臨床研究等提出・公開システム

Single arm study to evaluate the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma patients in Japanese real-world practice; focusing on the completion of the REACH-2 study

R-evolution trial

17

Consent obtained:19 cases Study drug administered:17 cases Protocol deviation:0 cases Analysis:17 cases Age (median, range):73 (42-89) years, Male:14 (82.4%), HBV:8 (47.1%), HCV:4 (23.5%), ECOG-PS 0:15 (88.2%), Child-Pugh score 5:6 (35.3%), Child-Pugh score 6:11 (64.7%), Macrovascular invasion:8 (47.1%), Extrahepatic metastasis:9 (52.9%), BCLC stage C:14 (82.4%), previous treatment:lenvatinb in 7 (41.2%), atezolizumab + bevacizumab in 7 (41.2%), atezolizumab + bevacizumab to lenvatinib in 3 (17.6%)

Throughout the examination period, informed consent was obtained from 19 cases. One case experienced worsening of liver function during the screening period after obtaining consent and was subsequently excluded for not meeting the inclusion criteria. In one case, consent was later withdrawn, and the administration of the investigational drug did not proceed. The remaining 17 cases received the investigational drug. In all cases, the administration of the investigational drug was discontinued. The breakdown of reasons for discontinuation is as follows: Adverse events: 5 cases (29.4%) Tumor progression: 8 cases (47.1%) Consent withdrawal: 1 case (5.9%) Other (such as the judgment of the participating physician): 3 cases (17.6%). The annual progress is shown below. Study started (3 Mar 2020) - 2 Mar 2021: Consent obtained: 6 cases; drug administered: 5 cases; discontinued: 4 cases; discontinued: dropped out: 0 cases. Cases in which the drug was not administered due to deterioration of medical condition after consent was obtained: 1 case. 3 Mar 2021 - 2 Mar 2022: Consent obtained: 7 cases; administered: 7 cases; discontinued: 5 cases; discontinued: 0 cases 0 cases 3 Mar 2022 - 2 Mar 2023. Consent obtained: 6 cases; drugs administered: 5 cases; discontinued: 8 cases; discontinued: 0 cases. Discontinuations after consent obtained: 1 case

In the analysed population, there were 11 serious adverse events reported during the study. Four of these were attributable to the study and seven were not. The breakdown is as follows. Serious adverse events are defined as follows. A serious adverse event is defined as any of the following. (1) Death. (2) May result in death. (3) Disability (development of functional impairment to a degree that interferes with daily life). (4) A threat of leading to disability. (5) Requires hospitalisation or prolonged hospitalisation in a hospital or clinic for treatment. (6) Of the same severity as those listed in (1) to (5)*. (7) Those that leave a congenital disease or abnormality in later generations. Events resulting from: 4 cases. #1 Tumour collapse syndrome: 1 case #2 Fever: 1 case #3 Complete atrioventricular block: 1 case #4 Ascites: 1 case Events not attributable to: 7 cases #1 Death: 2 cases #2 Enterocolitis: 1 case #3 Bleeding gastric ulcer: 1 case #4 Hospitalisation for induction of next line treatment: 3 cases All of the above events have been previously reported with ramucirumab, were appropriately addressed and are not considered to interfere with the safety and scientific relevance of the study.

Primary Endpoint In this study cohort, the 6-month progression-free survival rate was 14.3% (95% CI 0.9-45). Secondary Endpoints Efficacy Assessment In the study cohort, the median overall survival (OS) was 12.0 months (95% CI 4.9-NE), and the median progression-free survival (PFS) was 3.7 months (95% CI 1.2-4.6) based on RECIST 1.1 criteria. The time to progression (TTP) was also 3.7 months (95% CI 1.2-NE). Regarding the duration of ramucirumab treatment, two cases were able to continue treatment for more than 3 months, while five cases discontinued treatment within 1 month. In terms of best response assessment, no cases achieved a complete response or partial response, with 12 cases having stable disease and 5 cases having progressive disease. The maximum change in target lesions showed approximately 40% enlargement in one case, but the remaining 16 cases had changes within 20% enlargement or shrinkage. Safety Assessment Commonly observed adverse events included hypertension (58.8%), decreased appetite (58.8%), fatigue (52.9%), hypoalbuminemia (47.1%), proteinuria (29.4%), edema (29.4%), constipation (23.5%), and thrombocytopenia (23.5%). Grade 3 or higher adverse events were observed in 12 cases (70.6%), with the main events being hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate of ramucirumab due to adverse events was 29.4% (5 cases). The changes in Child-Pugh scores before and after treatment with ramucirumab showed worsening by 1 point or more in 6 cases (35.3%), improvement in 1 case (5.9%), and the remaining 10 cases (58.8%) had the same score before and after treatment. Regarding the breakdown of subsequent treatment after the cessation of ramucirumab therapy, 13 cases (76.5%) were eligible for transitioning to the next line of treatment. The remaining 4 cases (23.5%) shifted towards palliative care after the discontinuation of ramucirumab. The treatment breakdown included changes in chemotherapy agents in 10 cases (58.8%), hepatic arterial infusion chemotherapy in 2 cases (11.8%), and radiation therapy in 1 case (5.9%).

Ramucirumab showed efficacy in real-world clinical practice comparable to that of the REACH-2 study. Although the incidence of adverse events was high, the rate of progression to next-line treatment was considered to be well maintained with appropriate management.

Mar. 31, 2024

No

no

https://jrct.niph.go.jp/latest-detail/jRCTs031190236

Ogasawara Sadahisa

Chiba University

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

ogasawaras@chiba-u.jp

Kobayashi Kazufumi

Chiba University

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

+81-43-222-7171

kobayashi-kazufumi@chiba-u.jp

Complete

Jan. 01, 2020

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

Patients who meet all of the following criteria will be included:
1) Patients must have been diagnosed with HCC by either of the following assessments:
a) Histological or cytological diagnosis of HCC
b) Radiographic image diagnosis of HCC by the typical findings 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) ECOG Performance Status (PS) of 0 or 1.
4) Patients with Child-Pugh class A
5) Patients must meet all of the following clinical testing criteria
a) White blood cell>=2000/uL
b) Neutrophil>=1000/uL
c) Hemoglobin>=9.0g/dL
d) Platelet>=75000/mm3
e) Total bilirubin<=1.5 times the upper limit of the facility reference
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) <=1.5 and activated partial thromboplastin time (APTT) <=1.5 times the upper limit of the facility reference
j) AFP>=400ng/mL
6) Patients must have measurable lesion with RECIST version 1.1.
7) Patients who received any of the following prior treatment as systemic chemotherapy and were discontinued for disease progression or intolerance
a) Lenvatinib
b) Combination chemotherapy of Atezolizumab and bevacizumab
c) Combination chemotherapy of Atezolizumab and bevacizumab followed by lenvatinib as a second line
8) Patients with no history of :
Systemic chemotherapy including sorafenib and regorafenib other than combination therapy of atezolizumab/ bevacizumab or lenvatinib.
Antineoplastic drug in development, antineoplastic chemotherapy, hormonal therapy, and immunotherapy within 28 days before enrollment.
9) Ages 20 and older (any gender).
10) Women of child bearing potential patients who agree to use 2 forms of effective contraception, where one form is highly effective (such as combined oral contraceptive), from study entry until at least 30 days after the last dose of study treatment and who have a negative pregnancy test within 7 days prior to enrollment. Women who are postmenopausal for at least 1 year (defined as cessation of menses for at least 1 year) or who are surgically sterilized do not require the test.
11) Patients who provide written informed consent based on free will after receiving sufficient explanation for the study.

Patients who meet any of the following criteria will be excluded from the study.
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 at least three years before enrollment and is considered to have not relapsed since then.
2) Patients on kidney dialysis.
3) Heart disease which falls into any of the following categories.
a) Heart failure of NYHA class 2 or higher.
b) Coronary artery disease with symptoms. History of myocardial infarction within 24 weeks prior to enrollment.
c) Arrhythmias that is uncontrolled by the treatment of antiarrhythmic drugs such as beta blocker and digoxin (CTCAE version 4.0 Grade 3 or higher).
d) Poorly controlled hypertension.
4) Severe and active infections (CTCAE version 4.0 Grade 3 orhigher).
5) History of HIV infection.
6) Portosystemic shunt with hepatic encephalopathy.
7) History of hepatic encephalopathy (Grade2 or higher).
8) Esophageal and gastric varices requiring treatment.
9) History of esophageal and gastric variceal bleeding.
10) Refractory ascites.
11) Patients with a history of gastrointestinal perforation or fistula within 6 months prior to enrollment.
12) Patients with a history of serious trauma or fracture within 6 months prior to enrollment.
13) Patients who have a serious or non-healing wound or ulcer within 28 days prior to the first dose of protocol therapy.
14) Detectable HBV-DNA without nucleic acid analog treatment.
15) Thromboembolism (cerebrovascular disorder including transient cerebral ischemic attack, deep vein thrombosis, pulmonary embolism etc.) within 6 months prior to enrollment.
16) Patients who use warfarin with therapeutic dose. Patients who have started treatment with or adjusted the dose of oral anticoagulants or low molecular weight heparin within 2 weeks of Ramucirumab administration.
17) Patients who are receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.
18) Patients who have a plan to undergo an operation during this study
19) Patients with the following medical history.
a) History of gastrointestinal bleeding which needs to be treated within 4 weeks prior to enrollment.
b) Medical history with invasive surgery within 4 weeks prior to enrollment.
c) History of homologous organ transplantation.
20) Pregnant or lactating woman; woman who plan or intend to become pregnant (In case of suspected pregnancy, pregnancy test should be conducted)
21) Possibility of allergic reaction to the study drug
22) Drug abuse. Health, psychological, social conditions that interfere with the participation of the study or evaluation of the results.
23) 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

Ramucirumab

Chemotherapy

Molecular targeted agent

013

Progression free survival ratio after six months

Overall survival (OS)
Progression free survival (PFS)
Time to progression (TTP)
Safety

+81-43-226-2616

Jan. 22, 2020

none