臨床研究等提出・公開システム

Safety and efficacy of regorafenib in advanced hepatocellular carcinoma patients who were not included in the RESORCE trial

REGAIN trial (REGAIN trial)

37

Study drug administration: 36 patients (1 patient could not start study treatment due to deterioration of health after enrollment) Protocol deviation: 0 FAS: 36 patients Arm A: 12 patients #6 in normal dose starting group (male 5 median age 66.5) #6 in dose reduction group (male 6 median age 80.0) Arm B:12 patients #6 in normal dose starting group (male 6 median age 69.5) #6 in dose reduction group (male 5 median age 73.0) Arm C: 12 patients #6 in normal dose starting group (male 6 median age 72.5) #6 in dose reduction group (male 6 median age 74.0)

Trial started: November 2019 January 2020 - December 2020: Number of consents obtained: 13 patients, number of assigned patients: 12, dropout patients: 1 January 2021 - December 2021: Number of consents obtained: 15 patients, number of assinged patients: 15, Dropout patients: 0 Jan 2022-Sep 2022: Number of consents obtained: 9 patients, number of assinged patients: 9, Dropout patients: 0

There were 40 serious adverse events reported during the study. Seven events were attributable to the study and 33 were not. The breakdown is as follows. Attributable:7 events #1 Edema:1 event #2 Hepatic encephalopathy: 1 event #3 Liver dysfunction: 1 event #4 Interstitial pneumonia: 1 event #5 Herpes zoster: 1 event #6 Fever: 2 events Not attributable:33 events #1 Exacerbation of primary disease: 7 events #2 Fever: 3 events #3 Bile duct bleeding: 2 events #4 Aspiration pneumonia: 1 event #5 Gastric ulcer: 1 event #6 Ruptured spleen tumor: 1 event #7 Cholangitis: 3 events #8 Swelling of lower limbs: 1 event #9 Hematemesis: 1 event #10 Hepatic abscess: 1 event #11 Loss of appetite: 1 event #12 Myocardial infarction: 1 event #13 Myocardial ischemia: 1 event #14 AST increase: 1 event #15 ALT increase: 1 event #16 Esophageal varices hemorrhage: 1 event #17 Traumatic splenic rupture: 1 event #18 Gallstone: 1 event #19 Fracture of right upper carpal bone: 1 event #20 Pedestrian impairment due to transplanted spinal ulcer: 1 event #21 Pulmonary decompensation: 1 event #22 Pneumothorax: 1 event

The Independent Monitoring Committee was consulted on the progress of the study (August 29, 2022). -Frequency of drug use in actual clinical practice in recent years -Study progress (first patient in: Jan 2020) The above information was presented to the Independent Monitoring Committee. The following recommendations were made Given the current rate of patient recruitment, further patients recruitment is not recommended and it is recommended that the study be stopped with the cases in the safety evaluation cohort. In accordance with the above recommendation, we have decided not to enroll additional patients in the study once they have been safely enrolled in the safety evaluation cohort. Therefore, the study did not reach its target number of patients for efficacy. The number of evaluable cases was enrolled for the safety evaluation, and the interim analysis was conducted as planned. Primary endpoint (time to progression) Median time to progression (95% CI) (modified RECIST) All arms Normal dose starting group: 4.6 months (2.63-10.32) Dose reduction starting group: 3.0 months (2.76-6.47) Arm A Normal dose starting group: 8.3 months (4.11-15.67) Dose reduction starting group: 13.5 months (2.76-21.39) Arm B Normal dose starting group 10.2 months (0.95-15.90) Dose reduction starting group: 2.8 months (0.92-NA) Arm C Normal dose starting group: 2.6 months (1.58-2.76) Dose reduction starting group: 4.1 months (2.53-NA) Secondary endpoints -Safet- Frequency of discontinuation due to adverse events within 1 month (evaluated at interim analysis) All arms (both groups) 1/36 (2.8%) Arm A Normal dose starting group 0/6 (0%) Dose reduction starting group 0/6 (0%) Arm B Normal dose starting group 0/6 (0%) Dose reduction starting group 0/6 (0%) Arm C Normal dose starting group 1/6 (17.6%) Dose reduction starting group 0/6 (0%) Frequency of discontinuation due to adverse events (all arms) Normal starting dose group (all arms) 17.6% Dose reduction starting group (all arms) 25.0% The most common treatment-emergent adverse events were as follows: -Normal dose starting group-. Palmoplantar erythropoietic syndrome 88.9% Hypertension 77.8% Increased lipase 72.2% Fatigue 72.2% Hoarseness 72.2% Anorexia 61.1% Decreased lymphocyte count 55.6% Hypophosphatemia 50.0% Proteinuria 50.0% Diarrhea 50.0% Hypoalbuminemia 44.4% Increased Aspartate Aminotransferase 44.4% Increased serum amylase 44.4% Hyponatremia 44.4% Abdominal pain 38.9% Elevated alanine aminotransferase 33.3% Hypokalemia 27.8% Constipation 27.8 Weight loss 27.8 Edema of the extremities 27.8% Maculopapular rash 27.8% Increased blood bilirubin 27.8% Decreased platelet count 22.2% Anemia 22.2% Fever 22.2% Pyrexia 22.2% Hyperkalemia 22.2% Decreased neutrophil count 22.2% Oral mucositis 16.7% -Dose reduction starting group- Palmoplantar Erythroderma Syndrome 94.4% Hypertension 88.9% Increased lipase 83.3% Fatigue 77.8% Hoarseness 77.8% Anorexia 55.6% Decreased lymphocyte count 38.9% Hypophosphatemia 66.7% Proteinuria 44.4% Diarrhea 33.3% Hypoalbuminemia 38.9% Increased Aspartate Aminotransferase 38.9% Increased serum amylase 38.9% Hyponatremia 16.7% Abdominal pain 22.2% Increased alanine aminotransferase 16.7% Hypokalemia 27.8% Constipation 22.2% Weight loss 22.2% Limb edema 16.7% Maculopapular rash 16.7% Increased blood bilirubin 16.7% Decreased platelet count 33.3% Anemia 27.8% Fever 16.7% Hyperkalemia 11.1% Decreased neutrophil count 11.1% Oral mucositis 44.4% Back pain 27.8% -Efficacy- Median overall survival (95% CI) All arms Normal dose starting group: 18.1 months (5.62-NA) Dose reduction starting group: 17.7 months (7.43-NA) Arm A Normal dose starting group: 18.1 months (5.62-NA) Dose reduction starting group: 17.7 months (7.92-NA) Arm B Normal starting dose group 20.6 months (3.45-20.63) Median not reached in dose reduction starting group Arm C Normal dose starting group 10.5 months (0.26-NA) Median not reached in dose reduction starting group Median progression-free survival (95% CI) (modified RECIST) All arms Normal dose starting group: 4.6 months (2.63-10.32) Dose reduction starting group: 3.4 months (2.76-5.55) Arm A Normal dose starting group: 8.3 months (4.11-15.67) Dose reduction starting group : 11.6 months (2.76-21.39) Arm B Normal dose starting group: 10.2 months (0.95-15.90) Dose reduction starting group: 2.8 months (0.92-4.01) Arm C Normal dose starting group: 2.6 months (1.58-2.76) Dose reduction starting group: 4.1 months (2.53-NA)

This study demonstrated the safety of regorafenib as second-line therapy in patients who were not included in the RESORCE study population. The study did not reach the target number of patients with respect to the evaluation of efficacy, and only the safety evaluation cohort was conducted. The safety of each arm were evaluated by IDMC, which recommended that there were no safety issues in either the normal dose starting group or the dose reduction group.

Sept. 30, 2025

No

We did not plan IPD in the present trial.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031190103

Kato Naoya

Chiba University Hospital

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

Sept. 25, 2019

Interventional

randomized controlled trial

open(masking not used)

dose comparison control

parallel assignment

treatment purpose

Patients must meet all of the following criteria to be included in this study:
1)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.
2) 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).
3)EOCG Performance Status(PS)of 0 or 1.
4)Liver function status is Child-Pugh class A.
a)HCC is classified into Child-Pugh class A to C,employing the added score of 5 clinical parameters.
b)Child-Pugh classification: A (5-6), B (7-9), and C(10-15)
5)Patients must meet all of the following criteria of clinical lab tests.
a)White blood cell>=2000/uL
b)Neutrophil>=1000/uL
c)Hemoglobin>=8.5g/dl
d)Platelet>=50000/mm3
e)Total bilirubin<=3.0mg/dl
f)AST, ALT<=5 times the upper limit of the facility reference
g)Serum Creatinine<=1.5 times the upper limit of the facility reference
h)Serum albumin>=2.8g/dl
i)Prothrombin time(PT-INR)<=2.3
6)Patients must have measurable lesion with RECIST version 1.1 and modified RECIST(mRECIST).
7)Ages 20 and older(any gender).
8)Patients with written consent after receiving sufficient explanation for this study. The consent is based on free will.
9)Men or Women who can agree to use adequate contraception.
10)The last treatment is one of the following.
[Arm A]The last treatment was sorafenib, which met all of the following:
Patients who have failed prior treatment with sorafenib(defined as radiological progression).
Patients who could be administered with sorafenib at a dose of 200 mg daily or 400 mg every other day for more than 28 days, but they couldn't meet an inclusion criterion of RESORCE study such as "Patients who can be administered with sorefenib for not less than 20 days at a minimum daily dose of 400mg within the last 28 days prior to withdrawal".
Patients whose dose control during sorafenib treatment are clear.
[Arm B]The last treatment was lenvatinib, which met all of the following:
Patients whose previous treatment was lenvatinib and no treatment history of sorafenib.
Patients who received prior treatment with lenvatinib and finished it due to disease progression or intolerance of the drug.
[Arm C]The last treatment was atezolizumab plus bevacizumab, which met all of the following:
Patients whose previous treatment was atezolizumab plus bevacizumab and no treatment history of sorafenib.
Patients who received prior treatment with atezolizumab+bevacizumab and finished them due to disease progression or intolerance of the drugs.
11)More than two weeks after the last treatment with sorafenib or lenvatinib.

Patients who fall under any of the following criteria, will be excluded from the study.
1) Patients who have been administered with regorafenib for advanced HCC
2) 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 two years prior to the study and is considered to have not relapsed since then.
3) 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.
4) Severe and active infections (CTCAE version 4.0 Grade 3 or higher).
5) Urine protein (CTCAE version 4.0 Grade3 or higher) other than the following cases.24-hour urine test (urine protein/urine creatinine ratio can be substituted as 24-hour urine test) is less than 3.5g.
6) History of HIV infection.
7) Detectable HBV-DNA without nucleic acid analog treatment.
8) Patients on kidney dialysis
9) Intracranial tumor (including intracranial metastasis).
10) History of hepatic encephalopathy (Grade2 or higher).
11) Esophageal and gastric varices requiring treatment
12) Refractory ascites
13) Thromboembolism (cerebrovascular disorder including transient cerebral ischemic attack, deep vein thrombosis, pulmonary embolism etc.) within 6 months before the start of the study
14) 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 providing consent
d) Prior treatment for HCC with local therapy (radiofrequency ablation, ethanol injection, microwave ablation) within 4 weeks prior to providing consent
e) Prior treatment for HCC with transvascular intervention therapy (transarterial chemoembolization etc.) within 4 weeks prior to providing consent
f) Medical history with invasive surgery within 12 weeks prior to providing consent
g) History of homologous organ transplantation
h) History of bone marrow transplantation / hematopoietic stem cell transplantation
15) Gastrointestinal disorders which may affect drug absorption and pharmacokinetics
16) Use of drugs which may affect drug absorption and pharmacokinetics
17) Pregnant or lactating woman; woman of child bearing age unless using effective contraception (In case of suspected pregnancy, pregnancy test should be conducted)
18) Possibility of allergic reaction to the study drug
19) Drug abuse. Health, psychological, social conditions that interfere with the participation of the study or evaluation of the results
20) 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

Regorafenib

Chemotherapy

Molecular targeted agent

013

Time to progression (modified RECIST and RECIST version 1.1)

Secondary outcomes of efficacy
Overall survival
Progression free survival (modified RECIST and RECIST version 1.1)
Secondary outcomes of safety
Frequency of adverse events
Rate of discontinuation by adverse events

+81-43-226-2616

Jan. 23, 2019

none