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

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

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).

Study Overview

• Status: Completed
• Conditions: Liver Neoplasms; Advanced Hepatocellular Carcinoma; Liver Cancer; Hepatic Cancer
• Intervention / Treatment: Drug: CS-1008 2 mg/kg; Drug: Sorafenib; Drug: CS-1008 4 mg/kg; Drug: CS-1008 6 mg/kg; Drug: CS-1008 6/2 mg/kg; Drug: CS-1008 6/6 mg/kg

• Study Type: Interventional
• Enrollment (Actual): 172
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 260-8677
    • Chiba University Hospital
  • Okayama, Japan, 700-8558
    • Okayama University Hospital
  • Osaka, Japan, 537-8511
    • Osaka Med Center Cancer and Cardiovascular Disease
  • Tokyo, Japan, 180-8610
    • Musashino Red-Cross Hospital
  • Fukuoka
    • Kurume-shi, Fukuoka, Japan, 830-0011
      • Kurume University Hospital
  • Hiroshima
    • Hiroshima-city, Hiroshima, Japan
      • Hiroshima University
  • Ishikawa
    • Kanazawa, Ishikawa, Japan
      • Kanazawa University
  • Osaka-sayama
    • Osaka, Osaka-sayama, Japan, 589-8511
      • Kinki University Hospital
  • Yamaguchi
    • Ube, Yamaguchi, Japan
      • Yamaguchi University Hospital
• Korea, Republic of
  • Daegu, Korea, Republic of, 700-712
    • Keimyung University Dongsan Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital
  • Seoul, Korea, Republic of, 136-705
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 137-701
    • Catholic Univ. of Korea, Seoul St. Mary's Hospital
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital
  • Chiayi City, Taiwan
    • Chang Gung Memorial Hospital
  • Kaohsiung, Taiwan, 807
    • Kaohslung Medical University Hospital
  • Tainan, Taiwan, 73657
    • Chi-Mei Medical Center
  • Tainan city, Taiwan, 704
    • National Cheng-Kung University Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taoyuan, Taiwan, 33305
    • Chang Gung Medical Foundation-Linkuo
  • Niaosung Hsiang
    • Kaohsiung, Niaosung Hsiang, Taiwan
      • Kaohiung Chang Gung Hospital
• United States
  • California
    • Los Angeles, California, United States, 90057
      • Kenmar Research Group
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown-Lombardi Cancer Center
  • New York
    • New York, New York, United States, 10029
      • The Mount Sinai Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Cohort 1 CS-1008 and Sorafenib; 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; On a once a week basis CS-1008 will be administered intravenously starting at 2 mg/kg.; Drug: Sorafenib; 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.; Other Names: Nexavar
Experimental: Safety Cohort 2 CS-1008 and Sorafenib; 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; 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.; Other Names: Nexavar; Drug: CS-1008 4 mg/kg; On a once a week basis CS-1008 will be administered intravenously at 4 mg/kg if tolerated.
Active Comparator: Safety Cohort 3 CS-1008 and Sorafenib; 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; 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.; Other Names: Nexavar; Drug: CS-1008 6 mg/kg; On a once a week basis CS-1008 will be administered intravenously at 6 mg/kg if tolerated.
Experimental: Treatment Group 1 CS-1008 and Sorafenib; 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; 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.; Other Names: Nexavar; Drug: CS-1008 6/2 mg/kg; 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.
Experimental: Treatment Group 2 with CS-1008 and Sorafenib; 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; 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.; Other Names: Nexavar; Drug: CS-1008 6/6 mg/kg; 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.
Experimental: Treatment Group 3 with Sorafenib Alone; Sorafenib. Treatment Group 3: sorafenib twice daily (N=50)	Drug: Sorafenib; 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.; Other Names: Nexavar

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Publications and helpful links

General Publications

• Cheng AL, Kang YK, He AR, Lim HY, Ryoo BY, Hung CH, Sheen IS, Izumi N, Austin T, Wang Q, Greenberg J, Shiratori S, Beckman RA, Kudo M; Investigators' Study Group. Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: A phase 2 randomized study. J Hepatol. 2015 Oct;63(4):896-904. doi: 10.1016/j.jhep.2015.06.001. Epub 2015 Jun 10.

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2010
• Primary Completion (Actual): July 13, 2012
• Study Completion (Actual): September 9, 2013

Study Registration Dates

• First Submitted: December 15, 2009
• First Submitted That Met QC Criteria: December 15, 2009
• First Posted (Estimate): December 16, 2009

Study Record Updates

• Last Update Posted (Actual): April 8, 2021
• Last Update Submitted That Met QC Criteria: April 6, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Sorafenib; CS-1008; Advanced Liver Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: CS1008-A-U204

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No