rank test. Hazard ratio with 95% confidence interval (CI) will be estimated between the two arms from the stratified Cox proportional hazard model, without and with adjustment for patient characteristics.

Outcome measures

Outcome measures
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Progression-free Survival (PFS)	5.9 months Interval 2.5 to 14.8	7.9 months Interval 2.3 to Due to an insufficient number of participants who have progressed (events), the upper CI bound is not estimable.	19.3 months Interval 2.8 to Due to an insufficient number of participants who have progressed (events), the upper CI bound is not estimable.	18.7 months Interval 1.8 to Due to an insufficient number of participants who have progressed (events), the upper CI bound is not estimable.

SECONDARY outcome

Timeframe: Time from randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 4 years

Will be defined as the proportion of response-evaluable patients who achieve complete response (CR) or partial response (PR) and assessed by RECIST 1.1 criteria. Will be estimated with a 95% exact CI and difference between the two arms will be compared by Fisher's exact test. Raw and adjusted odds ratio (OR) will be derived with 95% CI from logistic regression without and with adjustment for patient characteristics.

Outcome measures

Outcome measures
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Objective Response Rate (ORR)	1 Participants	0 Participants	2 Participants	2 Participants

SECONDARY outcome

Timeframe: Time from randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 4 years

Will be defined as the proportion of response-evaluable patients who achieve CR or PR or stable disease (SD) for at least 6 months and assessed by RECIST 1.1 criteria. Will be estimated with a 95% exact CI and difference between the two arms will be compared by Fisher's exact test. Raw and adjusted OR will be derived with 95% CI from logistic regression without and with adjustment for patient characteristics

Outcome measures

Outcome measures
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Clinical Benefit Rate	3 Participants	0 Participants	3 Participants	2 Participants

SECONDARY outcome

Timeframe: Time of randomization to time of death due to any cause or latest follow-up, whichever earlier, assessed up to 4 years

Will be assessed by RECIST 1.1 criteria. Will be estimated by the KM product limit method and survival difference will be compared between the two arms by stratified log rank test. Hazard ratio with 95% CI will be estimated between the two arms from the stratified Cox proportional hazard model, without and with adjustment for patient characteristics.

Outcome measures

Outcome measures
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=7 Participants Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Overall Survival	14.8 months Interval 2.5 to Due to an insufficient number of participants who have experienced death (events), the upper CI bound is not estimable.	12.2 months Interval 2.3 to Due to an insufficient number of participants who have experienced death (events), the upper CI bound is not estimable.	NA months Interval 20.1 to Due to an insufficient number of participants who have experienced death (events), the median and upper CI bound is not estimable.	NA months Interval 3.6 to Due to an insufficient number of participants who have experienced death (events), the median and upper CI bound is not estimable.

Adverse Events

Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant)

Serious events: 2 serious events

Other events: 7 other events

Deaths: 5 deaths

Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant)

Serious events: 3 serious events

Other events: 3 other events

Deaths: 3 deaths

Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant)

Serious events: 4 serious events

Other events: 7 other events

Deaths: 2 deaths

Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant)

Serious events: 5 serious events

Other events: 7 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Cynthia X. Ma, M.D., Ph.D.

Washington University in St. Louis School of Medicine

Phone: 314-362-9383

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=7 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=7 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=7 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Cardiac disorders Atrial fibrillation	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders Heart failure	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Abdominal pain	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Dysphagia	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Nausea	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Obstruction gastric	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Vomiting	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	33.3% 1/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
General disorders Death NOS	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
General disorders Fatigue	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
General disorders Fever	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Infections and infestations Lung Infection	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	33.3% 1/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Nervous system disorders Presyncope	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Nervous system disorders Syncope	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	66.7% 2/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Psychiatric disorders Depression	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Renal and urinary disorders Acute kidney injury	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Renal and urinary disorders Urinary tract obstruction	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Reproductive system and breast disorders Perineal pain	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Respiratory, thoracic and mediastinal disorders Adult respiratory distress	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	33.3% 1/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Respiratory, thoracic and mediastinal disorders Pulmonary Edema	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Skin and subcutaneous tissue disorders Chest wall necrosis	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Vascular disorders Hypertension	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).

Other adverse events
Measure	Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant) n=7 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant) n=3 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg ulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 1b (Copanlisib, Abemaciclib, Fulvestrant) n=7 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.	Phase I Part B Dose Level 2b (Copanlisib, Abemaciclib, Fulvestrant) n=7 participants at risk Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
Blood and lymphatic system disorders Anemia	100.0% 7/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	33.3% 1/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	57.1% 4/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	85.7% 6/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Diarrhea	85.7% 6/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	100.0% 3/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	71.4% 5/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	100.0% 7/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Blood and lymphatic system disorders Blood Lymph - other - macrocytosis	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Dry mouth	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Blood and lymphatic system disorders Eosinophilia	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Dyspepsia	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Blood and lymphatic system disorders Leukocytosis	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders Aortic valve disease	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders Atrial fibrillation	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Dysphagia	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Fecal incontinence	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders GI disorders - Other - Hematochezia	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders Cardiac disorders - Other - Brain Natriuretic Peptide Increased	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Gastroesophageal reflux disease	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Hemorrhoids	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders First-degree atrioventricular block	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders Palpitations	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders Pericardial effusion	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Cardiac disorders Sinus tachycardia	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	42.9% 3/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Ear and labyrinth disorders Ear and Labyrinth - Other - Ear Drainage	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Ear and labyrinth disorders Ear pain	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Ear and labyrinth disorders Hearing impaired	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Ear and labyrinth disorders Tinnitus	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Eye disorders Floaters	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Abdominal distension	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Abdominal pain	42.9% 3/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	33.3% 1/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Ascites	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Bloating	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Colitis	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Constipation	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	42.9% 3/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Investigations - Other, specify - Loose Stool	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Mucositis oral	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	33.3% 1/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	71.4% 5/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Nausea	85.7% 6/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	100.0% 3/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	71.4% 5/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	71.4% 5/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Oral pain	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Toothache	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
Gastrointestinal disorders Vomiting	42.9% 3/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	42.9% 3/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
General disorders Chills	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
General disorders Edema limbs	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	33.3% 1/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	28.6% 2/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
General disorders Edema trunk	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).
General disorders Facial pain	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/3 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	0.00% 0/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).	14.3% 1/7 • Adverse events (AEs) were collected from start of treatment through the end of treatment visit. Patients removed due to unacceptable AE(s), were followed until resolution or stabilization of the AE. Median AE length of follow-up was 126 days (full range 28-710 days). All-cause mortality was collected from start of treatment to death due to any cause or latest follow-up, whichever earlier. Overall median length of follow-up was 439 days (full range 66-1198 days).