Trial Outcomes & Findings for Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer (NCT NCT01661972)

NCT ID: NCT01661972

Last Updated: 2018-10-29

Results Overview

Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

63 participants

Primary outcome timeframe

RPTD for the study will be determined at the completion of Phase I; up to 1 year.

Results posted on

2018-10-29

Participant Flow

Participant milestones

Participant milestones
Measure	Phase 1 Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.	Phase 2 Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Overall Study STARTED	13	50
Overall Study COMPLETED	11	46
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 1 Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.	Phase 2 Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Overall Study Adverse Event	1	2
Overall Study Death during Treatment period	1	1
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1 n=13 Participants Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.	Phase 2 n=50 Participants Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.	Total n=63 Participants Total of all reporting groups
Age, Continuous	58.1 years STANDARD_DEVIATION 12.3 • n=5 Participants	57.7 years STANDARD_DEVIATION 9.9 • n=7 Participants	57.8 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	20 Participants n=7 Participants	26 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	30 Participants n=7 Participants	37 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	14 Participants n=7 Participants	16 Participants n=5 Participants
Race (NIH/OMB) White	11 Participants n=5 Participants	29 Participants n=7 Participants	40 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	13 Participants n=5 Participants	50 Participants n=7 Participants	63 Participants n=5 Participants

PRIMARY outcome

Timeframe: RPTD for the study will be determined at the completion of Phase I; up to 1 year.

Outcome measures

Outcome measures
Measure	Phase 1 n=13 Participants Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.	Phase 1 Cohort 2 Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination	850 mg/m2	—

PRIMARY outcome

Timeframe: 28 days

Number of patients experiencing a dose-limiting toxicity in each cohort. A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST \> 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization

Outcome measures

Outcome measures
Measure	Phase 1 n=7 Participants Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.	Phase 1 Cohort 2 n=6 Participants Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Number of Dose-Limiting Toxicities (Phase 1)	1 Participants	2 Participants

PRIMARY outcome

Timeframe: approximately 5 months

Population: Patients enrolled in Phase 2 were included in the analysis

Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.

Outcome measures

Outcome measures
Measure	Phase 1 n=50 Participants Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.	Phase 1 Cohort 2 Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Median Progression Free Survival (PFS)	3.91 Months Interval 2.3 to 4.47	—

SECONDARY outcome

Timeframe: approximately every 9 weeks and/or restaging, through study completion

Population: All evaluable Phase 2 patients. 5 patients were not evaluable for response and were not included in the analysis.

The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.

Outcome measures

Outcome measures
Measure	Phase 1 n=45 Participants Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.	Phase 1 Cohort 2 Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Response Rate	2.22 percentage of participants Interval 0.06 to 11.77	—

SECONDARY outcome

Timeframe: Subjects will be followed until death which is estimated to be on average 6 months - 1 year after coming off protocol therapy

Population: Patients enrolled in Phase 2 were included in the analysis

Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.

Outcome measures

Outcome measures
Measure	Phase 1 n=50 Participants Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.	Phase 1 Cohort 2 Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Median Survival	7.43 months Interval 5.78 to 10.68	—

Adverse Events

Phase 1

Serious events: 9 serious events

Other events: 13 other events

Deaths: 0 deaths

Phase 2

Serious events: 18 serious events

Other events: 46 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

John Strickler, M.D.

Duke University Medical Center

Phone: 919-668-1861

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Phase 1 n=13 participants at risk Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.	Phase 2 n=50 participants at risk Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Blood and lymphatic system disorders Anemia	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	4.0% 2/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Cardiac disorders Aortic valve disease	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Cardiac disorders Supraventricular tachycardia	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Abdominal pain	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	4.0% 2/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Anal fistula	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Ascites	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Colonic obstruction	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Colonic perforation	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Diarrhea	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Gastric hemorrhage	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Nausea	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Gastrointestinal disorders Vomiting	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
General disorders Death NOS	23.1% 3/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	8.0% 4/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
General disorders Fever	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Hepatobiliary disorders Cholecystitis	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Hepatobiliary disorders Hepatic failure	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Infections and infestations Appendicitis	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Infections and infestations Sepsis	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Investigations Blood bilirubin increased	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	4.0% 2/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Metabolism and nutrition disorders Dehydration	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Nervous system disorders Depressed level of consciousness	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Nervous system disorders Intracranial hemorrhage	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Nervous system disorders Syncope	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Psychiatric disorders Confusion	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Psychiatric disorders Depression	0.00% 0/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Respiratory, thoracic and mediastinal disorders Dyspnea	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	0.00% 0/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Vascular disorders Hypertension	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Vascular disorders Thromboembolic event	7.7% 1/13 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	2.0% 1/50 • All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent. Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.