Trial Outcomes & Findings for A Study of IMC-A12 in Combination With Sorafenib in Participants With Advanced Cancer of the Liver (NCT NCT00906373)

NCT ID: NCT00906373

Last Updated: 2018-06-04

Results Overview

PFS is defined as the time from date of first dose of study drug until the date of objective PD or death due to any cause, whichever occurs first. PD defined as a ≥20% increase in the sum of the longest diameter (LD) of target lesions using as reference the smallest sum LD since baseline or ≥1 new lesions. Participants who died without PD were considered to have progressed on the date of death. Participants who were alive and without PD were censored at the time of the last objective tumor assessment. Participants who did not progress and are subsequently lost to follow-up were censored at the date of their last objective tumor assessment before loss to follow-up. Participants who progressed or died after ≥2 missed tumor assessment visits were censored at the date of their last objective tumor assessment before missed assessments. Participants who begin a new anticancer therapy were censored at the date of their last objective tumor assessment before initiation of new therapy.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 47 participants
• Primary outcome timeframe: Date of first dose of study drug up PD or death up to 12 months
• Results posted on: 2018-06-04

Participant Flow

Participants who died or had progressive disease (PD) were considered to complete the study.

Participant milestones

Measure	Cohort 1 - 10 mg/kg Cixutumumab Cixutumumab (IMC-A12/LY3012217): 10 milligrams/kilogram (mg/kg) administered by intravenous (IV) infusion on Day 1 of each 3-week cycle. Sorafenib: 400 milligrams (mg) administered orally, twice daily on Days 1 through 21 of each 3-week cycle. Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Overall Study STARTED	6	41
Overall Study Received Any Amount of Study Drug	6	41
Overall Study COMPLETED	6	33
Overall Study NOT COMPLETED	0	8

Reasons for withdrawal

Measure	Cohort 1 - 10 mg/kg Cixutumumab Cixutumumab (IMC-A12/LY3012217): 10 milligrams/kilogram (mg/kg) administered by intravenous (IV) infusion on Day 1 of each 3-week cycle. Sorafenib: 400 milligrams (mg) administered orally, twice daily on Days 1 through 21 of each 3-week cycle. Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Overall Study Withdrawal by Subject	0	5
Overall Study Other	0	1
Overall Study Still on treatment at cutoff date	0	2

Baseline Characteristics

A Study of IMC-A12 in Combination With Sorafenib in Participants With Advanced Cancer of the Liver

Baseline characteristics by cohort

Measure	Cohort 1 - 10 mg/kg Cixutumumab n=6 Participants Cixutumumab: 10 mg/kg administered by IV infusion on Day 1 of each 3-week cycle. Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle. Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab n=41 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Total n=47 Participants Total of all reporting groups
Age, Continuous	67.3 years STANDARD_DEVIATION 11.06 • n=5 Participants	63.7 years STANDARD_DEVIATION 8.79 • n=7 Participants	64.2 years STANDARD_DEVIATION 9.05 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	33 Participants n=7 Participants	38 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants n=5 Participants	33 Participants n=7 Participants	38 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	7 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	6 Participants n=5 Participants	28 Participants n=7 Participants	34 Participants n=5 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	6 Participants n=5 Participants	41 Participants n=7 Participants	47 Participants n=5 Participants

PRIMARY outcome

Timeframe: Date of first dose of study drug up PD or death up to 12 months

Population: All randomized participants in Cohort 2 who received any amount of study drug, per the protocol efficacy analysis was only performed for Cohort 2. Participants censored = 10.

PFS is defined as the time from date of first dose of study drug until the date of objective PD or death due to any cause, whichever occurs first. PD defined as a ≥20% increase in the sum of the longest diameter (LD) of target lesions using as reference the smallest sum LD since baseline or ≥1 new lesions. Participants who died without PD were considered to have progressed on the date of death. Participants who were alive and without PD were censored at the time of the last objective tumor assessment. Participants who did not progress and are subsequently lost to follow-up were censored at the date of their last objective tumor assessment before loss to follow-up. Participants who progressed or died after ≥2 missed tumor assessment visits were censored at the date of their last objective tumor assessment before missed assessments. Participants who begin a new anticancer therapy were censored at the date of their last objective tumor assessment before initiation of new therapy.

Outcome measures

Measure	Cohort 2 - 20 mg/kg Cixutumumab n=41 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Progression Free Survival (PFS)	2.9 months Interval 1.7 to 5.3	—

SECONDARY outcome

Timeframe: First day of treatment up to 22 months

Population: All randomized participants who received any amount of study drug.

Clinically significant events were defined as serious adverse events (SAEs) and other non-serious AEs regardless of causality. A summary of SAEs and other non-serious AEs regardless of causality, is located in the Reported Adverse Events module.

Outcome measures

Measure	Cohort 2 - 20 mg/kg Cixutumumab n=6 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab n=41 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Number of Participants With Adverse Events (AEs) SAEs	4 Participants	15 Participants
Number of Participants With Adverse Events (AEs) Other Non-Serious AEs	6 Participants	41 Participants

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Predose, 1 hour (h), 2 h, 168 h, 336 h, and 504 h after start of infusion (immediately prior to Cycle 2)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Predose, 1 h, 2 h, 168 h, 336 h, and 504 h after start of infusion (immediately prior to Cycle 2)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Predose, 1 h, 2 h, 168 h, 336 h, and 504 h after start of infusion (immediately prior to Cycle 2)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Predose, 1 h, 2 h, 168 h, 336 h, and 504 h after start of infusion (immediately prior to Cycle 2)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Predose, 1 h, 2 h, 168 h, 336 h, and 504 h after start of infusion (immediately prior to Cycle 2)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Predose, 1 h, 2 h, 168 h, 336 h, and 504 h after start of infusion (immediately prior to Cycle 2)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 3, Day 1: Predose, 2 h, 24 h, 48 h, 72 h, 168 h, 240 h, 336 h and 504 h after start of infusion (immediately prior to Cycle 4)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 3, Day 1: Predose, 2 h, 24 h, 48 h, 72 h, 168 h, 240 h, 336 h and 504 h after start of infusion (immediately prior to Cycle 4)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 3, Day 1: Predose, 2 h, 24 h, 48 h, 72 h, 168 h, 240 h, 336 h and 504 h after start of infusion (immediately prior to Cycle 4)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 3, Day 1: Predose, 2 h, 24 h, 48 h, 72 h, 168 h, 240 h, 336 h and 504 h after start of infusion (immediately prior to Cycle 4)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 3, Day 1: Predose, 2 h, 24 h, 48 h, 72 h, 168 h, 240 h, 336 h and 504 h after start of infusion (immediately prior to Cycle 4)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 3, Day 1: Predose, 2 h, 24 h, 48 h, 72 h, 168 h, 240 h, 336 h and 504 h after start of infusion (immediately prior to Cycle 4)

Population: Zero participants analyzed. No PK analysis was done, the assay used for PK assessment was not reliable and the values obtained could not be used. The samples expired before a new assay was developed, so data were not collected.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Date of first dose of study drug to PD up to 12 months

Population: All randomized participants in Cohort 2 who received any amount of study drug, per the protocol efficacy analysis was only performed for Cohort 2.

Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. CR was defined as the disappearance of all target and nontarget lesions and the normalization of tumor marker levels. PR was defined as having a ≥30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. Participants who did not have a tumor response assessment for any reason were considered nonresponders and were included in the denominator when calculating the response rate. Percentage of participants was calculated as: CR + PR / total number of participants in the treatment group * 100.

Outcome measures

Measure	Cohort 2 - 20 mg/kg Cixutumumab n=41 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Percentage of Participants With Complete Response (CR) and Partial Response (PR) [Objective Response Rate (ORR)]	12.2 percentage of participants Interval 4.1 to 26.2	—

SECONDARY outcome

Timeframe: Date of first dose of study drug to date of death up to 22 months

Population: All randomized participants in Cohort 2 who received any amount of study drug, per the protocol efficacy analysis was only performed for Cohort 2. Participants censored = 19.

OS was defined as the time from the date of first dose of study drug to the date of death from any cause. If the participant was alive at the end of the follow-up period or was lost to follow-up, OS was censored on the last date the participant was known to be alive.

Outcome measures

Measure	Cohort 2 - 20 mg/kg Cixutumumab n=41 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Overall Survival (OS)	11.6 months Interval 8.0 to 15.1	—

SECONDARY outcome

Timeframe: Date of first dose of study drug to date of PD up to 12 months

Population: All randomized participants in Cohort 2 who received any amount of study drug, per the protocol efficacy analysis was only performed for Cohort 2. Participants censored = 14.

TTP is defined as the time from the date of first dose of study drug until the date of objective disease progression. Participants without PD were censored at the time of the last objective tumor assessment. Participants who did not progress and lost to follow-up were censored at the date of the last objective tumor assessment before loss to follow-up. Participants who began new anticancer therapy prior to PD or death were censored at date of last tumor assessment prior to new therapy. Participants who died or had PD after ≥2 missed tumor assessments were censored at date of last tumor assessment prior to the missed assessments.

Outcome measures

Measure	Cohort 2 - 20 mg/kg Cixutumumab n=41 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Time to Disease Progression (TTP)	3.0 months Interval 1.6 to 5.8	—

SECONDARY outcome

Timeframe: Date of first occurrence of CR or PR to first date of PD or death up to 8 months

Population: All randomized participants in Cohort 2 who received any amount of study drug, per the protocol efficacy analysis was only performed for Cohort 2. Participants censored = 1.

Duration of CR or PR was defined as time from first objective assessment of CR or PR until first date of PD or death from any cause. Response was defined using RECIST v 1.0 criteria. CR was defined as disappearance of all target and nontarget lesions and normalization of tumor marker levels. PR was defined as a ≥30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. PD defined as a ≥20% increase in the sum of LD of target lesions using as reference the smallest sum LD since baseline or ≥1 new lesions. Participants with no PD, who discontinued treatment for toxicity or a reason other than PD, or were lost to follow-up, were censored at date of last tumor assessment. Participants who began new anticancer therapy prior to PD or death were censored at date of last tumor assessment prior to new therapy. Participants who died or had PD after ≥2 missed tumor assessments were censored at date of last tumor assessment prior to the missed assessments

Outcome measures

Measure	Cohort 2 - 20 mg/kg Cixutumumab n=41 Participants Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle Sorafenib: 400 mg administered orally, twice daily on Days 1 through 21 of each 3-week cycle Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Duration of Response (DOR)	7.1 months Interval 2.1 to 7.4	—

SECONDARY outcome

Timeframe: Predose, immediately prior to the first Cycle 3 and Cycle 5 infusions (3-week cycle) and 30 days after last dose of study drug

Population: Zero participants were analyzed. No assay was available to assess serum anti-cixutumumab antibodies.

A participant's serum sample was considered positive for antibodies against cixutumumab if it exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-cixutumumab level seen in healthy untreated individuals. A participant was considered to have an anti-cixutumumab response if there were 2 consecutive positive samples or if the final sample tested was positive.

Outcome measures

Outcome data not reported

Adverse Events

Cohort 1 - 10 mg/kg Cixutumumab

Serious events: 4 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort 2 - 20 mg/kg Cixutumumab

Serious events: 15 serious events

Other events: 41 other events

Deaths: 0 deaths

Serious adverse events

Measure	Cohort 1 - 10 mg/kg Cixutumumab n=6 participants at risk Cixutumumab: 10 mg/kg administered by IV infusion on Day 1 of each 3-week cycle. Sorafenib: 400 mg administered orally, twice per day on Days 1 through 21 of each 3-week cycle. Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab n=41 participants at risk Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle. Sorafenib: 400 mg administered orally, twice per day on Days 1 through 21 of each 3-week cycle. Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Eye disorders Retinal tear	0.00% 0/6	2.4% 1/41 • Number of events 1
Gastrointestinal disorders Abdominal pain	0.00% 0/6	2.4% 1/41 • Number of events 1
Gastrointestinal disorders Colitis	0.00% 0/6	2.4% 1/41 • Number of events 1
Gastrointestinal disorders Diarrhoea	16.7% 1/6 • Number of events 1	0.00% 0/41
Gastrointestinal disorders Gastrointestinal haemorrhage	33.3% 2/6 • Number of events 2	4.9% 2/41 • Number of events 2
Gastrointestinal disorders Pancreatitis	16.7% 1/6 • Number of events 1	0.00% 0/41
Gastrointestinal disorders Small intestinal perforation	0.00% 0/6	2.4% 1/41 • Number of events 1
General disorders Asthenia	0.00% 0/6	2.4% 1/41 • Number of events 1
General disorders Chest pain	0.00% 0/6	2.4% 1/41 • Number of events 1
General disorders Pyrexia	0.00% 0/6	4.9% 2/41 • Number of events 2
Hepatobiliary disorders Bile duct stenosis	0.00% 0/6	2.4% 1/41 • Number of events 1
Hepatobiliary disorders Cholangitis	16.7% 1/6 • Number of events 1	0.00% 0/41
Hepatobiliary disorders Hepatic haemorrhage	0.00% 0/6	2.4% 1/41 • Number of events 1
Infections and infestations Peritonitis	0.00% 0/6	2.4% 1/41 • Number of events 1
Infections and infestations Peritonitis bacterial	0.00% 0/6	2.4% 1/41 • Number of events 1
Infections and infestations Septic shock	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Injury, poisoning and procedural complications Infusion related reaction	16.7% 1/6 • Number of events 1	0.00% 0/41
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/6	2.4% 1/41 • Number of events 1
Investigations Blood bilirubin increased	0.00% 0/6	2.4% 1/41 • Number of events 1
Investigations Lipase increased	0.00% 0/6	2.4% 1/41 • Number of events 1
Investigations Liver function test abnormal	0.00% 0/6	2.4% 1/41 • Number of events 1
Metabolism and nutrition disorders Dehydration	16.7% 1/6 • Number of events 1	0.00% 0/41
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/6	4.9% 2/41 • Number of events 2
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	16.7% 1/6 • Number of events 1	4.9% 2/41 • Number of events 2
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm progression	0.00% 0/6	2.4% 1/41 • Number of events 1
Nervous system disorders Headache	0.00% 0/6	2.4% 1/41 • Number of events 1
Renal and urinary disorders Renal failure acute	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/6	2.4% 1/41 • Number of events 1
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/6	2.4% 1/41 • Number of events 1

Other adverse events

Measure	Cohort 1 - 10 mg/kg Cixutumumab n=6 participants at risk Cixutumumab: 10 mg/kg administered by IV infusion on Day 1 of each 3-week cycle. Sorafenib: 400 mg administered orally, twice per day on Days 1 through 21 of each 3-week cycle. Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.	Cohort 2 - 20 mg/kg Cixutumumab n=41 participants at risk Cixutumumab: 20 mg/kg administered by IV infusions on Day 1 of each 3-week cycle. Sorafenib: 400 mg administered orally, twice per day on Days 1 through 21 of each 3-week cycle. Treatment cycles were repeated until there was evidence of PD, toxicity, or participant withdrawal.
Blood and lymphatic system disorders Anaemia	33.3% 2/6 • Number of events 4	4.9% 2/41 • Number of events 2
Blood and lymphatic system disorders Leukopenia	16.7% 1/6 • Number of events 2	2.4% 1/41 • Number of events 1
Blood and lymphatic system disorders Neutropenia	16.7% 1/6 • Number of events 1	9.8% 4/41 • Number of events 6
Blood and lymphatic system disorders Thrombocytopenia	16.7% 1/6 • Number of events 1	29.3% 12/41 • Number of events 28
Cardiac disorders Palpitations	16.7% 1/6 • Number of events 1	0.00% 0/41
Ear and labyrinth disorders Ear discomfort	0.00% 0/6	12.2% 5/41 • Number of events 5
Ear and labyrinth disorders Hearing impaired	16.7% 1/6 • Number of events 1	0.00% 0/41
Eye disorders Vision blurred	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Gastrointestinal disorders Abdominal discomfort	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Gastrointestinal disorders Abdominal pain	33.3% 2/6 • Number of events 3	19.5% 8/41 • Number of events 8
Gastrointestinal disorders Abdominal pain upper	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Gastrointestinal disorders Ascites	16.7% 1/6 • Number of events 1	0.00% 0/41
Gastrointestinal disorders Constipation	33.3% 2/6 • Number of events 2	24.4% 10/41 • Number of events 12
Gastrointestinal disorders Diarrhoea	16.7% 1/6 • Number of events 2	43.9% 18/41 • Number of events 36
Gastrointestinal disorders Dry mouth	0.00% 0/6	22.0% 9/41 • Number of events 9
Gastrointestinal disorders Dyspepsia	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Gastrointestinal disorders Dysphagia	16.7% 1/6 • Number of events 1	0.00% 0/41
Gastrointestinal disorders Gastritis	16.7% 1/6 • Number of events 1	0.00% 0/41
Gastrointestinal disorders Gastrointestinal haemorrhage	16.7% 1/6 • Number of events 1	0.00% 0/41
Gastrointestinal disorders Nausea	50.0% 3/6 • Number of events 3	24.4% 10/41 • Number of events 13
Gastrointestinal disorders Pancreatitis	16.7% 1/6 • Number of events 2	0.00% 0/41
Gastrointestinal disorders Stomatitis	16.7% 1/6 • Number of events 1	4.9% 2/41 • Number of events 3
Gastrointestinal disorders Vomiting	16.7% 1/6 • Number of events 1	24.4% 10/41 • Number of events 11
General disorders Asthenia	16.7% 1/6 • Number of events 1	4.9% 2/41 • Number of events 3
General disorders Fatigue	50.0% 3/6 • Number of events 9	61.0% 25/41 • Number of events 40
General disorders Gait disturbance	0.00% 0/6	7.3% 3/41 • Number of events 3
General disorders Mucosal inflammation	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
General disorders Pyrexia	0.00% 0/6	9.8% 4/41 • Number of events 4
Hepatobiliary disorders Hyperbilirubinaemia	16.7% 1/6 • Number of events 5	9.8% 4/41 • Number of events 5
Infections and infestations Candidiasis	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Infections and infestations Upper respiratory tract infection	0.00% 0/6	9.8% 4/41 • Number of events 4
Infections and infestations Urinary tract infection	16.7% 1/6 • Number of events 1	0.00% 0/41
Infections and infestations Vulvovaginal mycotic infection	100.0% 1/1 • Number of events 1	0.00% 0/8
Injury, poisoning and procedural complications Fall	16.7% 1/6 • Number of events 2	2.4% 1/41 • Number of events 1
Investigations Alanine aminotransferase increased	0.00% 0/6	12.2% 5/41 • Number of events 11
Investigations Aspartate aminotransferase increased	0.00% 0/6	9.8% 4/41 • Number of events 11
Investigations Blood albumin decreased	16.7% 1/6 • Number of events 2	0.00% 0/41
Investigations Blood alkaline phosphatase increased	0.00% 0/6	7.3% 3/41 • Number of events 5
Investigations Blood bilirubin increased	0.00% 0/6	7.3% 3/41 • Number of events 3
Investigations Blood creatinine increased	33.3% 2/6 • Number of events 2	4.9% 2/41 • Number of events 2
Investigations Lipase increased	0.00% 0/6	19.5% 8/41 • Number of events 20
Investigations Weight decreased	16.7% 1/6 • Number of events 1	31.7% 13/41 • Number of events 14
Metabolism and nutrition disorders Acidosis	16.7% 1/6 • Number of events 1	0.00% 0/41
Metabolism and nutrition disorders Decreased appetite	66.7% 4/6 • Number of events 4	39.0% 16/41 • Number of events 23
Metabolism and nutrition disorders Dehydration	16.7% 1/6 • Number of events 1	9.8% 4/41 • Number of events 4
Metabolism and nutrition disorders Hyperglycaemia	16.7% 1/6 • Number of events 1	31.7% 13/41 • Number of events 26
Metabolism and nutrition disorders Hyperkalaemia	16.7% 1/6 • Number of events 1	4.9% 2/41 • Number of events 2
Metabolism and nutrition disorders Hypoglycaemia	16.7% 1/6 • Number of events 1	0.00% 0/41
Metabolism and nutrition disorders Hypokalaemia	16.7% 1/6 • Number of events 1	7.3% 3/41 • Number of events 3
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/6	7.3% 3/41 • Number of events 9
Musculoskeletal and connective tissue disorders Arthralgia	16.7% 1/6 • Number of events 1	9.8% 4/41 • Number of events 5
Musculoskeletal and connective tissue disorders Back pain	16.7% 1/6 • Number of events 1	22.0% 9/41 • Number of events 12
Musculoskeletal and connective tissue disorders Flank pain	16.7% 1/6 • Number of events 1	4.9% 2/41 • Number of events 2
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/6	24.4% 10/41 • Number of events 15
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/6	7.3% 3/41 • Number of events 3
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/6	7.3% 3/41 • Number of events 3
Nervous system disorders Dysgeusia	0.00% 0/6	17.1% 7/41 • Number of events 7
Nervous system disorders Headache	16.7% 1/6 • Number of events 2	17.1% 7/41 • Number of events 8
Nervous system disorders Lethargy	16.7% 1/6 • Number of events 1	0.00% 0/41
Nervous system disorders Syncope	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Psychiatric disorders Anxiety	0.00% 0/6	7.3% 3/41 • Number of events 3
Psychiatric disorders Confusional state	16.7% 1/6 • Number of events 2	0.00% 0/41
Psychiatric disorders Depression	33.3% 2/6 • Number of events 2	12.2% 5/41 • Number of events 5
Psychiatric disorders Insomnia	0.00% 0/6	7.3% 3/41 • Number of events 3
Psychiatric disorders Mental status changes	16.7% 1/6 • Number of events 1	0.00% 0/41
Renal and urinary disorders Bladder pain	16.7% 1/6 • Number of events 1	0.00% 0/41
Renal and urinary disorders Renal failure acute	16.7% 1/6 • Number of events 1	0.00% 0/41
Renal and urinary disorders Urinary retention	0.00% 0/6	7.3% 3/41 • Number of events 3
Respiratory, thoracic and mediastinal disorders Cough	16.7% 1/6 • Number of events 1	9.8% 4/41 • Number of events 4
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/6	12.2% 5/41 • Number of events 5
Respiratory, thoracic and mediastinal disorders Dyspnoea	33.3% 2/6 • Number of events 3	19.5% 8/41 • Number of events 10
Respiratory, thoracic and mediastinal disorders Epistaxis	33.3% 2/6 • Number of events 3	12.2% 5/41 • Number of events 6
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	16.7% 1/6 • Number of events 1	4.9% 2/41 • Number of events 2
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/6	14.6% 6/41 • Number of events 6
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/6	19.5% 8/41 • Number of events 8
Skin and subcutaneous tissue disorders Pain of skin	16.7% 1/6 • Number of events 1	0.00% 0/41
Skin and subcutaneous tissue disorders Palmar erythema	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.00% 0/6	36.6% 15/41 • Number of events 26
Skin and subcutaneous tissue disorders Pruritus	16.7% 1/6 • Number of events 1	17.1% 7/41 • Number of events 12
Skin and subcutaneous tissue disorders Purpura	16.7% 1/6 • Number of events 1	0.00% 0/41
Skin and subcutaneous tissue disorders Rash	16.7% 1/6 • Number of events 1	7.3% 3/41 • Number of events 5
Skin and subcutaneous tissue disorders Rash erythematous	16.7% 1/6 • Number of events 2	9.8% 4/41 • Number of events 6
Skin and subcutaneous tissue disorders Rash macular	16.7% 1/6 • Number of events 2	2.4% 1/41 • Number of events 1
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/6	12.2% 5/41 • Number of events 5
Skin and subcutaneous tissue disorders Rash papular	16.7% 1/6 • Number of events 1	2.4% 1/41 • Number of events 1
Skin and subcutaneous tissue disorders Scab	16.7% 1/6 • Number of events 1	0.00% 0/41
Vascular disorders Hypertension	16.7% 1/6 • Number of events 1	17.1% 7/41 • Number of events 8

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

• Principal investigator is a sponsor employee Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.
• Publication restrictions are in place

Restriction type: OTHER