Comparing Efficacy of Sorafenib Versus Sorafenib in Combination With Low-dose FP in Patients With Advanced HCC

Randomized Controlled Trial Comparing Efficacy of Sorafenib Versus Sorafenib In Combination With Low Dose Cisplatin /Fluorouracil Hepatic Arterial InfUSion Chemotherapy in Patients With Advanced Hepatocellular Carcinoma

The purpose of this study is to evaluate the efficacy of sorafenib in combination with low dose cisplatin /fluorouracil hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma.

Study Overview

• Status: Unknown
• Conditions: Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Advanced Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Sorafenib with Low-dose FP; Drug: Sorafenib

Detailed Description

Sorafenib with Low-dose FP Group

Sorafenib will be administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid) for 28 days. Cisplatin at the dose of 20mg/m2 will be administered at day 1 and day8, and fluorouracil at the dose of 330mg/m2 will be administered continuously at day1-day5, and day8-day12 via the implanted catheter system.

Sorafenib Group

Sorafenib will be administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid) for 28 days.

The treatment regimen will be continued until radiographic or symptomatic progression, the development of unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Anticipated): 190
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Masatoshi Kudo, Professor; Phone Number: 3149 +81-72-366-0221; Email: m-kudo@med.kindai.ac.jp
• Study Contact Backup: Name: Kazuomi Ueshima, Dr; Phone Number: 3525 +81-72-366-0221; Email: kaz-ues@med.kindai.ac.jp

Study Locations

• Japan
  • Chiba, Japan, 260-8677
    • Recruiting
    • Chiba University Hospital
    • Contact: Fumihiko Kanai, Dr.
    • Principal Investigator: Fumihiko Kanai, Dr.
  • Gifu, Japan, 500-8513
    • Recruiting
    • Gifu Municipal Hospital
    • Contact: Eiichi Tomita, Dr.
    • Principal Investigator: Eiichi Tomita, Dr.
  • Hiroshima, Japan, 730-8518
    • Recruiting
    • Hiroshima City Hospital
    • Contact: Yoshiyuki Kobayashi, Dr.
    • Principal Investigator: Yoshiyuki Kobayashi, Dr.
  • Hiroshima, Japan, 734-8551
    • Recruiting
    • Hiroshima University Hospital
    • Contact: Hiroshi Aikata, Dr.
    • Principal Investigator: Hiroshi Aikata, Dr.
  • Kumamoto, Japan, 860-8556
    • Recruiting
    • Kumamoto University Hospital
    • Contact: Yutaka Sasaki, Professor
    • Principal Investigator: Yutaka Sasaki, Professor
  • Kyoto, Japan, 606-8507
    • Recruiting
    • Kyoto University Hospital
    • Contact: Etsuro Hatano, Professor
    • Principal Investigator: Etsuro Hatano, Professor
  • Miyazaki, Japan, 880-0003
    • Recruiting
    • Center for Gastroenterological and Hepatological Diseases
    • Contact: Hidemori Sakamoto, Dr.
    • Principal Investigator: Hidemori Sakamoto, Dr.
  • Niigata, Japan, 950-1104
    • Recruiting
    • Saiseikai Niigata Dai-ni Hospital
    • Contact: Toru Ishikawa, Dr.
    • Principal Investigator: Toru Ishikawa, Dr.
  • Niigata, Japan, 951-8520
    • Recruiting
    • Niigata University Medical And Dental Hospital
    • Contact: Kouhei Akazawa
    • Principal Investigator: Kouhei Akazawa
  • Okayama, Japan, 700-8558
    • Recruiting
    • Okayama University Hospital
    • Contact: Kazuhide Yamamoto, Professor
    • Principal Investigator: Kazuhide Yamamoto, Professor
  • Osaka, Japan, 543-8555
    • Recruiting
    • Osaka Red Cross Hospital
    • Contact: Ikuo Osaki, Dr.
    • Principal Investigator: Ikuo Osaki, Dr.
  • Tokushima, Japan, 770-8503
    • Recruiting
    • The University of Tokushima Faculty of Medicine
    • Contact: Tetsuji Takayama, Dr.
    • Principal Investigator: Tetsuji Takayama, Dr.
  • Tokyo, Japan, 104-0045
    • Recruiting
    • National Cancer Center Hospital
    • Contact: Takushi Okusaka, Dr.
    • Principal Investigator: Takushi Okusaka, Dr.
  • Tokyo, Japan, 101-0062
    • Recruiting
    • Kyoundo Hospital
    • Contact: Shuntaro Obi, Dr.
    • Principal Investigator: Shuntaro Obi, Dr.
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Recruiting
      • National Cancer Center Hospital East
      • Contact: Masafumi Ikeda, Dr.
      • Principal Investigator: Masafumi Ikeda, Dr.
  • Fukuoka
    • Kurume, Fukuoka, Japan, 839-0863
      • Recruiting
      • Kurume University Medical Center
      • Contact: Masatoshi Tanaka, Professor
      • Principal Investigator: Masatoshi Tanaka, Professor
  • Gifu
    • Ogaki, Gifu, Japan, 503-8502
      • Recruiting
      • Ogaki Municipal Hospital
      • Contact: Takashi Kumada, Dr
      • Principal Investigator: Takashi Kumada, Dr.
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8556
      • Recruiting
      • Sapporo Medical University
      • Contact: Junji Kato, Dr.
      • Principal Investigator: Junji Kato, Dr.
    • Sapporo, Hokkaido, Japan, 060-8556
      • Recruiting
      • Sapporo-Kosei General Hospital
      • Contact: Takumi Ohmura, Dr.
      • Principal Investigator: Takumi Ohmura, Dr.
  • Kagawa
    • Takamatsu, Kagawa, Japan, 760-0017
      • Recruiting
      • Japanese Red Cross Takamatsu Hospital
      • Contact: Chikara Ogawa, Dr.
      • Principal Investigator: Chikara Ogawa, Dr.
  • Mie
    • Tsu, Mie, Japan, 514-8507
      • Recruiting
      • Mie University Hospital
      • Contact: Katsuya Shiraki, Dr.
      • Principal Investigator: Katsuya Shiraki, Dr.
  • Nagasaki
    • Ohmura, Nagasaki, Japan, 856-8562
      • Recruiting
      • National Hospital Organization Nagasaki Medical Center
      • Contact: Hiromi Ishibashi, Dr.
      • Principal Investigator: Hiromi Ishibashi, Dr.
  • Okayama
    • Kurashiki, Okayama, Japan, 701-0192
      • Recruiting
      • Kawasaki Medical School Hospital
      • Contact: Keisuke Hino, Dr.
      • Principal Investigator: Keisuke Hino, Dr.
  • Osaka
    • Ikeda, Osaka, Japan, 563-8510
      • Recruiting
      • Ikeda Municipal Hospital
      • Contact: Yasuharu Imai, Dr.
      • Principal Investigator: Yasuharu Imai, Dr.
    • Osaka-Sayama, Osaka, Japan, 589-8511
      • Recruiting
      • Kinki University Hospital
      • Contact: Masatoshi Kudo, Professor; Phone Number: 3149 +81-72-366-0221; Email: m-kudo@med.kindai.ac.jp
      • Contact: Kazuomi Ueshima, Dr.; Phone Number: 3525 +81-72-366-0221; Email: kaz-ues@med.kindai.ac.jp
      • Principal Investigator: Masatoshi Kudo, Professor
      • Sub-Investigator: Kazuomi Ueshima, Dr.
      • Principal Investigator: Kazuto Nishio, Professor
    • Suita, Osaka, Japan, 565-0871
      • Recruiting
      • Osaka University Hospital
      • Contact: Hiroaki Nagano, Professor
      • Principal Investigator: Hiroaki Nagano, Professor
  • Tokyo
    • Mitaka, Tokyo, Japan, 181-8611
      • Recruiting
      • Kyorin University Hospital
      • Contact: Junji Furuse, Professor
      • Principal Investigator: Junji Furuse, Professor
    • Musashino, Tokyo, Japan, 180-8610
      • Recruiting
      • Musashino Red Cross Hospital
      • Contact: Namiki Izumi, Dr.
      • Principal Investigator: Namiki Izumi, Dr.
    • Nerima, Tokyo, Japan, 177-0033
      • Recruiting
      • Juntendo University Nerima Hospital
      • Contact: Shigehiro Kokubu, Dr.
      • Principal Investigator: Shigehiro Kokubu, Dr.
  • Yamaguchi
    • Ube, Yamaguchi, Japan, 755-8505
      • Recruiting
      • Yamaguchi University Hospital
      • Contact: Isao Sakaida, Prof
      • Principal Investigator: Isao Sakaida, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 20 Years and older.
2. Life expectancy of at least 12 weeks at the pre-treatment evaluation.
3. Advanced hepatocellular carcinoma with histological evidence on a biopsy specimen, or typical findings by dynamic CT or CT during hepatic arteriography/arterioportography.
4. Not suitable for resection or local ablation therapy or transcatheter arterial chemoembolization.
5. ECOG Performance status of 0 or 1.
6. Cirrhotic status of Child-Pugh score ≤ 7.

7. Adequate bone marrow, liver and renal function, as assessed by the following laboratory requirements:

   • Hemoglobin ≥8.5 g/dl
   • Granulocytes≥1500/μL
   • Platelet count ≥50,000 /μL
   • PT-INR ≤ 2.3
   • Total serum bilirubin ≤ 2 mg/dl
   • AST(SGOT) and ALT(SGPT) ≤ 6 × upper limit of normal
   • Serum creatinine ≤ 1.5 × upper limit of normal
   • Amylase ≤ 2 × upper limit of normal
8. Written Informed Consent must be obtained.

Exclusion Criteria:

1. Previous malignancy (except for cervical carcinoma in situ, adequate treated basal cell carcinoma, or superficial bladder tumors [Ta, Tis and T1], early gastric cancer, or other malignancies curatively treated > 3 years prior to entry
2. Renal failure

3. Any heart disease as follows

   • Congestive heart failure defined as NYHA class III or IV
   • Active coronary artery disease or ischemic heart disease such as cardiac infarction within 6 months prior to screening
   • Serious cardiac arrhythmia
   • Serious hypertension
4. Active clinically serious infections except for HBV and HCV
5. Active chicken pox.
6. Auditory disorder.
7. Known history of HIV infection.
8. Known metastatic or meningeal tumors.
9. Extrahepatic tumor spread which affects patient's prognosis
10. History of seizure disorder.
11. Clinically significant gastrointestinal bleeding within 4 weeks prior to study entry.
12. Embolization or infarction such as transient ischemic disease, deep vein thrombosis, pulmonary embolization.

13. Any history of treatment as follows:

    • Treatment with the agent which induces CYP3A4
    • Surgical procedure within 4 weeks prior to start of study drug
    • History of organ allograft
14. Patients unable to swallow oral medications.
15. Gastrointestinal disease that may affect to the absorption of drug or pharmacokinetics.
16. Medication that may affect to the absorption of drug or pharmacokinetics.
17. Any disease or disorder that may affect the evaluation of study drug.
18. Entry to the other clinical trial within 4 weeks prior to entry to this study.
19. Pregnant or breast-feeding patients.
20. Known allergy to the investigational agent or any agent given in association with this trial.
21. Substance abuse, medical, psychological or social conditions that, in the judgment of the investigator, is likely to interfere with the patient's participation in the study or evaluation of the stuy results.
22. Any condition that is unstable or could jeopardize the safety of the patient and its compliance in the study, in the investigator's judgment.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sorafenib	Drug: Sorafenib; Sorafenib will be administered orally at a dose of 400 mg bid for 28 days in each cycle.A cycle is defined as 28 days.; Other Names: Nexavar
Experimental: Sorafenib with Low-dose FP	Drug: Sorafenib with Low-dose FP; Sorafenib will be administered orally at a dose of 400 mg bid for 28 days in a cycle. Cisplatin at the dose of 20 mg/m2 will be administered at day 1 and day8, and fluorouracil at the dose of 330 mg/m2 will be administered continuously at day 1-day 5, and day8-day12 via the implanted catheter system. A cycle is defined as 28 days.; Other Names: Nexavar; Low-dose FP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	Overall survival is defined as the time from randomization to death due to any cause

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to progression	TTP is defined as the time from randomization to radiological progression.
Progression Free Survival	PFS is defined as the time from randomization to radiological progression or death due to any cause
Change of tumor marker	Every 4-6 weeks
Biomarker predicting the efficacy	Pre and after treatment

Collaborators and Investigators

• Sponsor: Ministry of Health, Labour and Welfare, Japan
• Investigators: Study Chair: Masatoshi Kudo, Professor, Kinki University Faculty of Medicine, Department of Gastroenterology and Hepatology

Publications and helpful links

General Publications

• Kudo M, Ueshima K, Yokosuka O, Ogasawara S, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Kanai F, Akazawa K, Yoshimura KI, Johnson P, Arai Y; SILIUS study group. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Jun;3(6):424-432. doi: 10.1016/S2468-1253(18)30078-5. Epub 2018 Apr 7.
• Ueshima K, Kudo M, Tanaka M, Kumada T, Chung H, Hagiwara S, Inoue T, Yada N, Kitai S. Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil. Liver Cancer. 2015 Dec;4(4):263-73. doi: 10.1159/000367751. Epub 2015 Oct 21.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Anticipated): September 1, 2013
• Study Completion (Anticipated): September 1, 2013

Study Registration Dates

• First Submitted: October 4, 2010
• First Submitted That Met QC Criteria: October 4, 2010
• First Posted (Estimate): October 5, 2010

Study Record Updates

• Last Update Posted (Estimate): June 15, 2011
• Last Update Submitted That Met QC Criteria: June 14, 2011
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Keywords: cisplatin; fluorouracil; sorafenib; HAIC; Low dose FP; Hepatic intraarterial infusion chemotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: SILIUS Phase III trial