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

Study Description

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Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Advanced Hepatocellular Carcinoma; Liver Cancer; Hepatic Cancer; Liver Neoplasms	Drug: CS-1008; Drug: sorafenib	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	172 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	March 2010
Actual Primary Completion Date :	November 2014
Actual Study Completion Date :	December 2014

Arms and Interventions

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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 [PO] twice daily [BID]) over 4 weeks observation, and may continue treatment until progression.	Drug: CS-1008; On a once a week basis CS-1008 will be administered intravenously starting at 2 mg/kg, followed by 4 mg/kg if tolerated, followed by 6 mg/kg if tolerated. 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 Name: Nexavar
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 {BID} (N=50)	Drug: CS-1008; On a once a week basis CS-1008 will be administered intravenously starting at 2 mg/kg, followed by 4 mg/kg if tolerated, followed by 6 mg/kg if tolerated. 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 Name: Nexavar
Active Comparator: Treatment Group 3 with sorafenib alone; Combination of CS-1008 and sorafenib. Treatment Group 3: sorafenib BID (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 Name: 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 [PO] twice daily [BID]) over 4 weeks observation, and may continue treatment until progression.	Drug: CS-1008; On a once a week basis CS-1008 will be administered intravenously starting at 2 mg/kg, followed by 4 mg/kg if tolerated, followed by 6 mg/kg if tolerated. 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 Name: Nexavar
Experimental: 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 [PO] twice daily [BID]) over 4 weeks observation, and may continue treatment until progression.	Drug: CS-1008; On a once a week basis CS-1008 will be administered intravenously starting at 2 mg/kg, followed by 4 mg/kg if tolerated, followed by 6 mg/kg if tolerated. 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 Name: Nexavar
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 BID (N=50)	Drug: CS-1008; On a once a week basis CS-1008 will be administered intravenously starting at 2 mg/kg, followed by 4 mg/kg if tolerated, followed by 6 mg/kg if tolerated. 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 Name: Nexavar

Outcome Measures

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Primary Outcome Measures :

1. time to progression (TTP) for chemotherapy naive subjects with advanced hepatocellular carcinoma (HCC) [ Time Frame: time to progression, up to 2 years ]

Secondary Outcome Measures :

1. objective response rate (ORR) i.e. the proportion of subjects with the best response of complete response or partial response [ Time Frame: time to progression, up to 2 years ]
2. overall survival (OS) [ Time Frame: time to progression, up to 2 years ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed 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
  • AFP level > 200 ng/mL

• Advanced diseases

  • Extrahepatic metastasis, OR
  • Locally advanced diseases which are not amendable for surgical resection or other loco-regional therapies including transhepatic arterial (chemo)embolization (TACE or TAE) and local ablative therapy
• Measurable disease based on RECIST criteria (version 1.0) 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 109/L
  • Platelet count ≥ 75 x 109/L
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/min
  • 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 subjects of childbearing potential must have a negative pregnancy test (serum or urine) result
• Subjects 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 IRB/IEC approved ICF before performance of any study specific procedures or tests
• Subjects 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, VEGF/VEGFR-inhibitors, epidermal growth factor receptor inhibitors or 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 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 IV congestive heart failure (Section 17.2)
  • 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. Subjects 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 subject'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

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Daiichi Sankyo, Inc.

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier:	NCT01033240 History of Changes
Other Study ID Numbers:	CS1008-A-U204
First Posted:	December 16, 2009
Last Update Posted:	March 17, 2016
Last Verified:	February 2016

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases	Sorafenib; Niacinamide; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Vitamin B Complex; Vitamins; Micronutrients; Growth Substances; Physiological Effects of Drugs