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A randomized, open, Phase II comparison of the safety and efficacy of a reduced and re-escalated dose of sorafenib versus a reduced and maintained dose of sorafenib in patients with advanced hepatocellular carcinoma

Dose re-escalation study of sorafenib in patients with HCC

114

First enrollment: 114 patients Stud drug administration: 113 patients Second enrollment: 48 patients Re-escalation dose group: 24 patients Reduced dose group: 24 patients At the time of first enrollment (n = 113) Age (median): 70 years (39-84), male: 94 pt (83.2%), HBV: 21 pt (18.6%), HCV: 56 pt (49.6%), ECOG-PS 0: 100 pt (87.7%), Child-Pugh score 5: 67 pt (59.3%), Child-Pugh score 6: 31 pt (27.4%), Child-Pugh score 7 : 15pt (13.3%), MVI: 35 pt (31.0%), EHM: 47 pt (41.6%), BCLC stage C: 68 pt (60.2%),AFP >400 mg/dL: 52 pt (46.0%), pre-treatment: 105 (93.0%) At the time of second enrollment Re-escalation dose group (n = 24) Age (medina): 71 years (60-83), male: 22 pt (91.7%), HBV: 3 pt (12.5%), HCV: 15 pt (62.5%), ECOG-PS 0: 23 pt (95.8%), Child-Pugh score 5: 15 pt (62.5%), Child-Pugh score 6: 5 pt (20.8%), Child-Pugh score 7:4 pt 16.7% ),MVI: 2 pt (8.3%), EHM 9 pt (37.5%), BCLC stage C: 15 pt (62.5%), AFP >400 mg/dL: 8 pt (33.3%), pre-treatment: 23 pt (95.8%) Reduced dose group (n = 24)

Number of enrollment (number of second enrollment) Start date - 31st March 2015: 19 patients (5 patients) 1st April 2015 - 31st March 2016: 33 patients (15 patients) 1st April 2016 - 31st March 2017: 40 patients (19 patients) 1st April 2017 - Finish data: 22 patients (9 patients)

Frequencies of adverse events are indicated the next section. Cases sever adverse events during the present trial was listed as bellow. #1 Tumor lysis syndrome (Grade 3, not related) #2 Esophagus hemorrhage (Grade 5, not related) #3 Tumor lysis syndrome (Grade 3, related) #4 Tumor lysis syndrome (Grade 3, related) #5 Ascites (Grade 3, not related) #6 Death (Grade 5, unknown) #7 Heart failure (Grade 3, not related) #8 Esophagus hemorrhage (Grade 5, not related) #9 Stomach hemorrhage (Grade 3, related) #10 Stroke (Grade 3, not related) #11 Pain (Grade 3, not related) #12 Hepatocellular carcinoma (underlying disease (Grade 5, not related) #13 Liver failure (Grade 5, not related)

Primary endpoint Time to progression after randomization Re-escalation dose: 2.8 months (95%CI, 2.3-4.2) Reduced dose: 2.6 months (95%CI, 0.9-4.3) P = 0.868 Secondary endpoints Overall survival Re-escalation dose: 27.5 months (95%CI, 12.0-undefined) Reduced dose: 17.8 months (95%CI, 11.8-39.9) P = 0.676 Overall survival after randomization Re-escalation dose: 25.6 months (95%CI, 10.1-undefined) Reduced dose: 15.9 months (95%CI, 9.7-38.0) P = 0.705 Time to progression e-escalation dose: 4.7 months (95%CI, 4.6-6.5) Reduced dose: 4.7 months (95%CI, 2.9-6.5) P = 0.905 Drug concentration of sorafenib Week 4 Re-escalation dose group: 5.58 (2.67) Reduced dose group: 3.91 (0.75) Week 8 Re-escalation dose group: 4.45 (3.74) Reduced dose group: 2.30 (0.94) Week 12 Re-escalation dose group: 5.71 (3.31) Reduced dose group: 2.50 (1.19) Safety Before second enrollment The most common adverse events were hypertension (re-escalation dose: 70.8%, reduced dose: 70.8%, lipase increased (re-escalation dose: 70.8%, reduced dose: 70.8%), palmoplantar erythrodysesthesia,(re-escalation dose: 62.5%, reduced dose: 50.0 %,), hypophosphatemia (re-escalation dose: 58.3%, reduced dose: 41.7%), and amylase increased (re-escalation dose: 54.2%, reduced dose: 50.0%). After second enrollment The most common adverse events were hypertension (re-escalation dose: 70.8%, reduced dose: 56.5%), palmoplantar erythrodysesthesia, (re-escalation dose: 58.3%, reduced dose: 39.1 %), and hypoalbuminemia (re-escalation dose: 54.2%, reduced dose: 39.1%).

Time to progression after randomization, which was the primary endpoint of this study, were not significantly longer in the re-escalation dose group compared with that of the reduced dose group. Moreover, other secondary endpoints did not suggest effectiveness of the re-escalation dose group as well. There were no adverse events which increased significantly in the re-escalation dose group compared with the reduced dose group.

Oct. 31, 2022

No

We did not plan IPD in the present trial.

https://jrct.niph.go.jp/latest-detail/jRCTs031180429

Kato Naoya

Chiba University

1-8-1, Inohana, Chuo-ku, Chiba city, Chiba, Japan

kato.naoya@chiba-u.jp

Ogasawara Sadahisa

Chiba University

1-8-1, Inohana, Chuo-ku, Chiba city, Chiba, Japan

+81-43-222-7171

ogasawaras@chiba-u.jp

Complete

July. 08, 2014

Interventional

randomized controlled trial

open(masking not used)

historical control

parallel assignment

treatment purpose

1) Age: 20 years or more
2) Patients with written consent after receiving sufficient explanation for this study. The consent is based on free will.
3) Patients must have been diagnosed with HCC base on either of the following assessments:
a) Histological or cytological diagnosis of HCC
b) Radiographic image diagnosis of HCC by the typical findings of a hypervascular tumor on dynamic CT, CTHA/CTAP, dymamic MRI.
4) Patients must meet all of the following criteria on treatment of HCC:
a) Not applicable for surgical resection.
b) Not applicable for any local therapies (radio frequency ablation, percutaneous ethanol injection, microwave ablation).
c) Not applicable for transarterial chemoembolization (TACE). imum target lesion diameter>=10mm
5) Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1
6) Child Pugh score <= 7
7) Life expectation of 12 weeks or over
8) Capablity of complying with procedures and visits as specified by the protocol
9) Patients must meet all of the following criteria of clinical lab tests.
a) Hemoglobin>=8.5g/dl
b) White blood cell>=2000/mm3
c) Platelat>=50000/mm3 d) Total bilirubin<=3.0mg/dL
e) AST, ALT<=5 times the upper limit of the facility reference
f) Serum albumin>=2.5g/dL
g) Serum Creatinine<=1.5 times the upper limit of the facility reference
h) Serum Amylase<=2 times the upper limit of the facility reference
i) Prothrombin time(PT-INR) <=2.3

1) Patients with a history of malignant tumors except for the following cases.
a) Early stage cancers with a low risk of relapse after appropriate radical treatment such as intraepithelial cervical cancer, basal cell carcinoma, superficial bladder tumor (Ta, Tis and T1) and early gastric cancer.
b) Malignant tumors that have been given radical treatment for more than three years prior to the study and is considered to have not relapsed since then.
2) Heart disease which falls under any of the following.
a) Heart failure of NYHA class 3 or higher.
b) Coronary artery disease with symptoms. History of myocardial infarction within 24 weeks prior to enrollment.
c) Arrhythmias requiring control with antiarrhythmic drugs such as beta blocker and digoxin (CTCAE version 4.0 Grade 3 or higher).
d) Poor control hypertension.
3) Severe and active infections (CTCAE version 4.0 Grade 3 or higher).
4) History of HIV infection
5) Detectable HBV-DNA without nucleic acid analog treatment
6) Patients on kidney dialysis
7) Intracranial tumor, including Metastatic Brain Tumor
8) History of hepatic encephalopathy(Grade2 or higher)
9) Esophageal and gastric varices requiring treatment
10) Refractory ascites
11) Thromboembolism (cerebrovascular disorder including transient cerebral ischemic attack, deep vein thrombosis, pulmonary embolism etc.) within 6 months before the start of study
12) Patients with the following medical history, but not with history of palliative radiation exposure to bone metastasis
a) Use of CYP3A4 inducer (rifampicin etc.)
b) Use of Warfarin
c) History of bleeding which needs to be treated within 4 weeks prior to the start of study
d) Local therapy for HCC, such as radio frequency ablation, percutaneous ethanol injection or microwave ablation within 4 weeks prior to the start of study
e) History of Percutaneous therapy (TACE etc.)
f) History of invasive surgery within 12 weeks prior to the start of study
g) History of homologous organ transplantation
h) History of bone marrow transplantation or hematopoietic stem cell transplantation
13) Gastrointestinal disorders which may affect drug absorption and pharmacokinetics
14) Use of drugs which may affect drug absorption and pharmacokinetics
15) Pregnant or lactating woman; woman of child bearing age unless using effective contraception (In case of susupected pregnancy, pregnanvy test should be conducted)
16) Possibility of allergic reaction to the study drug
17) Drug abuse. Health, psychological or social conditions that interfere with the participation of the study or evaluation of the results
18) Any condition that in the opinion of the investigators could Impair the patient' s safety or make the study difficult to comply with the protocol by participating in the study

Both

Hepatocellular carcinoma

sorafneib

Chemotherapy

Molecular targeted agent

013

Time to progression after randomization

Overall survival
Overall survival after randomization
Time to progression
Drug concentration of sorafenib
Safety

+81-43-226-2616

Feb. 27, 2019

none