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

Study Overview
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Brief Summary
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To determine if IMC-A12 given in combination with Sorafenib is safe and effective for participants with advanced liver cancer.

Detailed Description
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The purpose of this study is to determine progression-free survival (PFS) in participants with unresectable hepatocellular carcinoma who have received no prior systemic therapy when treated with IMC-A12 administered every three weeks in combination with oral sorafenib administered twice daily.

Official Title
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A Multicenter, Phase 2 Study Evaluating IMC-A12 in Combination With Sorafenib as First-Line Therapy for Patients With Advanced Hepatocellular Carcinoma (HCC)

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: IMC-A12 (cixutumumab) - 10 milligrams/kilogram (mg/kg)
* Biological: IMC-A12 (cixutumumab) - 20 mg/kg
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has histologically or cytologically confirmed, unresectable HCC The participant has at least one target lesion measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Target lesion(s) must not lay within a previously irradiated, ablated, or chemoembolized area. If a lesion does lie in such an area, there must be evidence of growth on successive imaging studies, including tumor hypervascularity, in order for such a lesion to be considered a target lesion The participant has not received prior systemic therapy for HCC. Participants may have received prior embolization, chemoembolization, intra-arterial chemotherapy infusion, ethanol injection, radiofrequency ablation, or cryosurgery The participant has fasting serum glucose <160 milligrams/deciliter (mg/dL) or below the upper limit of normal (ULN) and/or hemoglobin A1C <7%. If baseline nonfasting glucose <160 mg/dL, fasting glucose measurement is not required The participant has the ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: The participant has brain metastases The participant has acute hepatitis The participant has poorly controlled diabetes mellitus. Participants with a history of diabetes mellitus are allowed to participate, provided that their blood glucose is within normal range and that they are on a stable dietary or therapeutic regimen for this condition The participant has congestive heart failure > class II New York Heart Association (NYHA), unstable angina pectoris, new onset of angina pectoris, myocardial infarction within the past 6 months, or cardiac ventricular arrhythmias requiring antiarrhythmic therapy The participant has experienced a hemorrhage or bleeding event ≥ National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 3 within 4 weeks prior first dose of study therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1, IMC A12 - 10 mg/kg<br>Treatment cycles will repeat until there is evidence of progressive disease (PD), toxicity, or withdrawal. If any participant experiences a dose-limiting toxicity (DLT), an additional 3 participants will be enrolled at this dose level (for a total of 6). If no further DLTs, enrollment into Cohort 2 will occur. | Biological: IMC-A12 (cixutumumab) - 10 milligrams/kilogram (mg/kg)<br>* intravenous infusions 10 mg/kg on Day 1 of each 3-week cycle<br>* Other names: LY3012217;Drug: Sorafenib<br>* 400 milligrams (mg) twice per day orally<br>|
| Active Comparator: Cohort 2, IMC A12 20 - mg/kg<br>Treatment cycles will repeat until there is evidence of PD, toxicity, or withdrawal. | Biological: IMC-A12 (cixutumumab) - 20 mg/kg<br>* intravenous infusions 20 mg/kg on Day 1 of each 3-week cycle<br>* Other names: LY3012217;Drug: Sorafenib<br>* 400 milligrams (mg) twice per day orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | 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. | Date of first dose of study drug up PD or death up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | 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. | First day of treatment up to 22 months | 
| Pharmacokinetic (PK): Maximum Concentration (Cmax) Cycle 1 |  | 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) | 
| PK: Minimum Concentration (Cmin) Cycle 1 |  | 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) | 
| PK: Half-Life (t1/2) Cycle 1 |  | 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) | 
| PK: Clearance (CL) Cycle 1 |  | 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) | 
| PK: Area Under the Concentration Versus Time Curve (AUC) Cycle 1 |  | 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) | 
| PK: Volume of Distribution at Steady State (Vss) Cycle 1 |  | 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) | 
| PK: Cmax Cycle 3 |  | 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) | 
| PK: Cmin Cycle 3 |  | 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) | 
| PK: t1/2 Cycle 3 |  | 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) | 
| PK: CL Cycle 3 |  | 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) | 
| PK: AUC Cycle 3 |  | 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) | 
| PK: Vss Cycle 3 |  | 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) | 
| Percentage of Participants With Complete Response (CR) and Partial Response (PR) [Objective Response Rate (ORR)] | 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. | Date of first dose of study drug to PD up to 12 months | 
| Overall Survival (OS) | 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. | Date of first dose of study drug to date of death up to 22 months | 
| Time to Disease Progression (TTP) | 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. | Date of first dose of study drug to date of PD up to 12 months | 
| Duration of Response (DOR) | 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 | Date of first occurrence of CR or PR to first date of PD or death up to 8 months | 
| The Number of Participants With Serum Anti-Cixutumumab Antibody Assessment (Immunogenicity) | 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. | Predose, immediately prior to the first Cycle 3 and Cycle 5 infusions (3-week cycle) and 30 days after last dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma, Liver Neoplasms, Antibodies, Monoclonal