2023-506291-28-00RecruitingPhase 3
CIME - Combination of Immune checkpoint in locally advanced or metastatic MSI/dMMR Esogastric adenocarcinomas : A multicenter, randomised, comparative, open-label Phase III aiming to compare the survival of patients with locally advanced or metastatic MSI/dMMR Esogastric adenocarcinomas treated by a combination of Immune checkpoint inhibitors (botensilimab + balstilimab) versus the standard of care (FOLFOX/XELOX + nivolumab)
Trial Snapshot
- Phase
- Phase 3
- Status
- Recruiting
- Sponsor
- Centre Leon Berard
- Enrollment
- 124
- Locations
- 9
- Primary Endpoint
- Overall Survival
Study Overview
Brief Summary
To compare the survival of patients under Botensilimab + Balstilimab versus the standard of care FOLFOX/XELOX + nivolumab
Study Design
- Allocation
- Randomized
- Primary Purpose
- Overal study period
- Masking
- None
Eligibility Criteria
- Ages
- 18 years to 65+ years (65+ Years, 18-64 Years)
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male or female patient ≥18 years of age at time of informed consent form signature
- •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 of protocol
- •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
- •Patient with MSI-H/dMMR HER2 negative advanced 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. Note - adjuvant or neoadjuvant chemotherapy is allowed providing that 6 months have elapsed 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
- •Patient with PS ECOG 0 or 1
- •Adequate hematologic and end-organ function, defined by the following laboratory test results (cf. protocol)
- •Availability of a representative formalin-fixed paraffin-embedded (FFPE) sample of the primary or metastatic tumor tissue (resection or biopsy) with an associated pathology report must be available. This tumor sample must meet the following quality/quantity control criteria: ≥30 % of tumor cells and a tumor surface area ≥ 5mm2 or biopsable disease
- •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
Exclusion Criteria
- •Oesogastric cancer eligible to treatment with curative intent
- •Any evidence of current interstitial lung disease (ILD) or pneumonitis, or prior history 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 C1D
- •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).
- •Patients previously treated by anti-PD-1, anti-PD-L1, or anti-CTLA-4 or any other immunotherapy
- •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 C1D
- •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.
- •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 I
- •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.
- •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.
Outcomes
Primary Outcomes
Overall Survival
Overall Survival
Secondary Outcomes
- PFS, Objective response rate after 16 weeks of treatment (ORR-16W) and duration of response (DoR) as per RECIST V1.1
- Adverse events (AEs), drugs related AEs, drugs related AE leading to dose reduction or discontinuation during treatment, SAE and SUSAR, immune-related AE graded according to NCI-CTCAE V5.0.
- Patient quality of life according to EORTC QLQC30 and items selected form the PRO CTC-AE
- Translational program : TMB on tumor sample and ctDNA ; RNASeq and WES on pre and on-treatment tumor samples ; multi-IF or IHC (eg but not limited to PD-L1, TIGIT, LAG3, TIM3)
Investigators
Medical oncology doctor
Scientific
Centre Leon Berard
Study Sites (9)
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