Phase II Study of EXL01, Nivolumab, and FOLFOX in First-Line Treatment of PD-L1 CPS ≥5 Metastatic Gastric Adenocarcinoma
- Trial ID
- 2023-506753-38-00
- Protocol
- BIG G-122
- Sponsor
- Gercor
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **objective response rate (ORR)** at 4 months in patients with PD-L1 CPS ≥ 5 metastatic gastric adenocarcinoma treated with EXL01 in combination with nivolumab and FOLFOX as a first-line treatment. This evaluation is clinically relevant as it aims to determine the efficacy of this combination therapy in inducing tumor response, which is crucial for improving patient outcomes in this aggressive cancer type.
Secondary objectives include:
- Evaluating the safety of nivolumab plus FOLFOX with or without EXL01.
- Assessing progression-free survival (PFS) per RECIST v1.1 and iRECIST criteria.
- Determining 1-year and 2-year PFS rates per RECIST v1.1 and iRECIST criteria.
- Assessing overall survival (OS) and 2-year and 3-year OS rates.
- Evaluating the best ORR per RECIST v1.1 criteria.
- Assessing the duration of response (DoR).
- Evaluating shifts in peripheral blood and serum markers, including T cell subpopulations and myeloid-derived suppressor cells (MDSCs).
- Exploring the association between the immunogenicity of EXL01 and efficacy, safety, and outcome parameters.
- Exploring potential biomarkers associated with clinical efficacy and/or incidence of adverse events (AEs) by analyzing biomarker measures within the tumor microenvironment and periphery.
- Exploring the impact of nivolumab plus FOLFOX with or without EXL01 on gut microbiota composition.
- Exploring the impact of previous gastrectomy on the efficacy and tolerability of the treatment regimen.
Participants
The clinical trial involves participants diagnosed with **metastatic gastric adenocarcinoma**. The study population includes both male and female subjects, aged 18 years and older, who are part of a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have adequate hematologic and end-organ function and must not have received prior systemic cancer treatment for advanced nonresectable or metastatic disease, except for completed neoadjuvant or adjuvant therapy at least six months prior to the diagnosis of metastatic or recurrent disease. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The selection criteria emphasize the need for a representative tumor tissue specimen and the expression of PD-L1 with a combined positive score of 5 or greater. The trial population was selected based on these criteria to ensure the study's objectives are met effectively.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **nivolumab**, EXL01, and FOLFOX in patients with metastatic gastric adenocarcinoma. This is a randomized, double-blind, controlled phase II study. The primary objective is to assess the objective response rate (ORR) at four months in patients with PD-L1 CPS ≥ 5. The trial is expected to commence recruitment on April 16, 2024, and is estimated to conclude by December 31, 2028. Participants will be involved in the study for a maximum treatment period of 24 months.
The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the **screening** visit, eligibility will be confirmed based on inclusion criteria such as age, reproductive status, and the presence of inoperable, advanced, or metastatic gastric cancer. Participants must also provide a tumor tissue specimen for exploratory research. Follow-up visits will occur at regular intervals to monitor treatment response and safety, with assessments including computed tomography (CT) or magnetic resonance imaging (MRI) scans to evaluate measurable lesions. The end-of-study visit will involve a final assessment of the participant's health status and treatment outcomes.
Participants are expected to comply with scheduled visits, treatment regimens, and laboratory tests. Conditions that may lead to early termination from the study include non-compliance with study protocols, adverse events, or withdrawal of consent. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding of treatment efficacy in this patient population.
Treatment
The clinical trial involves the administration of several treatments, including the experimental medication **EXL01**, a live biotherapeutic product. EXL01 is provided in capsule form and is administered orally. The maximum daily dose is one capsule, with a total treatment period of up to 24 months. This product is developed by EXELIOM BIOSCIENCES and is classified as a structurally diverse substance.
**Nivolumab**, marketed as OPDIVO, is another key component of the trial. It is a concentrate for solution for infusion, administered via intravenous infusion. The maximum daily dose is 240 mg, with a total dose not exceeding 12,480 mg over the treatment period. Nivolumab is a protein-based medication produced by BRISTOL-MYERS SQUIBB PHARMA EEIG, and it is used in combination with other treatments in this study.
**Anhydrous Calcium Folinate** is used as an auxiliary treatment in the trial. It is administered intravenously, with a maximum daily dose of 400 mg/m² and a total dose of 20,800 mg/m² over the course of the study. This chemical substance plays a supportive role in the treatment regimen.
**Fluorouracil Sodium** is included as part of the treatment protocol, provided as a solution for injection or infusion. It is administered via intravenous infusion, with a maximum daily dose of 2800 mg/m² and a total dose of 145,600 mg/m². This medication is used in conjunction with other treatments to enhance therapeutic outcomes.
**Oxaliplatin**, marketed as OXALIPLATINE ACCORD, is also part of the treatment regimen. It is a solution for infusion administered intravenously. The maximum daily dose is 85 mg/m², with a total dose of 4420 mg/m² over the treatment period. This chemical substance is produced by ACCORD HEALTHCARE FRANCE SAS and is used as an auxiliary treatment in the study.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)** at 4 months in patients with PD-L1 CPS ≥5 advanced gastric cancer treated with EXL01, nivolumab, and FOLFOX as a first-line treatment. Secondary endpoints include the safety of nivolumab plus FOLFOX with or without EXL01, progression-free survival (PFS) per RECIST v 1.1 and iRECIST criteria, 1-year and 2-year PFS, overall survival (OS), 2-year and 3-year OS, and ORR per RECIST v 1.1 criteria. Additional secondary endpoints involve the duration of response (DoR), shifts in peripheral blood and serum markers, association between immunogenicity of EXL01 and efficacy, and safety outcomes, as well as biomarkers associated with clinical efficacy and adverse events.
Measurements will be conducted using validated scales and laboratory tests, with radiographic tumor assessments performed within 28 days prior to randomization. The trial will also analyze biomarker measures within the tumor microenvironment and periphery, comparing them to clinical outcomes. The impact of nivolumab plus FOLFOX with or without EXL01 on gut microbiota composition and the effect of previous gastrectomy on efficacy and tolerability will also be evaluated. The trial is scheduled to start recruitment on December 15, 2023, with an estimated end date of December 31, 2028.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study
- Inoperable, advanced, or metastatic gastric cancer or gastroesophageal junction or distal esophageal carcinoma and histologically confirmed predominant adenocarcinoma,
- Expression of PD-L1 with a combined positive score (PD-L1 CPS) ≥5
- No prior systemic cancer treatment given as primary therapy for advanced nonresectable or metastatic disease, 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
- At least one measurable lesion as assessed by computed tomography (CT)-scan or magnetic resonance imaging (MRI) according to RECIST v 1.1 and feasibility of repeated radiological assessments; radiographic tumor assessment should be performed within 28 days prior to randomization
- Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1
- Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization of study treatment:
- Baseline-corrected QT interval ≤ 450 msec for males and ≤ 470 msec for females,
- 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,
- Registration in a national health care system (PUMa-Protection Universelle Maladie included.
- Age ≥ 18 years
- Women must not be pregnant, breastfeeding, or expecting to conceive during the study
- Reproductive status: a. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the start of study drug, b. WOCBP must agree to use an adequate method of contraception or birth control for the duration of study treatment and 5 months (nivolumab), 4 months (oxaliplatin), 6 months (5-FU) or at least 1 month (EXL01) of the patient’s last dose of the study drug, c. 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
- Known HER-2 positive status
- Active brain metastases or known history of leptomeningeal carcinomatosis
- Ascites, which cannot be controlled with appropriate interventions,
- 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
- 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
- Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity,
- 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
- 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,
- 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,
- Major surgery within 28 days (4 weeks) prior to first dose of study treatment,
- Concomitant unplanned antitumor therapy (e.g., chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy),
- GI obstruction, poor oral intake, or difficulty in taking oral medication or difficulties in swallowing; nasogastric tubes are not permitted,
- Known GI malabsorption,
- 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
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
- 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.
- Probiotics or prebiotic supplements should be avoided during the study,
- 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,
- 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,
- 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,
- 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 PCR 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
- 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
- Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs, such as brivudine
- Known dihydropyrimidine dehydrogenase deficiency (partial or complete),
- 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,
- Impossibility of submitting to the medical follow-up of the study for geographical, social, or psychiatric illness
- Patient under a legal protection regime (guardianship, curatorship, judicial safeguard) or administrative decision or incapable of giving his/her consent.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 15 Dec 2023 | 120 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
OXALIPLATINE ACCORD 5 mg/ml, solution à diluer pour perfusion | Other | SOLUTION À DILUER POUR PERFUSION | INTRAVENOUS | 85 | 24 | PRD4609431 |
EXL01 | Test | CAPSULE | ORAL | 1 | 24 | PRD9479623 |
CALCIUM FOLINATE | Other | PHF00169MIG | INTRAVENOUS | 400 | 24 | SCP26549405 |
FLUOROURACIL SODIUM | Other | — | INTRAVENIOUS INFUSION | 2800 | 24 | SUB02225MIG |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 240 | 24 | PRD2941372 |