CS1008- in Combination With Sorafenib Compared to Sorafenib Alone in Subjects With Advanced Liver Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of CS-1008 in combination with sorafenib to sorafenib alone for treating liver cancer. Approximately 160 participants will take part in this study at approximately 22 sites (4 in the US, 8 in Japan, and 10 in Asia).

Official Title
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Clinical Study Protocol Phase 2, Randomized Study of CS-1008 in Combination With Sorafenib Compared to Sorafenib Alone as First-Line Systemic Therapy in Subjects With Advanced Hepatocellular Carcinoma

Conditions
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Advanced Hepatocellular Carcinoma, Liver Cancer, Hepatic Cancer, Liver Neoplasms

Intervention / Treatment
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* Drug: CS-1008 2 mg/kg
* Drug: Sorafenib
* Drug: CS-1008 6/2 mg/kg
* Drug: CS-1008 6/6 mg/kg
* Drug: CS-1008 4 mg/kg
* Drug: CS-1008 6 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed hepatocellular carcinoma (HCC) or clinical diagnosis of HCC when the following criteria are all met: History of chronic hepatitis and/or cirrhosis of liver; Typical features of HCC demonstrated in dynamic imaging studies, such as three-phase computed tomography (CT); AND Alpha-fetoprotein (AFP) level > 200 ng/mL Advanced diseases Extrahepatic metastasis, OR Locally advanced diseases which are not amenable for surgical resection or other loco-regional therapies including transhepatic arterial (chemo) embolization (TACE or TAE) and local ablative therapy Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 of at least 1 untreated target lesion that can be measured in 1 dimension At least 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Child-Pugh class A Life expectancy of at least 12 weeks Adequate organ and bone marrow function as assessed by clinical laboratory evaluations: Hemoglobin ≥ 8.5 g/dL (transfusion and/or growth factor support allowed) Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L Platelet count ≥ 75 x 10^9/L Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/min Aspartate Aminotransferase (AST) and alkaline phosphatase ≤ 5.0 x ULN Total bilirubin ≤ 1.5 x ULN Serum amylase and lipase ≤ 1.5 x ULN Women of childbearing potential must be willing to consent to using effective contraception (eg, abstinence, hormonal contraceptives, bilateral tubal ligation, barrier with spermicide, intrauterine device) while on treatment and for 3 months thereafter. Men who are the partner of a woman of childbearing potential must be willing to consent to using effective contraception (eg, vasectomy or barrier with spermicide) while on treatment and for 3 months thereafter All female participants of childbearing potential must have a negative pregnancy test (serum or urine) result Participants must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an International Review Board (IRB)/ Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) before the performance of any study specific procedures or tests Participants must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Exclusion Criteria: Any prior systemic therapy for HCC, including systemic chemotherapy (prior exposure to chemotherapy by TACE is allowed), immunotherapy, sorafenib or other Raf kinase inhibitors, Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth Factor Receptor (VEGFR)-inhibitors, epidermal growth factor receptor inhibitors or mechanistic target of rapamycin (mTOR) inhibitors Radiotherapy or major surgical procedure within 4 weeks of the screening/baseline visit or minor surgical procedures (eg, core biopsy or fine needle aspiration) within 2 weeks of the screening/baseline visit Anticipation of need for radiotherapy (RT) or a major surgical procedure during the study Any investigational agent within 4 weeks before the screening/baseline visit History of any of the following conditions within 6 months before the screening/baseline visit: Myocardial infarction with significant impairment of cardiac function (eg, ejection fraction ≤ 30%) Severe/unstable angina pectoris New York Heart Association (NYHA) class III or intravenous (IV) congestive heart failure Clinically significant pulmonary disease (eg, severe chronic obstructive pulmonary disease or asthma) Clinically active brain metastases (defined as untreated, symptomatic or requiring steroids or anticonvulsants medications to control associated symptoms), uncontrolled seizure disorder; spinal cord compression; or carcinomatous meningitis. Participants with treated brain metastasis will be included in the study if they have recovered from the acute, toxic effects of radiotherapy. A minimum of 15 days must have elapsed between the end of RT and the screening/baseline visit History of organ transplantation Clinically significant, severe, active infection requiring IV antibiotics Known history of human immunodeficiency virus (HIV) infection History of prior sensitivity reaction to any components of CS-1008 or sorafenib formulations History of a second malignancy, with the exception of in situ cervical cancer or adequately treated basal cell or squamous cell carcinoma of the skin Pregnant or breast feeding Serious intercurrent medical illnesses that, in the opinion of the Investigator, would impair the participant's ability to provide informed consent or unacceptably reduce the safety of the proposed treatment Clinically significant (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grade ≥ 3) gastrointestinal bleeding in the past 12 months or current active gastrointestinal bleeding Presence of esophageal varices at risk of bleeding, such as large esophageal/gastric varices or those with red sign, or active peptic ulcer with or without exposed vessels at risk of bleeding (as documented by endoscopy) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within past 6 months

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Cohort 1 CS-1008 and Sorafenib<br>Combination of CS-1008 and sorafenib; CS-1008 (2 mg/kg per week) in combination with sorafenib (400 mg self-administered by mouth twice daily) over 4 weeks observation, and may continue treatment until progression. | Drug: CS-1008 2 mg/kg<br>* On a once a week basis CS-1008 will be administered intravenously starting at 2 mg/kg.<br>Drug: Sorafenib<br>* On a daily basis, one sorafenib tablet, 400 mg, is taken orally twice a day. The total daily dose of sorafenib is 800 mg. The sorafenib tablets are taken at least 1 hour before or 2 hours after a meal.<br>* Other names: Nexavar;|
| Experimental: Safety Cohort 2 CS-1008 and Sorafenib<br>Combination of CS-1008 and sorafenib; CS-1008 (4 mg/kg per week) in combination with sorafenib (400 mg self-administered by mouth twice daily) over 4 weeks observation, and may continue treatment until progression. | Drug: Sorafenib<br>* On a daily basis, one sorafenib tablet, 400 mg, is taken orally twice a day. The total daily dose of sorafenib is 800 mg. The sorafenib tablets are taken at least 1 hour before or 2 hours after a meal.<br>* Other names: Nexavar;Drug: CS-1008 4 mg/kg<br>* On a once a week basis CS-1008 will be administered intravenously at 4 mg/kg if tolerated.<br>|
| Active Comparator: Safety Cohort 3 CS-1008 and Sorafenib<br>Combination of CS-1008 and sorafenib; CS-1008 (6 mg/kg per week) in combination with sorafenib (400 mg self-administered by mouth twice daily) over 4 weeks observation, and may continue treatment until progression. | Drug: Sorafenib<br>* On a daily basis, one sorafenib tablet, 400 mg, is taken orally twice a day. The total daily dose of sorafenib is 800 mg. The sorafenib tablets are taken at least 1 hour before or 2 hours after a meal.<br>* Other names: Nexavar;Drug: CS-1008 6 mg/kg<br>* On a once a week basis CS-1008 will be administered intravenously at 6 mg/kg if tolerated.<br>|
| Experimental: Treatment Group 1 CS-1008 and Sorafenib<br>Combination of CS-1008 and sorafenib. Treatment Group 1: CS-1008 (6 mg/kg [or as determined] loading, 2 mg/kg/week maintenance) + sorafenib twice daily (N=50) | Drug: Sorafenib<br>* On a daily basis, one sorafenib tablet, 400 mg, is taken orally twice a day. The total daily dose of sorafenib is 800 mg. The sorafenib tablets are taken at least 1 hour before or 2 hours after a meal.<br>* Other names: Nexavar;Drug: CS-1008 6/2 mg/kg<br>* A 6 mg/kg loading dose of CS-1008 will be administered intravenously, followed by a 2 mg/kg/week maintenance dose on a once-a-week basis.<br>|
| Experimental: Treatment Group 2 with CS-1008 and Sorafenib<br>Combination of CS-1008 and sorafenib. Treatment Group 2: CS-1008 (6 mg/kg [or as determined] loading, 6 mg/kg/week [or maximum tolerated dose {MTD}] maintenance) + sorafenib twice daily (N=50) | Drug: Sorafenib<br>* On a daily basis, one sorafenib tablet, 400 mg, is taken orally twice a day. The total daily dose of sorafenib is 800 mg. The sorafenib tablets are taken at least 1 hour before or 2 hours after a meal.<br>* Other names: Nexavar;Drug: CS-1008 6/6 mg/kg<br>* A 6 mg/kg loading dose of CS-1008 will be administered intravenously, followed by a 6 mg/kg/week maintenance dose on a once-a-week basis.<br>|
| Experimental: Treatment Group 3 with Sorafenib Alone<br>Sorafenib. Treatment Group 3: sorafenib twice daily (N=50) | Drug: Sorafenib<br>* On a daily basis, one sorafenib tablet, 400 mg, is taken orally twice a day. The total daily dose of sorafenib is 800 mg. The sorafenib tablets are taken at least 1 hour before or 2 hours after a meal.<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) Following CS1008 in Combination With Sorafenib Compared to Sorafenib Alone in Participants With Advanced Liver Cancer | Time to progression was defined as the time from randomization to the date of the first objective documentation of radiographic or symptomatic progression, whichever came first. | Baseline up to approximately 2 years post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Following CS1008 in Combination With Sorafenib Compared to Sorafenib Alone in Participants With Advanced Liver Cancer | Overall survival (OS) was defined as the time from randomization to the date of death. The factors in the final model were treatment, Eastern Cooperative Oncology Group (ECOG) performance status, presence of extrahepatic metastasis and/or macrovessel invasion, and region. | Baseline up to approximately 3 years 2 months post-dose. | 
| Best Overall Response and Objective Response Rate Following CS1008 in Combination With Sorafenib Compared to Sorafenib Alone in Participants With Advanced Liver Cancer | The best overall response is the best response (in the order of confirmed complete response [CR], confirmed partial response [PR], unconfirmed CR, unconfirmed PR, stable disease [SD], and progressive disease [PD]) among all overall responses recorded from the start of treatment until the participant withdraws from the study based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. If there is no tumor assessment after the first dose of study drug, the best overall response is classified as Inevaluable. CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD defined as at least a 20% increase in the sum of diameters of target lesions. Objective response rate was defined as confirmed CR and confirmed PR. | Baseline up to disease progression, death, lost to follow up, or study discontinuation (whichever comes first), up to approximately 3 years 2 months post-dose. | 
| Treatment-Emergent Adverse Events Following CS1008 in Combination With Sorafenib Compared to Sorafenib Alone in Participants With Advanced Liver Cancer | Treatment-Emergent Adverse Events (TEAEs) were defined as those adverse events (AEs) that occurred, having been absent before the study, or worsened in severity after the initiation of study treatment administration. An AE that occurred more than 30 days after the last dose of study medication was not included as a TEAE unless it was considered related to treatment or the assessment of relatedness was missing. | Baseline up to 30 days after last dose, up to approximately 3 years 2 months post-dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sorafenib, CS-1008, Advanced Liver Cancer