Trial Outcomes & Findings for Paclitaxel Followed by FEC Versus Paclitaxel and RAD001 Followed by FEC In Women With Breast Cancer (NCT NCT00499603)

Last Updated: 2016-11-01

Results Overview

Number of participants with inhibition of the PI3K/PTEN/AKT pathway at 48 hours after the start of treatment, regardless of the status of the pathway at the time of randomization. Molecular changes (inhibition/activation) of the PI3K/PTEN/AKT pathway evaluated using reverse phase protein arrays (RPPA) where fine-needle aspirations (FNAs) from the primary breast cancer obtained pretreatment, and at 48 hours. Bioinformatics cluster analysis of arrays used to define molecular changes as inhibition or activation where pathways called 'active' with presence of 2 or more phosphorilated pathway proteins (pAKT, pmTOR, pGSK3, pS6K1, pS6), and 'inhibited' with one or none phosphorilated pathway proteins present.

Recruitment status

UNKNOWN

Study phase

PHASE2

Target enrollment

62 participants

Primary outcome timeframe

48 hours after start of treatment

Results posted on

2016-11-01

Participant Flow

Participants with triple negative breast cancer who were seen in the Breast Medical Oncology clinic of the MD Anderson Cancer Center were enrolled in the study prior to surgery from August 16, 2007 to September 14, 2010.

Sixty-two (62) participants were registered but only fifty (50) were randomized. Nine patients failed the screening process, two patients withdrew consent, and one patient was discontinued due to therapy interruption for greater than 21 days.

Participant milestones

Participant milestones
Measure	Paclitaxel + FEC Paclitaxel 80 mg/m\^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m\^2, Epirubicin at 100 mg/m\^2 and Cyclophosphamide at 500 mg/m\^2 (FEC) on day 1 every 3 weeks (+/- 7 days). 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. Cyclophosphamide: 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 + FEC Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. RAD001 : 30 mg by mouth weekly on Days 1, 8, \& 15 for 12 cycles. Cyclophosphamide: 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Overall Study STARTED	27	23
Overall Study COMPLETED	27	22
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Paclitaxel + FEC Paclitaxel 80 mg/m\^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m\^2, Epirubicin at 100 mg/m\^2 and Cyclophosphamide at 500 mg/m\^2 (FEC) on day 1 every 3 weeks (+/- 7 days). 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. Cyclophosphamide: 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 + FEC Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. RAD001 : 30 mg by mouth weekly on Days 1, 8, \& 15 for 12 cycles. Cyclophosphamide: 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Overall Study Adverse Event	0	1

Baseline Characteristics

Paclitaxel Followed by FEC Versus Paclitaxel and RAD001 Followed by FEC In Women With Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Paclitaxel + FEC n=27 Participants Paclitaxel 80 mg/m\^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m\^2, Epirubicin at 100 mg/m\^2 and Cyclophosphamide at 500 mg/m\^2 (FEC) on day 1 every 3 weeks (+/- 7 days). 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 + FEC n=23 Participants Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. RAD001 : 30 mg by mouth weekly on Days 1, 8, \& 15 for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Total n=50 Participants Total of all reporting groups
Age, Continuous	52 years n=5 Participants	46 years n=7 Participants	48 years n=5 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	23 Participants n=7 Participants	50 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	25 Participants n=5 Participants	23 Participants n=7 Participants	48 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	17 Participants n=7 Participants	35 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	27 participants n=5 Participants	23 participants n=7 Participants	50 participants n=5 Participants
Cancer Clinical Stage T1	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Cancer Clinical Stage T2	18 participants n=5 Participants	17 participants n=7 Participants	35 participants n=5 Participants
Cancer Clinical Stage T3	4 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants
Cancer Clinical Stage T4	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Cancer Clinical Stage Unknown or Not Reported	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Regional Lymph Node Stage N0	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Regional Lymph Node Stage N1	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Regional Lymph Node Stage N2	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Regional Lymph Node Stage Nx	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Regional Lymph Node Stage Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Breast Cancer Stage IIA	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Breast Cancer Stage IIB	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Breast Cancer Stage IIIA	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Breast Cancer Stage IIIB	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Breast Cancer Stage IIIC	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: 48 hours after start of treatment

Population: Participants were randomly assigned 1:1 to receive T-FEC or TR-FEC using a balanced block design stratified by disease stage and menopausal status. One participant in Arm 2 started treatment but had untolerable side effects and was taken off the study and thus was considered inevaluable.

Outcome measures

Outcome measures
Measure	Paclitaxel + FEC n=27 Participants Paclitaxel 80 mg/m\^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m\^2, Epirubicin at 100 mg/m\^2 and Cyclophosphamide at 500 mg/m\^2 (FEC) on day 1 every 3 weeks (+/- 7 days). 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 + FEC n=22 Participants Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. RAD001 : 30 mg by mouth weekly on Days 1, 8, \& 15 for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Number Participants With Inhibition of PI3K/PTEN/AKT Pathway at 48 Hours	27 participants	22 participants

SECONDARY outcome

Timeframe: 12 weeks

Population: Participants who did not complete the entire 12 week of paclitaxel +/- RAD001 or the entire 4 cycles of FEC are evaluable for response.

Radiographic criteria of response based on regional ultrasound examination (decrease in size of the primary tumor and/or fatty replacement in regional lymph nodes), and includes partial response and complete response. A decrease in size of the product of the two largest dimensions =/\> 50% considered a partial response (PR), and a complete disappearance of the primary tumor by physical exam and or ultrasound and normalization of the lymph nodes by ultrasound will be considered a complete clinical response (CR). Stable Disease (SD) is carcinoma neither decreasing nor increasing in extent or severity, and Progression of disease (PD) defined as 30% increase in size primary tumor and/or lymph nodes on physical exam and/or ultrasound.

Outcome measures

Outcome measures
Measure	Paclitaxel + FEC n=27 Participants Paclitaxel 80 mg/m\^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m\^2, Epirubicin at 100 mg/m\^2 and Cyclophosphamide at 500 mg/m\^2 (FEC) on day 1 every 3 weeks (+/- 7 days). 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 + FEC n=23 Participants Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. RAD001 : 30 mg by mouth weekly on Days 1, 8, \& 15 for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Participant Responses Per Treatment Arm at 12 Weeks CR	3 participants	0 participants
Participant Responses Per Treatment Arm at 12 Weeks PR	5 participants	11 participants
Participant Responses Per Treatment Arm at 12 Weeks SD	16 participants	11 participants
Participant Responses Per Treatment Arm at 12 Weeks PD	3 participants	1 participants

SECONDARY outcome

Timeframe: 24 weeks

Population: Participants who did not complete the entire 12 week of paclitaxel +/- RAD001 or the entire 4 cycles of FEC are evaluable for response.

Outcome measures

Outcome measures
Measure	Paclitaxel + FEC n=27 Participants Paclitaxel 80 mg/m\^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m\^2, Epirubicin at 100 mg/m\^2 and Cyclophosphamide at 500 mg/m\^2 (FEC) on day 1 every 3 weeks (+/- 7 days). 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 + FEC n=23 Participants Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. RAD001 : 30 mg by mouth weekly on Days 1, 8, \& 15 for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Participant Responses Per Treatment Arm at 24 Weeks PR	16 participants	11 participants
Participant Responses Per Treatment Arm at 24 Weeks SD	7 participants	7 participants
Participant Responses Per Treatment Arm at 24 Weeks PD	0 participants	3 participants
Participant Responses Per Treatment Arm at 24 Weeks CR	4 participants	2 participants

Adverse Events

Paclitaxel + FEC

Serious events: 27 serious events

Other events: 0 other events

Deaths: 0 deaths

Paclitaxel + RAD001 + FEC

Serious events: 23 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Clinical Research Operations, Office of VP Clinical Research

The University of Texas MD Anderson Cancer Center

Phone: 713-792-7734

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Paclitaxel + FEC n=27 participants at risk Paclitaxel 80 mg/m\^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m\^2, Epirubicin at 100 mg/m\^2 and Cyclophosphamide at 500 mg/m\^2 (FEC) on day 1 every 3 weeks (+/- 7 days). 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 + FEC n=23 participants at risk Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 80 mg/m\^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles. RAD001 : 30 mg by mouth weekly on Days 1, 8, \& 15 for 12 cycles. Cyclophosphamide : 500 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m\^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Blood and lymphatic system disorders Fatigue	7.4% 2/27 • Number of events 2 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	17.4% 4/23 • Number of events 4 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Gastrointestinal disorders GI Disturbaces	18.5% 5/27 • Number of events 5 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	26.1% 6/23 • Number of events 6 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Vascular disorders Neuropathy	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	4.3% 1/23 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Musculoskeletal and connective tissue disorders Pain	7.4% 2/27 • Number of events 2 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	13.0% 3/23 • Number of events 3 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Blood and lymphatic system disorders Neutropenia	40.7% 11/27 • Number of events 11 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	52.2% 12/23 • Number of events 12 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Infections and infestations Infection	0.00% 0/27 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	13.0% 3/23 • Number of events 3 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Blood and lymphatic system disorders Increased leukocytes	11.1% 3/27 • Number of events 3 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	17.4% 4/23 • Number of events 4 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Skin and subcutaneous tissue disorders Rash	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	8.7% 2/23 • Number of events 2 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Blood and lymphatic system disorders Anemia	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	17.4% 4/23 • Number of events 4 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Blood and lymphatic system disorders Lymphopenia	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	0.00% 0/23 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
General disorders Nail changes	0.00% 0/27 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	4.3% 1/23 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
General disorders Edema of extremities	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	0.00% 0/23 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Investigations Hyperglycemia	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	0.00% 0/23 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Blood and lymphatic system disorders Thrombocytopenia	7.4% 2/27 • Number of events 2 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	4.3% 1/23 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Investigations Hypokalemia	0.00% 0/27 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	4.3% 1/23 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
General disorders Syncope	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	0.00% 0/23 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Gastrointestinal disorders Small bowel obstruction	3.7% 1/27 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	0.00% 0/23 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Respiratory, thoracic and mediastinal disorders Pulmonary embolus	0.00% 0/27 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.	4.3% 1/23 • Number of events 1 • 3 years and 9 months Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.