Trial Outcomes & Findings for Carboplatin+Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting (NCT NCT00618657)

Last Updated: 2024-02-28

Results Overview

Progression is defined as a new lesion or a greater than or equal to 25% increase in the product of the largest perpendicular diameters of any one lesion on clinical exam or by ultrasound (U/S) or MRI. Analyzed using the Kaplan-Meier method. Cox proportional-hazards analysis will be used to derive the hazard ratio and 95% confidence interval between the two treatment arms, adjusted for clinical and demographic variables.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

127 participants

Primary outcome timeframe

2 years

Results posted on

2024-02-28

Participant Flow

Participant milestones

Participant milestones
Measure	Arm I (HER-2 Positive) Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Arm II (HER-2 Negative) Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV bevacizumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts
Overall Study STARTED	42	85
Overall Study COMPLETED	42	85
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Carboplatin+Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (HER-2 Positive) n=42 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Arm II (HER-2 Negative) n=85 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV bevacizumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Total n=127 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	38 Participants n=5 Participants	80 Participants n=7 Participants	118 Participants n=5 Participants
Age, Categorical >=65 years	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	85 Participants n=7 Participants	127 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	14 Participants n=5 Participants	36 Participants n=7 Participants	50 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants n=5 Participants	49 Participants n=7 Participants	77 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	15 Participants n=5 Participants	15 Participants n=7 Participants	30 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	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	53 Participants n=7 Participants	71 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	8 Participants n=5 Participants	14 Participants n=7 Participants	22 Participants n=5 Participants
Region of Enrollment United States	42 participants n=5 Participants	85 participants n=7 Participants	127 participants n=5 Participants

PRIMARY outcome

Timeframe: 2 years

Outcome measures

Outcome measures
Measure	Arm I (HER-2 Positive) n=42 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Arm II (HER-2 Negative) n=85 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV bevacizumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts
Progression Free Survival	95 percentage of participants	93 percentage of participants

SECONDARY outcome

Timeframe: Up to 5 years

Population: Clinical complete response data was not collected.

Defined as normal breast on physical exam. No mass, no thickening, no erythema, no peau d'orange. The 95% confidence interval (CI) will be computed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 5 years

Defined as no evidence of microscopic invasive tumor at the primary tumor site in the surgical specimen. The 95% CI will be computed.

Outcome measures

Outcome measures
Measure	Arm I (HER-2 Positive) n=42 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Arm II (HER-2 Negative) n=85 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV bevacizumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts
Number of Participants With no Evidence of Microscopic pCR in the Neoadjuvant Setting	21 Participants	15 Participants

SECONDARY outcome

Timeframe: Up to 5 years

Population: See adverse events section for complete report of adverse events.

The frequency of toxicities will be recorded.

Outcome measures

Outcome measures
Measure	Arm I (HER-2 Positive) n=42 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Arm II (HER-2 Negative) n=85 Participants Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV bevacizumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts
Number of Participants With Toxicity of the Combinations in HER2 Positive and HER2 Negative Breast Cancer Assessed Using the National Cancer Institute (NCI) Common Toxicity Criteria Version 3.0	19 Participants	50 Participants

Adverse Events

Arm I (HER-2 Positive)

Serious events: 2 serious events

Other events: 19 other events

Deaths: 5 deaths

Arm II (HER-2 Negative)

Serious events: 1 serious events

Other events: 50 other events

Deaths: 11 deaths

Serious adverse events

Serious adverse events
Measure	Arm I (HER-2 Positive) n=42 participants at risk Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Arm II (HER-2 Negative) n=85 participants at risk Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV bevacizumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts
Blood and lymphatic system disorders Neutropenia	4.8% 2/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Blood and lymphatic system disorders Thrombocytopenia	2.4% 1/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	0.00% 0/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Blood and lymphatic system disorders Febrile Neutropenia	2.4% 1/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	0.00% 0/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.

Other adverse events

Additional Information

UC Irvine Health / Chao Family Comprehensive Cancer Center

Phone: 1-877-UC-STUDY

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm I (HER-2 Positive) n=42 participants at risk Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts	Arm II (HER-2 Negative) n=85 participants at risk Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery. Carboplatin: Given IV paclitaxel albumin-stabilized nanoparticle formulation: Given IV bevacizumab: Given IV magnetic resonance imaging: Optional correlative studies therapeutic conventional surgery: Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts
Blood and lymphatic system disorders Neutropenia	33.3% 14/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	34.1% 29/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Blood and lymphatic system disorders Anemia	19.0% 8/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	4.7% 4/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Blood and lymphatic system disorders Thrombocytopenia	2.4% 1/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	7.1% 6/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Gastrointestinal disorders Mucositis	2.4% 1/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	3.5% 3/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Renal and urinary disorders Urinary Tract Infection	4.8% 2/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	10.6% 9/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Gastrointestinal disorders Diarrhea	7.1% 3/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	2.4% 2/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Nervous system disorders Peripheral Neuropathy	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
General disorders Fatigue	4.8% 2/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	4.7% 4/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
General disorders Nausea	9.5% 4/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	7.1% 6/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
General disorders Rhinitis	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Respiratory, thoracic and mediastinal disorders Cough	2.4% 1/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Respiratory, thoracic and mediastinal disorders Upper Respiratory Infection	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	2.4% 2/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Reproductive system and breast disorders Amenorrhea	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Product Issues Carboplatin Allergic Reaction	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	3.5% 3/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Reproductive system and breast disorders Vaginal Infection	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Blood and lymphatic system disorders Hypertension	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	5.9% 5/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Blood and lymphatic system disorders Febrile Neutropenia	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Gastrointestinal disorders Pancreatitis	2.4% 1/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	0.00% 0/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Gastrointestinal disorders Biliary Tract Infection	2.4% 1/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	0.00% 0/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
General disorders Epistaxis	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	2.4% 2/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Skin and subcutaneous tissue disorders Maculopapular Rash	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	2.4% 2/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
General disorders Hot Flashes	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
General disorders Tooth Infection	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
General disorders Headache	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Respiratory, thoracic and mediastinal disorders Bronchial Infection	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Injury, poisoning and procedural complications Nonhealing Would	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.
Skin and subcutaneous tissue disorders Hand Foot Syndrome	0.00% 0/42 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.	1.2% 1/85 • Up to 5 years Toxicity was graded according to National Cancer Institute Common Terminology Criteria of Adverse Events, version 5.0. Safety was assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests before each dosing.