Combination of Immune Checkpoint in Locally Advanced or Metastatic MSI/dMMR Esogastric Adenocarcinomas

NCT ID: NCT06346197

Last Updated: 2025-12-26

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 132 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-08
• Study Completion Date: 2028-05-15

Brief Summary

CIME is a multicenter, randomised, comparative, open-label phase III study aiming to compare the survival of patients suffering from MSI-H/dMMR locally advanced or metastatic oeasogastric adenocarcinoma treated by a bi-immunotherapy (experimental arm) versus standard current treatment (FOLFOX/XELOX + nivolumab : standard arm).

Conditions

Gastric Cancer; MSI-H; Metastatic Cancer; Advanced Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental arm

Patients treated with Botensilimab + Balstilimab

Group Type: EXPERIMENTAL

Balstilimab

Intervention Type: DRUG

Balstilimab: 240mg, IV, Q2W, until disease progression, unacceptable toxicity, patient or investigator decision or up to 2 years.

Botensilimab

Intervention Type: DRUG

Botensilimab: 75mg, IV for up to 4 doses, Q6W until disease progression, unacceptable toxicity, patient or investigator decision or up to 2 years.

Standard arm

o FOLFOX*, IV, Q2W + Nivolumab 240mg, IV, Q2. *FOLFOX = oxaliplatin 85 mg/m2 , leucovorin 400 mg/m2 , and fluorouracil 400 mg/m2 administered IV on Day 1 of each treatment cycle, and fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily or per local standard on Days 1 and 2 of each treatment cycle, every 2 weeks. Premedication is not usually required in the first cycle. For subsequent cycles, adequate premedication may be administrated per local standard.

OR

• XELOX*, IV, Q3W + Nivolumab (360 mg, IV, Q3W). XELOX = Oxaliplatin 130mg/m² IV on Day 1 of each treatment cycle + capecitabine 1000mg/m² orally twice daily on Days 1 to 14 of each treatment cycle, every 3 weeks
• Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Group Type: ACTIVE_COMPARATOR

Folfox Protocol

Intervention Type: DRUG

oxaliplatin 85 mg/m2 , leucovorin 400 mg/m2 , and fluorouracil 400 mg/m2 administered IV on Day 1 of each treatment cycle, and fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily or per local standard on Days 1 and 2 of each treatment cycle, every 2 weeks.Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

XELOX

Intervention Type: DRUG

Oxaliplatin 130mg/m² IV on Day 1 of each treatment cycle + capecitabine 1000mg/m² orally twice daily on Days 1 to 14 of each treatment cycle, every 3 weeks. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Nivolumab

Intervention Type: DRUG

240mg, IV, Q2. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Interventions

Balstilimab

Balstilimab: 240mg, IV, Q2W, until disease progression, unacceptable toxicity, patient or investigator decision or up to 2 years.

Intervention Type: DRUG

Botensilimab

Botensilimab: 75mg, IV for up to 4 doses, Q6W until disease progression, unacceptable toxicity, patient or investigator decision or up to 2 years.

Intervention Type: DRUG

Folfox Protocol

oxaliplatin 85 mg/m2 , leucovorin 400 mg/m2 , and fluorouracil 400 mg/m2 administered IV on Day 1 of each treatment cycle, and fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily or per local standard on Days 1 and 2 of each treatment cycle, every 2 weeks.Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Intervention Type: DRUG

XELOX

Oxaliplatin 130mg/m² IV on Day 1 of each treatment cycle + capecitabine 1000mg/m² orally twice daily on Days 1 to 14 of each treatment cycle, every 3 weeks. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Intervention Type: DRUG

Nivolumab

240mg, IV, Q2. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female patient ≥18 years of age at time of informed consent form signature.
• Patient with MSI-H/dMMR, HER2 negativeadvanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD-L1 with a combined positive score (CPS) ≥ 5.
• Patient to be treated with a first line therapy for locally advanced/metastatic disease.
• No prior treatment with chemotherapy for locally advanced/metastatic disease.

o Note - adjuvant or neoadjuvant chemotherapy is allowed providing that 6 months have relapsed between completion of adjuvant chemotherapy and recurrence.

• Measurable disease (outside any previous irradiated field within the past 6 months) defined as at least one unidimensional lesion that can be accurately measured as ≥ 10 mm with CT scan according to RECIST V1.1 (Appendix 01).

• Note: Lesions intended to be biopsied should not be defined as target lesions.
• Note: previously irradiated lesions can be selected as target lesion only if recurrence/PD is documented after RT.
• Patient with PS ECOG 0 or 1 (Appendix 02).
• Adequate hematologic and end-organ function, defined by the following laboratory test results:

Absolute neutrophil count ≥ 1.5 109/L (without growth factor support within 14 d) Platelets ≥ 100 109/L (without transfusion for platelets within 7 d) Hemoglobin ≥ 9 g/dL (without transfusion within 7 d) Creatinine clearance according to CKD-EPI ≥ 30 mL/min/1.73 m2 Serum total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3 x ULN is acceptable) ASAT and ALAT ≤ 3 x ULN (or up to 5 x ULN in case of liver metastasis or hepatic infiltration)

• Tumor lesion visible by medical imaging and accessible to repeatable percutaneous or endoscopic sampling that permits core needle biopsy without unacceptable risk of a significant procedural complications, and suitable for retrieval of a minimum of 4 cores with a needle minimum diameter :16-gauge.

• Note 1: Fine needle aspirates, bone biopsies do not satisfy the requirement for tumor tissue.
• Note 2: Tumor lesions used for biopsy should not be lesions used as RECIST 1.1 target lesions unless there are no other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy, the lesion must be ≥ 2 cm in longest diameter.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the Screening Visit (within 72 hours of first dose of study drugs) and must agree to use highly effective contraceptive measures starting with the Screening Visit through

• 9 months after the end of the treatment with oxaliplatin
• 6 months after the end of the treatment with fluorouracil
• 5 months after the end of the treatment with nivolumab or botensilimab or Balstilimab
• 6 months for capecitabine

• Highly effective contraception is defined in Appendix 03.

Note Non-childbearing potential is defined as:

1. ≥ 50 years of age and has not had menses for greater than 1 year.

2. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.

3. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation.

• Male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the screening visit through 6 months after the end of the treatment with oxaliplatine or 3 months after the last dose for other study treatments is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
• Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed and should be able and willing to comply with study visits and procedures as per protocol.
• Patients must be covered by a medical insurance.

Exclusion Criteria

• Oesogastric cancer eligible to treatment with curative intent
• Patients previously treated by anti-PD-1, anti-PD-L1, or anti-CTLA-4 or any other immunotherapy
• Patients with surgery or radiotherapy within less than 4 weeks before C1D1
• Patients with persistent AE Grade >1 related to previous anti-cancer treatment, except alopecia (all grades), laboratory value according to criteria I7.
• Patients with: hypokalemia, hypomagnesemia, hypocalcemia less than normal
• Patients with known prolongation QT/QTc interval i.e. QT/QTc interval longer than 450 msec for men and longer than 470 msec for women according to the inclusion ECG.
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

Note: Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:

• Measurable disease, per RECIST v1.1, must be present outside the CNS.
• The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
• Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
• There is no evidence of interim progression between completion of CNS-directed therapy and initiation of study treatment.
• The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, neurosurgical resection within 21 days prior to initiation of study treatment.
• The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anticonvulsant therapy at a stable dose is permitted. A minimal wash-out period of 10days for corticosteroids is required.

• Patients with other malignancy unless this malignancy is not expected to interfere with the evaluation of study endpoints (basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, localized prostate cancer), or with no evidence of disease for ≥ 2 years.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• of ILD or non-infectious pneumonitis requiring glucocorticoids.
• History of allogeneic organ transplant.
• Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Patient with peripheral sensory neuropathy with functional impairment.
• Patients with clinically significant active heart disease or myocardial infarction within 6 months, history of uncontrolled or symptomatic cardiac disease.
• Patient with recent (within 7d before C1D1) or concomitant treatment with brivudine.
• Patient with complete absence of dihydropyrimidine dehydrogenase (DPD) activity (blood uracil level ≥ 150 ng/mL) or partial deficit in DPD (i.e. blood uracil level between ≥ 16 ng/ml and < 150 ng/mL)
• Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses (≤ 10 mg daily prednisone equivalent) are permitted in the absence of active autoimmune disease.
• Patient with Live vaccines injection within 4 weeks before C1D1. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever and BCG. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs).
• History or current evidence of any condition, co-morbidity, therapy, any active infections, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
• Patients with documented:
• Active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) unless their HBV is stably controlled on nucleoside analogs (eg entecavir or tenofovir) which will be continued for the duration of the study. Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to C1D1.
• Active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA, or
• HIV infection

• Prior organ or bone marrow transplant.
• Pregnant or lactating women.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Agenus Inc.

INDUSTRY

Sponsor Role: collaborator

Centre Leon Berard

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Centre Léon Bérard

Lyon, , France

Site Status: RECRUITING

Institut Paoli Calmettes

Marseille, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Christelle DE LA FOUCHARDIERE, MD

Role: CONTACT

Phone: 04 91 22 35 03

Email: delafouchardierec@ipc.unicancer.fr

Facility Contacts

Clélia COUTZAC, MD

Role: primary

Christelle DE LA FOUCHARDIERE, MD

Role: primary

Other Identifiers

ET23-185

Identifier Type: -

Identifier Source: org_study_id