| Eligibility |
Inclusion Criteria:
The patient is eligible to be included in the study only if all of the following criteria
apply:
1. Patients must have dated and signed an approved written informed consent form. This
must be obtained before the performance of any protocol-related procedures that are
not part of normal patient care.
2. Patients must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests and other requirements of the study,
Target Population
3. Inoperable, advanced, or metastatic gastric cancer or gastroesophageal junction or
distal esophageal carcinoma and histologically confirmed predominant adenocarcinoma,
4. Expression of PD-L1 with a combined positive score (PD-L1 CPS) =5, Note: information
must be available at the time of inclusion, the examination will be performed locally
in the center and secondarily confirmed centrally,
5. No prior systemic cancer treatment given as primary therapy for advanced nonresectable
or metastatic disease, Nota bene (NB): if patient received neoadjuvant/adjuvant
therapy, this therapy should be completed at least 6 months prior to the diagnosis of
metastatic or recurrent disease is made. Palliative radiotherapy is allowed and must
be completed 2 weeks prior to randomization,
6. At least one measurable lesion as assessed by computed tomography (CT)-scan or
magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid
Tumors (RECIST) v 1.1 and feasibility of repeated radiological assessments;
radiographic tumor assessment should be performed within 28 days prior to
randomization,
7. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1,
8. Adequate hematologic and end-organ function, defined by the following laboratory test
results, obtained within 14 days prior to randomization of study treatment:
1. White blood cell = 2000/µL;
2. Neutrophils = 2000/µL;
3. Platelets = 100.000/µL;
4. Hemoglobin = 9.0 g/dL;
5. Serum albumin = 30 g/L;
6. Serum creatinine level = 150 µM and calculated creatinine clearance
(Cockcroft-Gault) > 50 mL/minute,
7. Total bilirubin = 1.5 x upper normal limit (ULN);
8. Alanine aminotransferase (ALT) = 3.0 x ULN (or = 5.0 x ULN if liver metastases
are present);
9. Aspartame aminotransferase (AST) = 3.0 x ULN (or = 5.0 x ULN if liver metastases
are present);
10. Potassium = 1.0 x lower limit of normal (LLN),
11. Magnesium = 1.0 x LLN,
12. Calcium = 1.0 x LLN,
9. Baseline-corrected QT interval = 450 msec for males and = 470 msec for females,
10. Availability of a representative tumor tissue specimen for exploratory translational
research; tumor tissue samples, either formalin-fixed paraffin-embedded (FFPE) tissue
block or unstained tumor tissue sections (minimum of 20 positively charged slides)
from primary or metastatic site must be submitted to the central laboratory,
11. Registration in a national health care system (PUMa-Protection Universelle Maladie
included.
Age and reproductive status
12. Age = 18 years,
13. Women must not be pregnant, breastfeeding, or expecting to conceive during the study,
14. Reproductive status:
1. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 72 hours prior to the start of study drug,
2. WOCBP must agree to use an adequate method of contraception or birth control for
the duration of study treatment and 5 months (nivolumab), 9 months (oxaliplatin),
6 months (5-FU) or at least 1 month (EXL01) of the patient's last dose of the
study drug,
3. Males who are fertile and sexually active with WOCBP must agree to follow
instructions for method(s) of contraception for the duration of study treatment
and 6 months (nivolumab, oxaliplatin, or 5-FU) or at least 1 month (EXL01) after
the last dose of study treatment. In addition, males must be willing to refrain
from sperm donation during this time,
Exclusion Criteria:
The patient is ineligible for the study if any of the following criteria apply:
Target Disease Exceptions
1. Known HER-2 positive status or unknown HER-2 status before inclusion,
2. Active brain metastases or known history of leptomeningeal carcinomatosis,
3. Ascites, which cannot be controlled with appropriate interventions,
Exclusion criteria related to medical history and concurrent disease
4. Prior malignancy active within the previous 3 years except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast,
5. Active, known, or suspected autoimmune disease; type I diabetes mellitus,
hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo,
psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected
to recur in the absence of an external trigger are permitted,
6. Interstitial lung disease that is symptomatic or may interfere with the detection or
management of suspected treatment-related pulmonary toxicity,
7. Prior treatment with an anti-PD(L)1, anti-LAG-3, or anti-CTLA-4 antibody, or any other
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory
antitumor agents,
8. Condition requiring systemic treatment with either corticosteroids (>10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days (2 weeks)
of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses
>10 mg daily prednisone equivalent, are permitted prior to randomization in the
absence of active autoimmune disease,
9. Persistence of toxicity (The National Cancer Institute Common Terminology Criteria for
Adverse Event [NCI CTCAE] v 5.0) grade >1 related to prior anticancer treatments,
10. Major surgery within 28 days (4 weeks) prior to first dose of study treatment,
11. Concomitant unplanned antitumor therapy (e.g., chemotherapy, molecular targeted
therapy, radiotherapy, immunotherapy),
Exclusion criteria related to EXL01
12. GI obstruction, poor oral intake, or difficulty in taking oral medication or
difficulties in swallowing; nasogastric tubes are not permitted,
13. Known GI malabsorption,
14. Is currently participating in or has participated in a study with an investigational
compound within 28 days prior to the first dose of study treatment, NB: Participants
who have entered the follow-up phase of an investigational study may participate so
long as it has been at least 3 months since the last dose of the previous
investigational agent,
15. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
16. Fecal microbiota transplant within 3 months prior to screening, Note: Patients must
have recovered adequately from the toxicity and/or complications from the treatment
prior to starting study intervention.
17. Current probiotics administration, or planned probiotics administration during
treatment course is not allowed,
NB: The following therapies should be avoided during the study; however, they are not
prohibited if, in the assessment of the Investigator, they are required for clinical
management:
- Nonsteroidal anti-inflammatories,
- Antacids,
- Proton-pump inhibitors.
18. Excessive alcohol intake: moderate consumption, defined as no more than 1 drink per
day for women and no more than 2 drinks per day for men, is permitted,
19. Known allergy and/or hypersensitivity to any component or excipients of study
treatments (nivolumab, EXL01), any other live pro-biotherapeutic product, and/or to
soybean or soy-containing products,
20. Known history or newly diagnosed GI parasitic infection within 3 months prior to
screening, NB: Patients must have recovered adequately from the toxicity and/or
complications from the treatment prior to starting study intervention,
21. Active inflammatory intestinal disease (Crohn disease, Hemorrhagic recto-colitis,
coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea,
or other inflammatory disease requiring anti-inflammatory medications (according to
exclusion criteria n°8),
Exclusion criteria related to chemotherapy
22. Active or chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and/or human
immunodeficiency virus infection (HIV 1/2 antibodies). Participants are eligible if
they:
- Have controlled HCV load defined as undetectable hepatitis C RNA by polymerase
chain reaction either spontaneously or in response to a successful prior course
of anti-hepatitis C therapy,
- Have received HBV vaccination with only anti-HBs positivity and no clinical signs
of hepatitis,
- Are HBV surface antigen (HBsAg)- and anti- Hepatitis B core antibody (HBc)+
(i.e., those who have cleared HBV after infection),
- Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet
conditions below:
- HBV DNA viral load <100 IU/mL,
- Have normal transaminase values, or, if liver metastases are present,
abnormal transaminases, with a result of AST/ALT <3 × ULN, which are not
attributable to HBV infection,
- Start or maintain antiviral treatment if clinically indicated as per the
investigator,
23. Any (attenuated) live vaccine use within 28 days (4 weeks) prior to randomization,
while in the study; live vaccines include, but are not limited to, the following:
yellow fever, varicella, shingles, measles, mumps, rubella, tuberculosis, rotavirus,
influenza,
24. Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related
analogs, such as brivudine,
25. Dihydropyrimidine dehydrogenase deficiency (DPD; uracilemia dosage >16 ng/ml),
Uracilemia dosing results must be available before inclusion,
26. Any condition that, in the opinion of the investigator, would interfere with
evaluation of the investigational product or interpretation of the patient's safety or
study results,
27. Known peripheral sensory neuropathy with functional impairment according exclusion
criteria n°9) prior to first treatment, according to the Summary of product
characteristics (SmPC) of oxaliplatin,
28. Known potentially serious infection, according to the SmPC of 5-FU
29. Has clinically significant active heart disease or myocardial infarction within 6
months given the cardiotoxicity of 5-FU, according to the SmPC of 5-FU,
30. Known history of hypersensitivity to 5-FU, oxaliplatin, or leucovorin, or to any of
their excipients, according to the Summary of Product Characteristic (SmPCs) of these
products.
Exclusion criteria related to geographical, social, and legal issues
31. Impossibility of submitting to the medical follow-up of the study for geographical,
social, or psychiatric illness,
32. Patient under a legal protection regime (guardianship, curatorship, judicial
safeguard) or administrative decision or incapable of giving his/her consent.
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