Trial Outcomes & Findings for Sorafenib and TRC105 in Hepatocellular Cancer (NCT NCT01306058)

Last Updated: 2019-01-23

Results Overview

MTD is the highest dose studied for which the incidence of DLT was less than 33%. DLT criteria included treatment-related grade 3 non-hematological toxicities or grade 4 hematological toxicities occurring within the first 28 days of treatment. Grade 3 electrolyte toxicities to be corrected to Grade 1 or less within 24 hours will be considered dose limiting (proteinuria \>3.5g/24 hour will be defined as a DLT). Drug-related Grade 4 hematological toxicity will be considered dose limiting. Toxicity requiring a dose reduction or a delay in treatment for \>7 days will be considered dose limiting. Other Grade 3 or higher toxicity related to TRC105 will be considered dose limiting.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

27 participants

Primary outcome timeframe

Completed in the first 28 days of treatment (cycle 1)

Results posted on

2019-01-23

Participant Flow

27 patients were enrolled. One patient signed consent but developed rapid disease progression and did not receive any treatment.

Participant milestones

Participant milestones
Measure	Sorafenib & TRC105 in Hepatocellular CA CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Overall Study STARTED	27
Overall Study COMPLETED	25
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Sorafenib & TRC105 in Hepatocellular CA CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Overall Study Death	1
Overall Study Enrolled but did not get treatment	1

Baseline Characteristics

One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sorafenib & TRC105 in Hepatocellular CA n=27 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Age, Categorical <=18 years	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	25 Participants n=27 Participants
Age, Categorical >=65 years	2 Participants n=27 Participants
Age, Continuous	55.3 years STANDARD_DEVIATION 13 • n=27 Participants
Sex: Female, Male Female	7 Participants n=27 Participants
Sex: Female, Male Male	20 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	26 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=27 Participants
Race (NIH/OMB) Asian	2 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	10 Participants n=27 Participants
Race (NIH/OMB) White	13 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=27 Participants
Region of Enrollment United States	27 Participants n=27 Participants
Participant Etiology of Hepatocellular Cancer (HCC) Hepatitis B Virus (HBV)	3 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Participant Etiology of Hepatocellular Cancer (HCC) Hepatitis C Virus (HCV)	15 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Participant Etiology of Hepatocellular Cancer (HCC) Cryptogenic	6 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Participant Etiology of Hepatocellular Cancer (HCC) Hematochromatosis	1 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Baseline Child Pugh Score Child Pugh Score - 5	10 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Baseline Child Pugh Score Child Pugh Score - 6	4 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Baseline Child Pugh Score Child Pugh Score - 7	1 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Baseline Child Pugh Score NA	10 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Number of Participants with Extrahepatic disease Yes	17 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Number of Participants with Extrahepatic disease No	8 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Prior Therapies No prior intervention	9 Participants n=27 Participants
Prior Therapies ≥2 locoregional procedures	7 Participants n=27 Participants
Prior Therapies Previous TACE	8 Participants n=27 Participants
Prior Therapies Surgery	5 Participants n=27 Participants
Prior Therapies Ablation	2 Participants n=27 Participants
Prior Therapies Radioembolization	2 Participants n=27 Participants
Prior Therapies Transplant	2 Participants n=27 Participants
Number of Participants with Liver Cirrhosis Yes	15 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Number of Participants with Liver Cirrhosis No	10 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0	8 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1	17 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Participants with Hepatocellular Cancer & Fibrolamellar Hepatocellular Cancer (HCC)	24 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.
Participants with Hepatocellular Cancer & Fibrolamellar Fibrolamellar	1 Participants n=25 Participants • One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.

PRIMARY outcome

Timeframe: Completed in the first 28 days of treatment (cycle 1)

Population: 24/27 analyzed. One patient signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=24 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Phase I: Maximum Tolerated Dose (MTD) of TRC105 When Given With Standard-dose Sorafenib for Hepatocellular Cancer (HCC)	15 mg/kg

PRIMARY outcome

Timeframe: 2 years

TTP is the time between the first day of treatment to the day of disease progression. Progressive disease was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions).

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=24 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Phase II: Time to Progression (TTP) for the Combination of TR105 With Sorafenib in Hepatocellular Cancer (HCC)	3.8 Months Interval 3.2 to 5.6

SECONDARY outcome

Timeframe: 2 years

Overall response (Complete Response (CR) + Partial Response (PR) was assessed by the Standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria for target lesions and assessed by magnetic resonance imaging (MRI). CR is disappearance of all target lesions. PR is at least a 30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=24 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Overall Response Rate (ORR) as Determined by the Standard Response Evaluation Criteria in Solid Tumors (RECIST) Criteria	21 percentage of participants Interval 7.1 to 42.2

SECONDARY outcome

Timeframe: 2 years

Overall response (Complete Response (CR) + Partial Response (PR) was assessed by the European Association for the Study of the Liver (EASL)-modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for target lesions and assessed by magnetic resonance imaging (MRI). CR is disappearance of all target lesions. PR is at least a 30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=24 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Overall Response Rate (ORR) as Determined by the European Association for the Study of the Liver (EASL)-Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria	21 percentage of participants Interval 7.1 to 42.2

SECONDARY outcome

Timeframe: Cycle 1 Day 1, 28 days post end of study (up to 2 years)

Population: 11/27 were analyzed because only 11 patients were evaluable at the highest dose level given to patients.

Patients who develop antidrug antibodies is measured by human anti-chimeric antibody (HACA) formation (e.g. immunogenicity of TRC105).

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=11 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Patients Who Developed Antidrug Antibodies	7 Participants

SECONDARY outcome

Timeframe: Baseline and then 28 days following the end of the study treatment, approximately two years

Population: 9/20, 8/20, and 3/20 participants were evaluable for the noted time periods below.

A 5mL blood sample will be collected to assess immunogenicity. Immunogenicity will be measured by the enzyme-linked immunosorbent assay (ELISA) and expressed in titres. The higher the titre, the higher the formation of HAMA antibody in the blood. A higher concentration of HAMA (higher titre result) is a negative finding. A higher level means the drug elimination is faster and the TRC 105 is then less effective. Lower level is 0-2 titre. Any value above 2 titre would be a positive HAMA result. The HAMA ( Human anti-mouse antibody) measurement at 28 days post treatment levels provides information as to the rate of drug elimination and effectiveness. Patients with 0 to \< 2.0 titre. eliminates the TRC 105 slower and the drug may be more effective than patients who have a low(\>2.0 titres) or high level of HAMA. Higher levels of HAMA reflect the TRC 105 elimination from the body faster and the drug potentially not as effective as negative HAMA titres.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=20 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Immunogenicity of TRC105 as Measured by Human Anti-mouse Antibody (HAMA) Formation Baseline	0.02 titres Interval 0.0 to 2.0
Immunogenicity of TRC105 as Measured by Human Anti-mouse Antibody (HAMA) Formation no evidence of HAMA 28 days post treatment	0 titres Interval 0.0 to 0.0
Immunogenicity of TRC105 as Measured by Human Anti-mouse Antibody (HAMA) Formation Low level of HAMA 28 days post treatment	65 titres Interval 2.0 to 128.0
Immunogenicity of TRC105 as Measured by Human Anti-mouse Antibody (HAMA) Formation High level of HAMA 28 days post treatment	515 titres Interval 256.0 to 1024.0

SECONDARY outcome

Timeframe: 4 years and 10.5 months

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=27 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Number of Participants With Serious and Non-serious Adverse Events by Common Terminology Criteria in Adverse Events (CTCAE)v4.0	27 Participants

SECONDARY outcome

Timeframe: First 28 days of treatment (cycle 1)

DLT was assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0. DLT criteria included treatment-related grade 3 non-hematological toxicities or grade 4 hematological toxicities occurring within the first 28 days of treatment. Grade 3 electrolyte toxicities to be corrected to Grade 1 or less within 24 hours will be considered dose limiting (proteinuria \>3.5g/24 hour will be defined as a DLT). Drug-related Grade 4 hematological toxicity will be considered dose limiting. Toxicity requiring a dose reduction or a delay in treatment for \>7 days will be considered dose limiting. Other Grade 3 or higher toxicity related to TRC105 will be considered dose limiting.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=27 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Number of Participants With Dose Limiting Toxicity (DLT)	1 Participants

SECONDARY outcome

Timeframe: 4 years and 10.5 months

Population: 25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Here are the number of treatment-emergent adverse events categorized by Any grade, Grade 3, Grade 4 and Grade 5 adverse events. Adverse events was assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0. Grade 1 is mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 is moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) (e.g. preparing meals, shopping for groceries or clothes). Grade 3 is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL (e.g. bathing, dressing and undressing). Grade 4 is life-threatening consequences; urgent intervention indicated. Grade 5 is death related to adverse event.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=25 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Treatment-emergent Adverse Events Grade 4 Amylase	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Hypoalbuminemia	2 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Headache	20 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Epistaxis	19 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Increased aspartate aminotransaminase	18 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Increased aspartate aminotransaminase	5 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Rash, other	18 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Rash, other	3 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Hypophosphatemia	18 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Hypophosphatemia	7 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Hypoalbuminemia	17 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Anemia	16 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Anemia	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Fatigue	15 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Increased alkaline phosphatase	15 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Increased alkaline phosphatase	5 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Diarrhea	15 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Diarrhea	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Increased blood bilirubin	14 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Increased blood bilirubin	6 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 4 Increased blood bilirubin	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Nausea	14 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Increased alanine transaminase	13 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Oral mucositis/pain	12 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Thrombocytopenia	10 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Thrombocytopenia	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Amylase	10 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Amylase	2 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Abdominal pain	9 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Hand-foot skin reaction	8 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Hand-foot skin reaction	2 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Infusion reaction	8 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 infusion reaction	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Neutropenia	8 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Weight loss	8 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Hypertension	6 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Hypertension	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Vomiting	6 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Hypomagnesemia	5 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Alopecia	5 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Insomnia	4 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Constipation	3 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Intracranial hemorrhage	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 5 Myocardial ischemia	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 4 Lipase	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Any Grade Hyperglycemia	1 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 3 Hyperglycemia	2 treatment-emergent adverse events
Treatment-emergent Adverse Events Grade 4 Hyperuricemia	2 treatment-emergent adverse events

SECONDARY outcome

Timeframe: up to 6 months

Population: 25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

PFS was calculated from the on-study date until date of progression, death, or an event that would render the patient inevaluable for further follow-up (liver dysfunction), or end of study. Probabilities were determined using the Kaplan-Meier method. Progressive disease was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions).

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=25 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Median Progression-free Survival (PFS)	3.8 Months Interval 3.2 to 5.6

SECONDARY outcome

Timeframe: 3 and 6 months

Population: 25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Percentage of participants who were progression free at 3 and 6 months. Progressive disease was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions).

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=25 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Percentage of Participants With Progression Free Survival (PFS) at 3 and 6 Months 3 month PFS	75.0 percentage of participants Interval 52.6 to 87.9
Percentage of Participants With Progression Free Survival (PFS) at 3 and 6 Months 6 month PFS	16.7 percentage of participants Interval 5.2 to 33.7

SECONDARY outcome

Timeframe: up to 2 years

Population: 25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

OS was calculated from the on-study date until the date of death or the date the patient was last known to be alive. Probabilities were determined using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=25 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Median Overall Survival (OS)	15.5 Months Interval 8.5 to 26.3

SECONDARY outcome

Timeframe: 6 and 12 months

Population: 25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Percentage of participants last known to be alive at 6 and 12 months.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=25 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Percentage of Participants With Overall Survival (OS) at 6 and 12 Months 6 month OS	74.0 percentage of participants Interval 50.9 to 87.4
Percentage of Participants With Overall Survival (OS) at 6 and 12 Months 12 month OS	59.2 percentage of participants Interval 35.9 to 76.4

SECONDARY outcome

Timeframe: Every 8 weeks, up to 180 days

Population: 7/27 participants were not evaluable (1 was not evaluable, 1 patient had dose limiting toxicity myocardial infarction, 1 could not tolerate sorafenib, 1 infusion reaction to TRC105 during first dose, 1 early progressive disease, 1 side effects, and 1 off due to severe skin toxicity).

Response is defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. To be assigned a confirmed PR, changes in tumor measurements must be confirmed by repeat assessments that should be performed at least 4 weeks after the criteria for response are first met. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters on study. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions).

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=20 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial Phase I - Stable disease	9 Participants
Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial Phase I - Progressive disease	2 Participants
Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial Phase I - Partial response	4 Participants
Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial Phase 2 - Stable disease	3 Participants
Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial Phase 2 - Partial response	1 Participants
Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial Phase 2 - Progressive disease	2 Participants

SECONDARY outcome

Timeframe: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, and prior to start of TRC105 infusion

Mean peak TRC105 serum trough concentrations were plotted over time by dose level to assess accumulation. (e.g. drug absorption). The lower limit of quantification (LLOQ) is 200 ng/mL.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=24 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Area Under the Plasma Concentration Dose level 1	75933 Hr*ng/mL Interval 73054.0 to 78813.0
Area Under the Plasma Concentration Dose level 2	152900 Hr*ng/mL Interval 123166.0 to 182634.0
Area Under the Plasma Concentration Dose level 3	242882 Hr*ng/mL Interval 196241.0 to 289524.0
Area Under the Plasma Concentration Dose level 4	362611 Hr*ng/mL Interval 324921.0 to 400301.0

SECONDARY outcome

Timeframe: Cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, or end of study, an average of 12 weeks

Population: 25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Plasma biomarker tests were performed for VEGF and PIGF using assay plates from Meso-Scale Discovery according to the product manual. The concentrations of the cytokines were determined with recombinant standards. Changes in biomarkers were determined by a Wilcoxon signed rank test.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=25 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) VEGF cycle 2 day 1	243.4 pg/ml Interval 136.1 to 418.1
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) PIGF cycle 2 day 1	68.8 pg/ml Interval 49.9 to 88.0
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) VEGF cycle 1 day 1	202.5 pg/ml Interval 100.9 to 341.5
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) PIGF cycle 1 day 1	44.6 pg/ml Interval 39.9 to 54.1
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) VEGF cycle 1 day 15	299 pg/ml Interval 149.2 to 520.5
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) PIGF cycle 1 day 15	81.6 pg/ml Interval 51.5 to 112.0
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) VEGF end of study (eos)	184.3 pg/ml Interval 62.9 to 311.6
Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) PIGF end of study (eos)	53.5 pg/ml Interval 32.4 to 100.0

SECONDARY outcome

Timeframe: Cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, or end of study (eos), an average of 12 weeks

Population: 25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Blood samples were collected and analyzed by the enzyme-linked immunosorbent assay (ELISA). Serum samples were measured using a validated ELISA with a lower limit of quantification (LLOQ) of 200 ng/ml. Soluble endoglin was only assessed in patient samples without detectable TRC105 concentrations.

Outcome measures

Outcome measures
Measure	Sorafenib & TRC105 in Hepatocellular CA n=25 Participants CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Changes in Biomarker Cluster of Differentiation 105 (CD105) Cycel 1 Day 1	27.5 ng/ml Interval 22.9 to 36.0
Changes in Biomarker Cluster of Differentiation 105 (CD105) Cycle 1 Day 15	60.4 ng/ml Interval 41.0 to 78.5
Changes in Biomarker Cluster of Differentiation 105 (CD105) Cycel 2 day 1	64.5 ng/ml Interval 51.4 to 87.3
Changes in Biomarker Cluster of Differentiation 105 (CD105) End of study (eos)	66.6 ng/ml Interval 31.5 to 86.4

SECONDARY outcome

Timeframe: Baseline and Cycle 1 Day 2 and Cycle 2 Day 1, an average of 12 weeks

Population: This analysis was not done as magnetic resonance imaging (MRI) scans not performed as planned.

The perfusion of tumors was evaluated and analysis of normalized signal intensity in unenhanced and enhanced MRIs at each time point with calculation of measured percentage of signal change to reflect tumor vascularity. Signal change and signal intensity is defined as the Initial Area Under the Gd Curve measured over 60 seconds (IAUC60) and the Transport Constant (Ktrans) and the difference in these values relative to baseline.

Outcome measures

Outcome data not reported

Adverse Events

Sorafenib & TRC105 in Hepatocellular CA

Serious events: 11 serious events

Other events: 27 other events

Deaths: 16 deaths

Serious adverse events

Serious adverse events
Measure	Sorafenib & TRC105 in Hepatocellular CA n=27 participants at risk CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Investigations Aspartate aminotransferase increased	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Blood bilirubin increased	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Diarrhea	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Epistaxis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Fever	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Vascular disorders Flushing	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Gastrointestinal pain	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Hepatobiliary disorders Hepatic failure	3.7% 1/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Vascular disorders Hypotension	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Infusion related reaction	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Intracranial hemorrhage	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Cardiac disorders Left ventricular systolic dysfunction	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Lipase increased	3.7% 1/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Lung infection	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Mucositis oral	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Cardiac disorders Myocardial infarction	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Pancreatitis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Rash maculo-papular	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Sepsis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Serum amylase increased	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Stroke	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.

Other adverse events

Other adverse events
Measure	Sorafenib & TRC105 in Hepatocellular CA n=27 participants at risk CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle
Gastrointestinal disorders Abdominal distension	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Abdominal pain	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Activated partial thromboplastin time prolonged	44.4% 12/27 • Number of events 27 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Alanine aminotransferase increased	59.3% 16/27 • Number of events 45 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Alkaline phosphatase increased	63.0% 17/27 • Number of events 41 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Alopecia	18.5% 5/27 • Number of events 5 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Blood and lymphatic system disorders Anemia	77.8% 21/27 • Number of events 62 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Anorexia	29.6% 8/27 • Number of events 11 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Musculoskeletal and connective tissue disorders Arthralgia	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Ascites	14.8% 4/27 • Number of events 5 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Aspartate aminotransferase increased	66.7% 18/27 • Number of events 62 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Hepatobiliary disorders Bile duct stenosis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Bloating	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Blood bilirubin increased	63.0% 17/27 • Number of events 60 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Bronchial infection	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Cardiac disorders Chest pain - cardiac	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Chills	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Cold sensitivity	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Constipation	11.1% 3/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 3/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Creatinine increased	22.2% 6/27 • Number of events 10 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Dehydration	14.8% 4/27 • Number of events 5 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Diarrhea	48.1% 13/27 • Number of events 31 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Dizziness	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Dry mouth	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Dry skin	14.8% 4/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Dysgeusia	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Dysphagia	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Dyspnea	7.4% 2/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Ear and labyrinth disorders Ear pain	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Edema limbs	18.5% 5/27 • Number of events 8 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Enterocolitis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Enterocolitis infectious	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Epistaxis	63.0% 17/27 • Number of events 36 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Eye disorders Eye disorders - Other, Bleeding; Puffy eyelids	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Fatigue	63.0% 17/27 • Number of events 25 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Fever	29.6% 8/27 • Number of events 9 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Fibrinogen decreased	3.7% 1/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Flu like symptoms	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Vascular disorders Flushing	11.1% 3/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Gait disturbance	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	11.1% 3/27 • Number of events 6 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Gastrointestinal pain	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Gastroparesis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders General disorders and administration site conditions - Other, specify	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Gingival pain	14.8% 4/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Headache	63.0% 17/27 • Number of events 39 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Hemorrhoidal hemorrhage	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Hiccups	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Hoarseness	11.1% 3/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Vascular disorders Hot flashes	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypercalcemia	22.2% 6/27 • Number of events 7 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hyperglycemia	7.4% 2/27 • Number of events 5 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Hyperhidrosis	11.1% 3/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hyperkalemia	14.8% 4/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypermagnesemia	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Vascular disorders Hypertension	22.2% 6/27 • Number of events 12 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hyperuricemia	22.2% 6/27 • Number of events 17 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypoalbuminemia	74.1% 20/27 • Number of events 53 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypocalcemia	11.1% 3/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypoglycemia	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypokalemia	18.5% 5/27 • Number of events 5 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypomagnesemia	25.9% 7/27 • Number of events 14 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hyponatremia	48.1% 13/27 • Number of events 28 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Metabolism and nutrition disorders Hypophosphatemia	81.5% 22/27 • Number of events 56 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Vascular disorders Hypotension	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Infections and infestations - Other, specify	18.5% 5/27 • Number of events 10 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Infusion related reaction	29.6% 8/27 • Number of events 11 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Psychiatric disorders Insomnia	11.1% 3/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Lipase increased	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Lung infection	3.7% 1/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Lymphocyte count decreased	63.0% 17/27 • Number of events 50 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Malaise	7.4% 2/27 • Number of events 6 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Mucositis oral	14.8% 4/27 • Number of events 8 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Musculoskeletal and connective tissue disorders Myalgia	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Nasal congestion	11.1% 3/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Nausea	48.1% 13/27 • Number of events 26 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Neutrophil count decreased	22.2% 6/27 • Number of events 11 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Oral hemorrhage	11.1% 3/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Oral pain	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
General disorders Pain	66.7% 18/27 • Number of events 47 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Musculoskeletal and connective tissue disorders Pain in extremity	14.8% 4/27 • Number of events 6 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Pain of skin	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	37.0% 10/27 • Number of events 27 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Periodontal disease	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Peripheral sensory neuropathy	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Platelet count decreased	37.0% 10/27 • Number of events 23 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Renal and urinary disorders Proteinuria	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Pruritus	14.8% 4/27 • Number of events 5 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Radiculitis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Rash acneiform	14.8% 4/27 • Number of events 4 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Rash maculo-papular	51.9% 14/27 • Number of events 52 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Rectal fistula	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Rectal hemorrhage	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Reproductive system and breast disorders Reproductive system and breast disorders - Other, specify	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Rhinitis infective	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Serum amylase increased	44.4% 12/27 • Number of events 31 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Sinus disorder	3.7% 1/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Cardiac disorders Sinus tachycardia	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Sinusitis	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	11.1% 3/27 • Number of events 8 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Skin infection	3.7% 1/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Somnolence	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Sore throat	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Nervous system disorders Stroke	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Vascular disorders Thromboembolic event	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Toothache	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Upper respiratory infection	11.1% 3/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Renal and urinary disorders Urinary retention	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Infections and infestations Urinary tract infection	7.4% 2/27 • Number of events 2 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Renal and urinary disorders Urinary tract pain	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Reproductive system and breast disorders Vaginal hemorrhage	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Voice alteration	7.4% 2/27 • Number of events 3 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Gastrointestinal disorders Vomiting	22.2% 6/27 • Number of events 12 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations Weight loss	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Respiratory, thoracic and mediastinal disorders Wheezing	3.7% 1/27 • Number of events 1 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.
Investigations White blood cell decreased	37.0% 10/27 • Number of events 26 • 4 years and 10.5 months 16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.

Additional Information

Dr. Tim Greten

Principal Investigator

Phone: 301-451-4723

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place