Clinical Trials /

Postoperative Immunotherapy vs Standard Chemotherapy for Gastric Cancer With High Risk for Recurrence

NCT03443856

Description:

The primary objective of the trial is to investigate if nivolumab plus ipilimumab given as adjuvant treatment improve disease free survival (DFS) in patients with stage Ib-IVa gastric and esophagogastric junction adenocarcinoma and high risk of recurrence (defined by ypN1-3 and/or R1 status) following neoadjuvant chemotherapy and resection. Other study objectives: - To investigate the safety and effect of adjuvant immunotherapy on long term oncologic outcomes and quality of life of patients in the study - To correlate nutritional status assessment on outcomes and quality of life of patients

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Postoperative Immunotherapy vs Standard Chemotherapy for Gastric Cancer With High Risk for Recurrence
  • Official Title: Adjuvant Immunotherapy in Patients With Resected Gastric Cancer Following Preoperative Chemotherapy With High Risk for Recurrence (N+ and/or R1): an Open Label Randomized Controlled Phase-2-study

Clinical Trial IDs

  • ORG STUDY ID: EORTC 1707-GITCG
  • SECONDARY ID: 2018-000406-36
  • NCT ID: NCT03443856

Conditions

  • Gastric and Esophagogastric Junction Adenocarcinoma

Interventions

DrugSynonymsArms
Nivolumab and Ipilimumabimmunotherapy arm

Purpose

The primary objective of the trial is to investigate if nivolumab plus ipilimumab given as adjuvant treatment improve disease free survival (DFS) in patients with stage Ib-IVa gastric and esophagogastric junction adenocarcinoma and high risk of recurrence (defined by ypN1-3 and/or R1 status) following neoadjuvant chemotherapy and resection. Other study objectives: - To investigate the safety and effect of adjuvant immunotherapy on long term oncologic outcomes and quality of life of patients in the study - To correlate nutritional status assessment on outcomes and quality of life of patients

Trial Arms

NameTypeDescriptionInterventions
chemotherapy armOtherCompletion of the perioperative treatment according to the 2016 ESMO guidelines (change of regimen is not allowed).
    immunotherapy armExperimentalTreatment: Nivolumab 1 mg/kg IV Q3W plus Ipilimumab 3 mg/kg IV Q3W for 4 cycles (3 months) followed by nivolumab 240 mg flat-dose IV Q2W for 9 months.Total treatment time 1 year. No chemotherapy.
    • Nivolumab and Ipilimumab

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Histologically proven gastric, lower esophageal or GE-junction adenocarcinoma (Siewert
                 I-III)
    
              -  Subjects must have completed pre-operative chemotherapy with a
                 fluoropyrimidine-platinum containing regimen and macroscopically complete surgery
                 prior to randomization
    
              -  Minimal duration of neoadjuvant chemotherapy should be 6 weeks, maximum 12 weeks.
    
              -  Total or distal gastrectomy with D2 lymphadenectomy according to ESMO guidelines
                 should have been completed for gastric and junctional Siewert type III cancers. Ivor
                 Lewis or McKeown oesophagectomy with two field lymphadenectomy should have been
                 performed for junctional Siewert type I cancers. For Siewert type II cancers either
                 total gastrectomy with D2-lymphadenectomy or oesophagectomy with two field
                 lymphadenectomy should have been completed. Open, minimal invasive or hybrid surgical
                 approaches are acceptable as long as the requirements above are fulfilled.
    
              -  Regardless of the type of surgery a minimum of 15 lymph nodes should have been
                 resected and examined.
    
              -  Recovered from surgery and fit for study treatment as assessed by a multidisciplinary
                 team. Ideally, surgery should have been completed 1 month before at the maximum.
    
              -  ypN1-3 status according to current (8th) version of TNM classification system. In case
                 of an ypN0 status patients must meet the inclusion criterion of R1 resection.
    
              -  R0 or R1 resection according to current (8th) version of TNM classification system. In
                 case of R0 resection, patients must meet the inclusion criterion of ypN1-3
    
              -  Availability of operative and pathology reports for review
    
              -  WHO performance status score of 0 or 1
    
              -  Age ≥ 18 years
    
              -  Adequate organ function assessed within 7 days before randomization:
    
              -  White blood cell count (WBC) > 2 x 109/L
    
              -  Absolute neutrophil count (ANC) > 1.5 x 109/L
    
              -  Platelets ≥ 100 x 109/L
    
              -  Hemoglobin ≥ 9 g/dL
    
              -  Measured/calculated creatinine clearance ≥ 60 mL/min (according to Cockroft-Gault
                 formula).
    
              -  Total bilirubin within normal limits (if the patient has documented Gilbert's disease
                 ≤ 1.5 * ULN or direct bilirubin ≤ ULN)
    
              -  Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5ULN
    
              -  All toxicities (exception alopecia) attributed to prior anti-cancer therapy must have
                 resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of study
                 drug.
    
              -  Availability of tumor tissue from the resected site of disease must be provided for
                 biobanking
    
              -  Women of childbearing potential (WOCBP*) must have a negative serum or urine pregnancy
                 test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
                 (HCG)) within 24 hours prior to randomization
    
              -  Patients of childbearing / reproductive potential should use highly effective method
                 of birth control measures during the study treatment period and for at least 5 months
                 after the last study treatment. A highly effective method of birth control is defined
                 as those which result in low failure rate (i.e. less than 1% per year) when used
                 consistently and correctly.
    
              -  Female subjects who are breast feeding should discontinue nursing prior to the first
                 dose of study treatment and until 5 months after the last study treatment.
    
              -  Absence of any psychological, familial, sociological or geographical condition
                 potentially hampering compliance with the study protocol and follow-up schedule; those
                 conditions should be discussed with the patient before registration in the trial
    
              -  Before patient registration/randomization, written informed consent must be given
                 according to ICH/GCP, and national/local regulations.
    
            Exclusion Criteria:
    
              -  R2 resection status
    
              -  M1 stage according to current (8th) version of TNM classification system
    
              -  Patients who have undergone complete resection of metastases
    
              -  Impaired renal, hepatic, cardiac, pulmonary or endocrine status that compromises the
                 eligibility of the patient for postoperative chemotherapy or immunotherapy
    
              -  Subjects with previous malignancies are excluded unless a complete remission or
                 complete resection was achieved at least 5 years prior to study entry. Adequately
                 treated cervical carcinoma in situ, and localized non-melanoma skin cancer are no
                 exclusion criteria, regardless of timepoint of diagnosis.
    
              -  Subjects with active, known, or suspected infectious or autoimmune disease
    
              -  Patients who have received antibiotics within the last 14 days before randomization
                 are excluded.
    
              -  Subjects with Type I diabetes mellitus, residual hypothyroidism due to autoimmune
                 thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo,
                 psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll
    
              -  Subjects with a condition requiring systemic treatment with either corticosteroids (≥
                 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14
                 days of study drug administration
    
              -  Subjects with interstitial lung disease that is symptomatic or may interfere with the
                 detection or management of suspected drug-related pulmonary toxicity
    
              -  Subjects with > Grade 1 peripheral neuropathy
    
              -  Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
                 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation
                 or immune checkpoint pathways
    
              -  Prior or concomitant treatment with radiotherapy/radiochemotherapy
    
              -  Any positive test result for HBV or HCV indicating acute or chronic infection
    
              -  Known history of testing positive for HIV or known AIDS
    
              -  Known uncontrollable hypersensitivity to the components of cisplatin/oxaliplatin,
                 fluorouracil (5-FU) or capecitabine, epirubicine or docetaxel
    
              -  Known dihydropyrimidine dehydrogenase (DPD) deficiency
    
              -  Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related
                 analogs, such as brivudine.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Disease free survival (DFS)
    Time Frame:22 months after last patient in
    Safety Issue:
    Description:Disease free survival is defined as the time interval between randomization and the date of disease recurrence or death from any cause, whichever comes first. Patients alive with no disease recurrence are censored at the date of the last follow-up examination. randomization and the date of disease recurrence or death from any cause, whichever comes first.

    Secondary Outcome Measures

    Measure:Overall survival (OS)
    Time Frame:5 years after last patient in
    Safety Issue:
    Description:Overall survival is defined as the time interval between the date of randomization and the date of death from any cause. Patients who are still alive when last traced are censored at the date of last follow up.
    Measure:Loco-regional failure rates
    Time Frame:5 years after last patient in
    Safety Issue:
    Description:Local recurrence is defined as evidence of tumor in the anastomotic area. Regional recurrence is defined as evidence of tumor in the locoregional lymph nodes or other surrounding structures apart from the anastomotic site. Death in absence of loco-regional failure will be considered as a competing risk in the estimation of the cumulative incidence of loco-regional failures. Patients who have not had any such event at the time of data analysis will be censored at the date of the last follow-up examination.
    Measure:Distant failure rates
    Time Frame:5 years after last patient in
    Safety Issue:
    Description:The diagnosis of distant recurrence requires imaging confirmed by pathology. Once recurrence is confirmed, the date of recurrence is the first date when recurrence was suspected. Distant recurrence is defined as recurrence not considered as local or regional.Death in absence of distant failure will be considered as a competing risk in the estimation of the cumulative incidence of distant failures. Patients who have not had any such event at the time of data analysis will be censored at the date of the last follow-up examination
    Measure:Rate of adverse events according to NCI-CTCAE
    Time Frame:5 years after last patient in
    Safety Issue:
    Description:All adverse events will be recorded; the investigator will assess whether those events are drug related (reasonable possibility, no reasonable possibility) and this assessment will be recorded in the database for all adverse events. AEs will be collected at baseline from randomization. Only the worst grade per CTCAE category will be recorded per cycle. All adverse events must be followed until resolution or stabilization. Adverse Events of Special Interest for ipilimumab and nivolumab requiring a close follow-up were identified as a result of signals observed from previous studies involving the protocol treatments. These events require a close follow-up
    Measure:Quality of life assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3
    Time Frame:questionnaires will be completed at baseline, week 6, 3 months, 6 months, 9 months, 12 months, 15 months
    Safety Issue:
    Description:Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. These include five functional scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health status/QoL scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). The primary HRQoL endpoints that are considered relevant for this study are global health status/QoL and physical functioning.A difference of 10 points on the 100-point QLQ-C30 scale between the two arms will be considered as clinically relevant

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

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