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An intergroup phase III trial of Ramucirumab plus Irinotecan in third or more line Beyond progression after Ramucirumab for Advanced Gastric cancer.(RINDBeRG trial) (RINDBeRG trial)

RINDBeRG trial (RINDBeRG trial)

402

402 patients were enrolled, and allocated to 202 in the ramucirumab plus irinotecan group and 200 in the irinotecan alone group. Baseline characteristics were almost well balanced assigned to both groups. The principal background factors in the ramucirumab plus irinotecan and irinotecan groups, respectively, were: median age = 68/68 years: male = 77%/79%: PS0 = 50%/52%: peritoneal dissemination = 39%/37%: duration of prior ramucirumab treatment > 3 months = 72%/72%: duration of prior ramucirumab treatment > 3 months = 72%/72% treatment pattern of previous ramucirumab administration Continuation of administration = 45% / 46%, Re-challenge 55% / 54%.

From February 22, 2017 to August 10, 2022, 402 patients were enrolled, allocated 202 to the ramucirumab plus irinotecan group and 200 to the irinotecan alone group. Due to the slower accrual pace than initially planned, the planned enrollment period had to be extended two times during the study. An interim analysis was performed when half of the 362 total planned events reached in April 2021, and the study was decided to be continued. At the end of the observation period, 3 patients were still on study treatment and 399 had discontinued study treatment. 11 patients had dropped out before starting study treatment. The primary reason for discontinuation was tumor progression in 324 patients (158 in the ramucirumab plus irinotecan arm vs. 166 in the irinotecan arm). Among all patients enrolled, By the data cutoff date (11, August 2023), with a median 8.9 months of follow-up for OS, 362 OS events (184 in the ramucirumab plus irinotecan arm vs. 178 in the irinotecan arm) were observed.

The common adverse events in the ramucirumab plus irinotecan and irinotecan groups were respectively as follows: White blood cell count decreased 133 (68.2%), 94 (48.0%) Neutropenia 149 (76.4%), 91 (46.7%) Hypoalbuminemia 99 (50.8%), 63 (32.1%) Increased AST 77 (39.5%), 58 (29.6%) Elevated ALT 60 (30.8%), 57 (29.1%) Anorexia 136 (69.7%), 120 (61.2%) Diarrhea 114 (58.5%), 90 (45.9%) Stomatitis 43 (22.1%), 16 (8.2%) Hypertension 23 (11.8%), 2 (1.0%) Infection 20 (10.3%), 15 (7.7%) Febrile neutropenia 8 (4.1%), 12 (6.1%) Treatment related death was observed in 1 case in the RAM+IRI arm and 2 cases in the IRI arm, all of which were pulmonary infections.

The analysis for overall survival, the primary endpoint, was conducted on the full set analysis population (FAS), excluding those who were found to have not met the study's eligibility criteria after enrollment. The median overall survival was 9.4 months in irinotecan plus ramucirumab group, and 8.5 months in irinotecan alone group, respectively. Adjusted hazard ratio (HR) by the stratification factors was 0.909 (95% confidence interval [CI] 0.738 - 1.119, p=0.369). Progression-free survival was 3.8 months and 2.8 months (HR 0.722, 95% CI 0.590 - 0.884, p=0.001), and objective response rate was 22.1% and 15.0%, respectively. In discussion, there was an additional benefit of ramucirumab in progression-free survival, but not in overall survival. This may be due to post-treatment chemotherapy given after completion of study treatment, which may have diluted the effect of the protocol treatment. Post-treatment was given in approximately 70% of cases in both groups. As noted above, some adverse events tended to occur more frequently in the ramucirumab combination arm, but the discontinuation of adverse events was similar, suggesting that the degree of adverse events had little impact on treatment outcome. The number of patients excluded from the FAS was about 5%, and there was no significant difference between the data from the analysis of all patients, so the impact on the efficacy data was considered to be small.

Although the addition of ramucirumab to irinotecan after disease progression of ramucirumab improved PFS and ORR, the primary endpoint of OS was not met. Some adverse events occurred more frequently in the ramucirumab combination arm, but the incidence of serious toxicities remained the same and the safety profile of ramucirumab plus irinotecan was similar to that previously reported, and were manageable.

May. 30, 2025

May. 23, 2025

https://ascopubs.org/doi/10.1200/JCO.24.01119

No

-

https://jrct.mhlw.go.jp/latest-detail/jRCTs051180187

SATOH Taroh

Osaka University Hospital

2-15, Yamadaoka, Suita City, Osaka Pref.

taroh@cfs.med.osaka-u.ac.jp

NISHIDA Naohiro

Osaka University Hospital

2-15, Yamadaoka, Suita City, Osaka Pref.

+81-6-6879-2641

nnishida@gesurg.med.osaka-u.ac.jp

Complete

Feb. 22, 2017

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1) Histopathologically confirmed adenocarcinoma of gastric or gastroesophageal junction (GEJ) with inoperable, locally advanced or metastatic disease, not amenable to curative therapy.
2) Documented objective radiographic or clinical disease progression directly after a ramucirumab-containing chemotherapy.
3) No previous history of IRI administration.
4) Neither tolerates nor responds to treatment with fluoropyrimidines, platinum, or taxanes.
*Does not respond is defined as: progression or recurrence of the tumor during chemotherapy or within 180 days after final chemotherapy.
**Does not tolerate is defined as: discontinuation of treatment due to safety reasons such as allergic reactions, neurotoxic or other toxic effects that delay recovery.
*** Patients without prior platinum, if the tumor recurs within 180 days after perioperative adjuvant chemotherapy such as S-1 monotherapy or S-1 / docetaxel, and then disease progression after a ramucirumab - containing chemotherapy, are eligible.
5)Has lesions that can be evaluated on CT or MRI images (measurable or non-measurable lesions according to RECIST ver. 1.1).
6)Age at enrollment =>20 years old.
7)ECOG performance status (PS) of 0 or 1 at study entry.
8)Oral intake is possible.
9)Adequate organ function, defined as no severe impairment of bone marrow, heart, lungs, liver or kidneys, and laboratory values at the start of treatment that meet the following criteria. (For enrollment, the most recent data within 14 days after the day of enrollment shall be used. The laboratory data of the day of enrollment shall be used as a reference. However, it is also possible to use the laboratory data that were obtained on the same weekday 2 weeks before.)
1.Absolute neutrophil count (ANC): =>1,500/mm3
2.Total bilirubin: =>8.5 g/dL
3.Platelet count: =>100,000/mm3
4.AST, ALT: =<100 IU/L (=<150 IU/L in patients with liver metastasis)
5.Total bilirubin: =<1.5 mg/dL
6.Serum creatinine: =<1.5 mg/dL, or creatinine clearance: =>40ml/min (estimated creatinine clearance rate using the Cockcroft-Gault formula or creatinine concentration measured after 24-hour urine collection)
7.Urinary protein: =<(1+) on dipstick or routine urinalysis or =>2 g/24 hours after 24-hour urine collection, or urinary protein/creatinine ratio <2
10)Life expectancy of at least 3 months.
11) Written informed consent obtained prior to any study-specific procedures.

1) History of another malignancy (simultaneous double cancers / multiple cancers and metachronous double cancers with a disease-free period of 5 years / multiple cancers; however, this does not include other malignancies / double cancers in carcinoma in situ that were judged to be curable by local treatment and intramucosal cancers).
2) Previous systemic chemotherapy with an angiogenesis inhibitor, except ramucirumab.
3) History of serious adverse events after treatment with RAM.
4) Uncontrolled arterial hypertension (e.g. =>150/90mmHg despite standard treatment).
5) Uncontrollable diarrhea that interferes with everyday activities even if receiving adequate treatment.
6) Undergoing anticoagulant therapy for the treatment of thromboembolism.
7) Local or systemic active infection that requires treatment (however, patients who are hepatitis B surface antigen (HBsAg) positive can also be enrolled if the disease can be controlled with a nucleic acid analogue and the patient was confirmed to be HBV-DNA negative).
8) Serious illness or medical condition(s) including, but not limited to the following: gastrointestinal bleeding, enteroparalysis, intestinal obstruction, interstitial pneumonitis, pulmonary fibrosis, symptomatic heart disease (including ischemic heart disease, myocardial infarction, and heart failure), renal failure, liver cirrhosis, glaucoma, uncontrollable diabetes mellitus, etc.
9) History of severe allergy or hypersensitivity to any drugs.
10) Transfusion treatment within 2 weeks prior to enrollment.
11) Moderate or large ascites or pleural effusion.
12) Continuous systemic steroid treatment.
13) Evidence of a psychological disorder that is judged to make it difficult to ensure the continuous use of the study drug.
14) Symptomatic evidence of known central nervous system metastases.
15) Daily treatment with atazanavir sulfate, which is incompatible with IRI.
16) Pregnant, possibly pregnant or breastfeeding, or unwilling to practice contraception during the study.
17) Duplicate in other interventional clinical studies.
18) Any condition that suggests that the patient is, in the investigator's opinion, not an appropriate candidate for the study.

Both

Gastric Cancer

Irinotecan alone group
IRI 150 mg/m2, day 1 q2w

Ramucirumab plus irinotecan group
RAM 8 mg/kg day1, q2w
IRI 150 mg/m2, day1, q2w

Overall survival

progression-free survival (PFS); time to treatment failure (TTF); response rate (RR); disease control rate (DCR); and adverse events (AEs)

+81-6-6210-8296

Feb. 04, 2019

None