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CompletedNCT03453164Updated Sep 19, 2024Results posted

Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer (CIRCUIT)

A Phase 1/2 interventional study of Radiotherapy and Nivolumab in Gastric Cancer, sponsored by Fukushima Medical University. Completed at 1 site in Japan. Open to participants aged 20 Years and older. Per ClinicalTrials.gov, last updated 2024-09-19.

Sponsored by Fukushima Medical University · Phase 1/2, Interventional, and Treatment

Phase
Phase 1/2
Study type
Interventional
Enrollment
41
Allocation
Not applicable
Ages
20 Years and older
Sex
All
01

Study summary

This study aims to evaluate safety and efficacy of nivolumab (anti-PD-1 antibody), which is approved as tertiary therapy, and neoadjuvant short-term limited local radiotherapy in patients with unresectable recurrent gastric cancer who progressed (intolerance or PD) after standard treatment (primary and secondary chemotherapy) and have more than one lesion assessable in diagnostic imaging (one lesion must be >=2cm).

Read the detailed description

In patients with unresectable recurrent gastric cancer who progressed (intolerance or PD) after standard treatment (primary and secondary chemotherapy) and have more than one lesion assessable in diagnostic imaging (one lesion must be >=2cm), localized short-term radiotherapy of 22.5 Gy/5 fractions/5 days is applied to a symptomatic lesion or the largest asymptomatic lesion suitable for irradiation (Day 1-5). Nivolumab is administered starting from Day 15-22 at a dose of 3 mg/kg (body wait) or 240 mg/body every 2 weeks to a total of 6 courses (end of intervention).

The patients are observed up to Day 180±14 and evaluated on Day 180±14 (end of study).

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Conditions studied

  • Gastric Cancer

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Keywords

  • Radiotherapy
  • anti-PD-1 antibody
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Who can participate

Ages eligible
20 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Unresectable advance or recurrent GC with intolerance or progression after standard treatment (primary and secondary chemotherapy).
  2. More than one measurable lesion defined by RECIST guideline version 1.1 in diagnostic imaging (whole-body contrast-enhanced CT or PET-CT) within 14 days before entry, with at least one lesion >=2 cm.
  3. Age: 20 =\<
  4. ECOG performance status (PS): 0-2
  5. No contraindication for nivolumab (anti-PD-1 antibody) administration.
  6. No contraindication for radiotherapy.
  7. The most recent laboratory results within 14 days before study entry fulfill the following: WBC ≥3000/μl, neutrophil ≥1500/μl, hemoglobin ≥9.0g/dl, platelets ≥100,000/μl, total bilirubin ≤2.0 times the institutional standard upper limit (ISUL), AST (GOT) and ALT (GPT) ≤3.0 times ISUL (in case with liver metastasis, ≤5.0 times ISUL), serum creatinine ≤1.5 times ISUL or creatinine clearance ≥ 60 ml/min calculated with cockcroft-Gault equation.
  8. Expected survival >=3 months.
  9. Written informed consent is obtained from the patient prior to study enrollment.

Exclusion criteria

Exclusion Criteria:

  1. No tumor lesions that can be irradiated.
  2. Metachronous and simultaneous overlapping cancers (excluding intraepithelial cancer of the uterine cervix, fully treated basal cell carcinoma of the skin, and malignant tumors that were treated more than 5 years ago and have not recurred).
  3. A history of severe hypersensitivity reactions to other Ab products.
  4. Taking immunosuppressive drugs or corticosteroids (prednisone or prednisolone equivalent ≥ 15 mg/day).
  5. Active autoimmune diseases or a history of recurrent autoimmune diseases (patients with type-1 diabetes, hypothyroid controllable by hormone replacement therapy, and dermatosis without the need for systemic therapy are eligible).
  6. Complications or history of interstitial pneumonia or pulmonary fibrosis diagnosed by imaging studies or clinical findings.
  7. Presence of severe disease or medical conditions: severe nutritional deficiencies, transient ischemic attack within 180 days prior to enrollment, cerebral vascular attack within 180 days prior to enrollment, thrombus or thromboembolism within 180 days prior to enrollment, congestive heart failure (NYHA class III or IV), unstable angina, myocardial infarction within 12 months, severe arrhythmias requiring medication, conduction abnormalities such as AV block beyond the second degree, uncontrollable hypertension, liver cirrhosis (Child Class B or higher), mental disorders that may interfere with compliance with this study protocol, unstable diabetes, uncontrolled pericardial fluid, uncontrolled ascites, uncontrolled pleural effusions, diseases requiring anticoagulation therapy (excluding antiplatelet therapy including low-dose aspirin), and systemic infection with treatment.
  8. Pregnant or lactating female.
  9. Fertile female who are unwilling to use contraception.
  10. Fertile male who are not willing to use contraception during study drug administration and for 7 months after study completion (if the partners are fertile females).
  11. Prohibited previous treatment: within 56 days of registration; radioactive drugs (except radiopharmaceuticals for examination or diagnostic purposes), within 28 days of registration; corticosteroids (excluding temporary use and predonine or prednisolone equivalent ≤15 mg/day), immunosuppressant drugs, anti-cancer drugs, adhesive treatment of pleura or pericardium, surgery with general anesthesia, and unapproved drugs, within 14 days of registration; surgery with local or superficial anesthesia.
  12. Participating in other clinical trials or clinical studies (excludes those without intervention).
  13. A positive HIV antigen/Ab test or HTLV-1 Ab test.
  14. History of treatment using ONO-4538, anti-PD-1 Ab, anti-PD-L1 Ab, anti-PD-L2 Ab, anti-CD137 Ab, anti-CTLA-4 Ab, or other Ab or drug therapies for T-cell regulation.
  15. Determined by the investigator to be ineligible for participation in this study.
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Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
41 participants (actual)

Study arms

  • Experimental
    Radiotherapy + Nivolumab

    Localized short-term radiotherapy (22.5 Gy/5 fractions/5 days, Day 1-5) + nivolumab (starting on Day 15-22, a dose of 3 mg/kg (body weight) or 240 mg/body, every 2 weeks to a total of 6 courses)

    Radiation: Radiotherapy · Drug: Nivolumab

Interventions

  • RadiationRadiotherapy

    Radiotherapy of 22.5 Gy/5 fractions/5 days was given to a symptomatic lesion or the largest asymptomatic lesion suitable for irradiation from Day 1.

  • DrugNivolumab

    Nivolumab was administered intravenously starting on Day 15-22 at a dose of 3 mg/kg (body weight) or 240 mg/body every 2 weeks to a total of 6 courses of administration.

    Also known as: Opdivo

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What researchers measure

Primary outcomes

  1. Disease Control Rate

    Analysis item: Disease control rate of non-irradiated target lesions. The rate of patients with a best overall response of stable disease (SD) or better confirmed by 180 days, starting from the start date of radiotherapy. The RECIST Guidelines Version 1.1 was used to determine overall response such as complete response (CR), partial response (PR), SD, and progressive disease (PD) at each imaging time. If imaging is not available, the patient is considered deficient (NE).

    Time frame: 6 months

Secondary outcomes

  1. Median Survival Time

    Overall survival is defined as the period from the start date of radiotherapy until the date of death from any cause or date of last documented survival. In surviving cases, the last date of confirmation of survival is the date of termination. Untraceable cases are terminated on the last date of confirmed survival before the loss of follow-up. At the end of the study period, all enrolled cases are confirmed alive.

    Time frame: From the start date of radiotherapy until the date of death from any cause or date of last documented survival, assessed up to approximately 31 months.

  2. Safety (Grade and Frequency of Adverse Events)

    The frequency of adverse events from all enrolled cases is tabulated by adverse event name and worst grade according to CTCAE ver.4.0. All adverse events are summarized without regard to causal relationships to the study treatment. The frequency and rate of grade 3 or higher adverse events are calculated.

    Time frame: Adverse events were monitored from the start date of radiotherapy until the end of study protocol or death from any cause, and were assessed up to approximately 6 months. All-Cause Mortality was assessed up to approximately 31 months.

  3. Local Control Rate

    Analysis item: Disease control rate of irradiated target lesions. The rate of patients with a best overall response of SD or better confirmed by 180 days, starting from the start date of radiotherapy. The RECIST Guidelines Version 1.1 was used to determine overall response such as CR, PR, SD, and PD at each imaging time. If imaging is not available, the patient is considered NE.

    Time frame: 6 months

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Results

Posted Sep 19, 2024

Participant flow

Participant flow — Overall Study
MilestoneRadiotherapy + Nivolumab
Started41
Completed22
Not completed19
Withdrew: Lack of efficacy16
Withdrew: 3 cases did not meet the criteria for nivolumab initiation.3

Outcome measures

PrimaryDisease Control Rate

Analysis item: Disease control rate of non-irradiated target lesions. The rate of patients with a best overall response of stable disease (SD) or better confirmed by 180 days, starting from the start date of radiotherapy. The RECIST Guidelines Version 1.1 was used to determine overall response such as complete response (CR), partial response (PR), SD, and progressive disease (PD) at each imaging time. If imaging is not available, the patient is considered deficient (NE).

Time frame:
6 months
Reported as:
Count of participants · Participants
Disease Control Rate
ParticipantsRadiotherapy + Nivolumab
Disease Control Rate9
SecondaryMedian Survival Time

Overall survival is defined as the period from the start date of radiotherapy until the date of death from any cause or date of last documented survival. In surviving cases, the last date of confirmation of survival is the date of termination. Untraceable cases are terminated on the last date of confirmed survival before the loss of follow-up. At the end of the study period, all enrolled cases are confirmed alive.

Time frame:
From the start date of radiotherapy until the date of death from any cause or date of last documented survival, assessed up to approximately 31 months.
Reported as:
Median · Days
Median Survival Time
DaysRadiotherapy + Nivolumab
Median Survival Time230 (157 to 330)
SecondarySafety (Grade and Frequency of Adverse Events)

The frequency of adverse events from all enrolled cases is tabulated by adverse event name and worst grade according to CTCAE ver.4.0. All adverse events are summarized without regard to causal relationships to the study treatment. The frequency and rate of grade 3 or higher adverse events are calculated.

Time frame:
Adverse events were monitored from the start date of radiotherapy until the end of study protocol or death from any cause, and were assessed up to approximately 6 months. All-Cause Mortality was assessed up to approximately 31 months.
Reported as:
Count of participants · Participants
Safety (Grade and Frequency of Adverse Events)
ParticipantsRadiotherapy + Nivolumab
Anemia8
Anorexia5
Tumor pain3
Dehydration2
Nausea2
Alkaline phosphatase increased1
Blood bilirubin increased1
Cholecystitis1
Dyspnea1
Febrile neutropenia1
Fever1
Gastric hemorrhage1
Hyperglycemia1
Hyperkalemia1
Hyperuricemia1
Hypoalbuminemia1
Hyponatremia1
Ileus1
Platelet count decreased1
Proteinuria1
Supraventricular tachycardia1
White blood cell decreased1
Lung infection1
SecondaryLocal Control Rate

Analysis item: Disease control rate of irradiated target lesions. The rate of patients with a best overall response of SD or better confirmed by 180 days, starting from the start date of radiotherapy. The RECIST Guidelines Version 1.1 was used to determine overall response such as CR, PR, SD, and PD at each imaging time. If imaging is not available, the patient is considered NE.

Time frame:
6 months
Reported as:
Count of participants · Participants
Local Control Rate
ParticipantsRadiotherapy + Nivolumab
Local Control Rate16

Adverse events

Collected over Adverse events were monitored from the start date of radiotherapy until the end of study protocol or death from any cause, and were assessed up to approximately 6 months. All-Cause Mortality was assessed up to approximately 31 months.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Radiotherapy + Nivolumab28/41 (68.3%)16/41 (39%)19/41 (46.3%)
Most frequent serious events
Showing 10 of 23
Most frequent serious events
EventRadiotherapy + Nivolumab
AnemiaBlood and lymphatic system disorders8/41
AnorexiaMetabolism and nutrition disorders5/41
Tumor painNeoplasms benign, malignant and unspecified (incl cysts and polyps)3/41
DehydrationMetabolism and nutrition disorders2/41
NauseaGastrointestinal disorders2/41
Alkaline phosphatase increasedInvestigations1/41
Blood bilirubin increasedInvestigations1/41
CholecystitisHepatobiliary disorders1/41
DyspneaRespiratory, thoracic and mediastinal disorders1/41
Febrile neutropeniaBlood and lymphatic system disorders1/41
Most frequent other events
Showing 10 of 12
Most frequent other events
EventRadiotherapy + Nivolumab
FatigueGeneral disorders9/41
Aspartate aminotransferase increasedInvestigations8/41
HypocalcemiaMetabolism and nutrition disorders8/41
PruritusSkin and subcutaneous tissue disorders6/41
VomitingGastrointestinal disorders6/41
Alanine aminotransferase increasedInvestigations5/41
ConstipationGastrointestinal disorders5/41
Edema limbsGeneral disorders5/41
Peripheral sensory neuropathyNervous system disorders5/41
Creatinine increasedInvestigations4/41

Baseline characteristics

A total of 41 patients enrolled in this study were subjected to the safety analysis, and 40 patients, excluding one ineligible patient (72 years old, male), were subjected to the efficacy analysis.

Age, Continuous
Age, Continuous(years)Radiotherapy + Nivolumab
Median70 (36 to 86)
Sex: Female, Male
Sex: Female, Male(Participants)Radiotherapy + Nivolumab
Female7
Male34
Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)Radiotherapy + Nivolumab
Eligible patients
Eligible patients(Participants)Radiotherapy + Nivolumab
Count of participants40
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Study locations

1 site
  • Fukushima Medical University Hospital
    Fukushima, 960-1295, Japan
08

References and documents

Publications

  • Suzuki Y, Mimura K, Yoshimoto Y, Watanabe M, Ohkubo Y, Izawa S, Murata K, Fujii H, Nakano T, Kono K. Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Res. 2012 Aug 15;72(16):3967-76. doi: 10.1158/0008-5472.CAN-12-0851. Epub 2012 Jun 14. PubMed 22700877 ↗
  • Yoshimoto Y, Suzuki Y, Mimura K, Ando K, Oike T, Sato H, Okonogi N, Maruyama T, Izawa S, Noda SE, Fujii H, Kono K, Nakano T. Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model. PLoS One. 2014 Mar 31;9(3):e92572. doi: 10.1371/journal.pone.0092572. eCollection 2014. PubMed 24686897 ↗
  • Sato H, Suzuki Y, Yoshimoto Y, Noda SE, Murata K, Takakusagi Y, Okazaki A, Sekihara T, Nakano T. An abscopal effect in a case of concomitant treatment of locally and peritoneally recurrent gastric cancer using adoptive T-cell immunotherapy and radiotherapy. Clin Case Rep. 2017 Feb 15;5(4):380-384. doi: 10.1002/ccr3.758. eCollection 2017 Apr. PubMed 28396751 ↗
  • Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. doi: 10.1016/S0140-6736(17)31827-5. Epub 2017 Oct 6. PubMed 28993052 ↗

Study documents

  • Study protocol · Sep 20, 2017
  • Statistical analysis plan · Jan 31, 2020
  • Informed consent form · Nov 13, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

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Registry details

Key details

Study ID
NCT03453164
Lead sponsor
Fukushima Medical University
Responsible party
Koji Kono (Professor, Fukushima Medical University) — Principal investigator
First posted
Mar 5, 2018
Start date
Mar 28, 2018
Primary completion
Jan 7, 2021
Completion
Jan 31, 2021
Results posted
Sep 19, 2024
Last update
Sep 19, 2024

Study contacts

Koji Kono, Professor
principal investigator · Fukushima Medical University Hospital

Oversight

FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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