Transcatheter Arterial Chemoembolization Therapy In Combination With Sorafenib (TACTICS)

Phase II Study: Transcatheter Arterial Chemoembolization Therapy In Combination With Sorafenib (TACTICS)

The purpose of this study is to evaluate the safety and efficacy of the combination therapy with Transcatheter Arterial Chemoembolization (TACE) and sorafenib compared to TACE alone in patients with unresectable hepatocellular carcinoma (HCC) who are not candidates for surgical resection or percutaneous ablation therapy.

Study Overview

• Status: Unknown
• Conditions: Carcinoma, Hepatocellular; Hepatocellular Carcinoma; Liver Neoplasm; Unresectable Hepatocellular Carcinoma
• Intervention / Treatment: Drug: TACE with sorafenib; Procedure: TACE alone

Detailed Description

TACE with sorafenib Group

Sorafenib will be administrated at a dose of 400mg o.d. before the first TACE. After 2days drug rest, TACE will be conducted. Sorafenib will be resumed at a dose of 400mg o.d. from 3 days after TACE(the resumption day can be postponed until 21 days after TACE). When tolerability is confirmed at 1 week after resumption, the dose of sorafenib will be increased to 400mg b.i.d. When tumor increases, TACE will be repeated.

Control group

TACE will be conducted at scheduled day. When tumor increases, TACE will be repeated.

The treatment regimen will be continued until untreatable progression which is defined as follows:

• Child-Pugh grade C
• Tumor growth (125 percent from baseline status)
• Vascular invasion(Vp3,Vp4)
• Extra hepatic spread which size is more than 10mm

• Study Type: Interventional
• Enrollment (Anticipated): 228
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Osaka
    • Osaka-Sayama, Osaka, Japan, 589-8511
      • Kinki University Hospital

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. Patients aged 20 Years or over
2. Patients who were fully informed of the study beforehand and signed the informed consent to participate in the study.
3. Patients who are expected to live more than 12 weeks.
4. Patients diagnosed with typical HCC by biopsy,cytology, or diagnostic imaging such as dynamic CT(MRI).Typical HCC is defined by AASLD criteria.
5. Patients in whom complete resection of the tumor by hepatectomy or complete tumor necrosis by local tumor necrosis therapy(RFA) cannot be expected to succeed.
6. Patients with tumors which are confirmed to the liver and can be treated by TACE(the maximum diameter equal to or less than 10cm,and the maximum number of nodule equal to or less than 10).
7. Patients with viable and measurable target lesion.
8. patients with no or one history of TACE therapy.
9. patients with an ECOG PS(Performance Status) Score of 0 or 1.
10. patients with Child-Pugh class A.

11. Patients with laboratory values that meet the following criteria:

    1. Hemoglobin ≥ 8.5 g/dl
    2. Granulocytes ≥ 1500/mm3
    3. Platelet count ≥ 50,000 /mm3
    4. Total serum bilirubin ≤ 3 mg/dl
    5. AST and ALT ≤ 6 times upper limits of normal
    6. Serum creatinine ≤ 1.5 times upper limits of normal

Exclusion Criteria:

1. History of malignant tumor, excluding the following cases:

   1. Curatively treated early stage cancer with a low risk of recurrence ,such as carcinoma in situ of the cervix, basal cell carcinoma, superficial bladder tumor, and early gastric cancer.
   2. Malignant tumor that was curatively treated more than 3 years prior to study entry and has not recurred since then

2. Cardiac disease that meet any of the following criteria:

   1. NYHA Class III or higher congestive heart failure
   2. History of symptomatic coronary artery disease or myocardial infarction within 6 months before enrollment
   3. Arrhythmia requiring control by antiarrhythmic drugs such as beta-blockers or digoxin
3. Serious and active infection, except for HBV and HCV
4. History of HIV infection
5. Renal dialysis
6. Diffuse tumor lesion
7. Extrahepatic metastasis
8. Vascular invasion
9. Intracranial tumor
10. Preexisting or history of hepatic encephalopathy
11. Clinically uncontrolled ascites or pleural effusion
12. Clinically severe gastrointestinal bleeding within 4 weeks of the start of treatment
13. Esophageal and/or gastric varices which has high risk of bleeding
14. History of thrombosis and/or embolism within 6 months of the start of treatment

15. History of receiving any of the following therapies:

    1. Systemic chemotherapy for advanced HCC(including sorafenib therapy)
    2. Local therapy, such as radiofrequency ablation, TACE, or hepatic arterial infusion within 3 months of the start of treatment
    3. Current treatment with CYP3A4 inducing agents
    4. Invasive surgery within 4 weeks of the start of treatment
    5. History of allogenic transplantation
    6. History of bone marrow transplant or haemopoietic stem cell transplant within 4 weeks of the start of this study
16. Unable to take oral medications
17. Gastrointestinal problems that may affect absorption or pharmacokinetics of the study drugs
18. Use of drugs that may affect absorption or pharmacokinetics of the study drugs
19. Concurrent disease or disability that may affect evaluation of the effects of the study drugs
20. Enrollment in another study within 4 weeks of study entry
21. Female patients who are pregnant, lactating, possibly pregnant, or planning to become pregnant
22. Risk of allergic reactions to the study drugs
23. Drug abuse or other physical, psychological , or social problems that may interfere with the participation in the study or evaluation of study results
24. Any condition that could jeopardize the safety of the patient or their compliance in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: TACE with sorafenib; TACE(on demand) with sorafenib till untreatable progression	Drug: TACE with sorafenib; Sorafenib will be administrated at a dose of 400mg o.d. before the first TACE. After 2days drug rest, TACE will be conducted. Sorafenib will be resumed at a dose of 400mg o.d. from 3 days after TACE(the resumption day can be postponed until 21 days after TACE). When tolerability is confirmed at 1 week after resumption, the dose of sorafenib will be increased to 400mg b.i.d. When tumor increases, TACE will be repeated.; Other Names: TACE with Nexavar
ACTIVE_COMPARATOR: TACE alone; TACE(on demand) till unreatable progression	Procedure: TACE alone; TACE will be conducted at scheduled day. When tumor increases, TACE will be repeated.; Other Names: TACE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Patients will be evaluated for these endpoints every 8 weeks	every 8 week
Overall Survival	The overall survival is defined as time from randomization to death due to any cause, and will be evaluated every 8 weeks in the protocol treatment, and every one year in the follow-up period,respectively.	every 8 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time To Progression	Time to progression is defined as time from randomization to radiological progression and will be evaluated every 8 week.	every 8 weeks
Objective Response Rate	Objective Response Rate is defined as best response	4week after TACE
Tumor markers	Change of tumor markers	every 4 weeks
Safety	Number of participants with adverse events as a measure of safety and tolerability(According to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0)	every 4 weeks
Time To Untreatable Progression(TTUP)	Time to untreatable progression is defined as time from randomization to untreatable progression and will be evaluated every 8 week.	every 8 week till untreatable progression, assessed up to 100 months
Time to Child-Pugh C	Time to Child-Pugh C is defined as time from randomization to Child-Pugh C and will be evaluated every 8 week.	every 8 week till liver deterioration to Child-Pugh C, assessed up to 100 months
Time to intrahepatic tumor progression	Time to intrahepatic tumor progression is defined as time from randomization to intrahepatic tumor progression and will be evaluated every 8 week.	every 8 week till intrahepatic tumor progression, assessed up to 100 months
Time to vascular invasion	Time to vascular invasion is defined as time from randomization to vascular invasion and will be evaluated every 8 week.	every 8 week till vascular invasion, assessed up to 100 months
Time to Extrahepatic spread	Time to extrahepatic spread is defined as time from randomization to extrahepatic spread and will be evaluated every 8 week.	every 8 week till extrahepatic spread, assessed up to 100 months

Collaborators and Investigators

• Sponsor: Kindai University
• Investigators: Principal Investigator: Masatoshi Kudo, Professor, Kindai University

Publications and helpful links

General Publications

• Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, Izumi N, Yamasaki T, Nojiri S, Hino K, Tsumura H, Kuzuya T, Isoda N, Moriguchi M, Aino H, Ido A, Kawabe N, Nakao K, Wada Y, Ogasawara S, Yoshimura K, Okusaka T, Furuse J, Kokudo N, Okita K, Johnson PJ, Arai Y. Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma. Liver Cancer. 2022 Feb 10;11(4):354-367. doi: 10.1159/000522547. eCollection 2022 Jul.
• Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, Izumi N, Yamasaki T, Nojiri S, Hino K, Tsumura H, Kuzuya T, Isoda N, Yasui K, Aino H, Ido A, Kawabe N, Nakao K, Wada Y, Yokosuka O, Yoshimura K, Okusaka T, Furuse J, Kokudo N, Okita K, Johnson PJ, Arai Y; TACTICS study group. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut. 2020 Aug;69(8):1492-1501. doi: 10.1136/gutjnl-2019-318934. Epub 2019 Dec 4.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ANTICIPATED): March 1, 2018
• Study Completion (ANTICIPATED): March 1, 2018

Study Registration Dates

• First Submitted: October 2, 2010
• First Submitted That Met QC Criteria: October 6, 2010
• First Posted (ESTIMATE): October 8, 2010

Study Record Updates

• Last Update Posted (ACTUAL): October 31, 2017
• Last Update Submitted That Met QC Criteria: October 30, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: TACE; sorafenib; Transcatheter arterial chemoembolization; Time to untreatable progression; TTUP
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Estrogens, Non-Steroidal; Estrogens; Protein Kinase Inhibitors; Chlorotrianisene; Sorafenib
• Other Study ID Numbers: JLOG 1001 trial