Gut microbiome intervention with EXL01 in combination with nivolumab and FOLFOX as first-line treatment for patients with PD-L1 CPS ≥5 metastatic gastric cancer: A randomized GERCOR phase II study (BIG)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gercor

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

16 Apr 2024 → ongoing

Decision date (initial)

2024-01-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Exceliom

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective is to assess the objective response rate (ORR) at 4 months of patients with PD-L1 CPS ≥ 5 advanced gastric cancer treated by EXL01 plus nivolumab and FOLFOX(experimental arm) as first-line treatment

Secondary objectives 13

1. To evaluate the safety of nivolumab plus FOLFOX with or without EXL01,
2. To assess PFS per RECIST v 1.1 and iRECIST (immune RECIST) of nivolumab plus FOLFOX with or without EXL01,
3. To assess the 1-year and 2-year PFS rates per RECIST v 1.1 and iRECIST criteria with nivolumab plus FOLFOX with or without EXL01,
4. To assess OS with nivolumab plus FOLFOX with or without EXL01,
5. To assess the 2-year and 3-year OS rate of nivolumab plus FOLFOX with or without EXL01,
6. To assess the best ORR reviewed by investigator per RECIST v 1.1 criteria nivolumab plus FOLFOX with or without EXL01.
7. To assess duration of response (DoR) with FOLFOX plus nivolumab with or without EXL01.
8. To assess shifts in peripheral blood and serum markers as T cell subpopulations, myeloid-derived suppressor cells (MDSCs), and other immune related markers.
9. To evaluate the association between immunogenicity of EXL01 and efficacy, and safety, outcome parameters.
10. To explore potential biomarkers associated with clinical efficacy (OS, PFS, and ORR) and/or incidence of AEs of nivolumab plus FOLFOX with or without EXL01 by analyzing biomarker measures within the tumor microenvironment (e.g., PD-L1 CPS, microsatellite instability, circulating tumor DNA) and periphery (e.g., blood, stool) in comparison to clinical outcomes.
11. To explore the impact of nivolumab plus FOLFOX with or without EXL01 on gut microbiota composition,
12. To explore the impact of previous gastrectomy on the efficacy and tolerability of nivolumab plus FOLFOX with or without EXL01.
13. To assess the best ORR reviewed by blinded independent central review (BICR) per RECIST v 1.1 criteria in the experimental arm.

Conditions and MedDRA coding

metastatic gastric adenocarcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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
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
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
6. 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
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:
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.
12. Age ≥ 18 years
13. Women must not be pregnant, breastfeeding, or expecting to conceive during the study
14. 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 27

1. Known HER-2 positive status
2. Active brain metastases or known history of leptomeningeal carcinomatosis
3. Ascites, which cannot be controlled with appropriate interventions,
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),
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
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. Probiotics or prebiotic supplements should be avoided during the study,
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 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
22. 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
23. Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs, such as brivudine
24. Known dihydropyrimidine dehydrogenase deficiency (partial or complete),
25. 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,
26. Impossibility of submitting to the medical follow-up of the study for geographical, social, or psychiatric illness
27. Patient under a legal protection regime (guardianship, curatorship, judicial safeguard) or administrative decision or incapable of giving his/her consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR at 4 months of patients with PD-L1 CPS ≥5 advanced gastric cancer treated by EXL01 plus nivolumab and FOLFOX as first-line treatment, investigator review according to RECIST v1.1 .

Secondary endpoints 13

1. Safety of nivolumab plus FOLFOX with or without EXL01
2. PFS per RECIST v 1.1 and iRECIST criteria in patients receiving nivolumab plus FOLFOX with or without EXL01,assessed by investigator review.
3. 1-year and 2-year PFS of patients receiving nivolumab plus FOLFOX with or without EXL01,assessed by investigator review.
4. OS of patients receiving nivolumab plus FOLFOX with or without EXL01,
5. 2-year and 3-year OS of patients receiving nivolumab plus FOLFOX with or without EXL01,
6. ORR per RECIST v 1.1 criteria in patients receiving nivolumab plus FOLFOX with or without EXL01, assessed by investigator review.
7. DoR in patients receiving nivolumab plus FOLFOX with or without EXL01.
8. Percentage of patients with shifts, on treatment versus baseline, in peripheral blood and serum markers as T cell subpopulations, MDSCs, and changes in immune related markers.
9. Association between immunogenicity of EXL01 and efficacy, and safety, outcome parameters.
10. Biomarkers associated with clinical efficacy (OS, PFS, and ORR) and/or incidence of adverse events (AEs) of nivolumab plus FOLFOX with or without EXL01 by analyzing biomarker measures within the tumor microenvironment (e.g., PD-L1 CPS microsatellite instability, circulating tumor DNA) and periphery (e.g., blood, stool) in comparison to clinical outcomes,
11. The impact of nivolumab plus FOLFOX with or without EXL01 on gut microbiota composition.
12. The impact of previous gastrectomy on the efficacy and tolerability of nivolumab plus FOLFOX with or without EXL01.
13. 6.7. ORR by blinded independent central review (BICR) per RECIST v 1.1 criteria,

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gercor

Sponsor organisation

Gercor

Address

151 Rue Du Faubourg Saint Antoine

City

Paris

Postcode

75011

Country

France

Scientific contact point

Organisation

Gercor

Contact name

Marie Line GARCIA LARNICOL

Public contact point

Organisation

Gercor

Contact name

Nelly ROLDAN

Locations

1 EU/EEA country · 40 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 44 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications