Gastric Cancer
Conditions
Brief summary
This is a randomized non-comparative, multicenter phase II study in patients with PD-L1 PD-L1 combined positive score (CPS) ≥5 advanced gastric cancer to evaluate the efficacy and safety of nivolumab and FOLFOX in combination with EXL01 as first-line treatment. After signing the informed consent form, and upon confirmation of the patient's eligibility, patients will be randomized in a 2:1 ratio to either the nivolumab and FOLFOX plus EXL01 arm (experimental) or the nivolumab and FOLFOX arm (control). In both arms, treatment will be given until PD, unacceptable toxicity or for a maximum of 24 months (52 cycles).
Detailed description
The primary objective of the study is to assess the objective response rate (ORR) at 4 months (based on Response Evaluation Criteria in Solid Tumor \[RECIST\] criteria v1.1) of patients with PD-L1 CPS ≥ 5 advanced gastric cancer treated by EXL01 plus nivolumab and FOLFOX as first-line treatment. With a randomization ratio of 2:1 it will be necessary to randomize 40 patients in the control arm, 80 patients in the experimental arm and so a total of 120 evaluable patients in the study. Randomization will be stratified by PD-L1 expression level, center, and prior gastrectomy. In the experimental arm, the primary analysis will be on modified intent-to-treat (mITT) population. Confirmative analysis will be conducted firstly in the ITT population and secondly, in the Per Protocol (PP). Analyses of safety will be conducted in safety population. The Kaplan-Meier method will be used to estimate time to event endpoints and described using the median and event-free rates over time with CI.
Interventions
DRUGNivolumab
Nivolumab 240 mg IV; every 2 weeks
DRUGFOLFOX regimen
Oxaliplatin 85 mg/m², leucovorin 400 mg/m², bolus of 5-FU 400 mg/m², continuous 5-FU 2400/m² in 46 hours; every 2 weeks
BIOLOGICALEXL01
Orally 1 capsule/day, starting on day 1 of each FOLFOX/nivolumab treatment.
Sponsors
GERCOR - Multidisciplinary Oncology Cooperative Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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, Note: 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
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,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) at 4 months | At 4 months | ORR measured at 4 months post randomization in patients with PD-L1 CPS ≥5 advanced gastric cancer treated by first-line EXL01 plus nivolumab and FOLFOX. ORR at 4 months is defined as the number of patients with a CR or PR evaluated by RECIST v 1.1 criteria divided by the number of patients evaluable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | Maximum 3 years after randomization | PFS per RECIST v 1.1 and iRECIST of nivolumab plus FOLFOX with or without EXL01. PFS is defined as the time from randomization to the date of the first documented PD determined by the Investigator assessment by RECIST 1.1 or death due to any cause, whichever occurs first. |
| Assessment of safety profile | Maximum 3 years after randomization | Safety of nivolumab plus FOLFOX with or without EXL01. Safety will be measured by the incidence of Adverse Events (AEs), Serious AEs (SAEs), deaths, laboratory abnormalities, and specific immune-related AEs (hepatitis, colitis, myositis, endocrinopathies). |
| Duration of response (DoR) | Maximum 3 years after randomization | DoR with FOLFOX plus nivolumab with or without EXL01. DoR is defined as the time between the date of first documented response (complete response \[CR\] or partial response \[PR\]) to the date of the first disease progression, per RECIST 1.1 or death due to any cause, whichever occurs first. For patients who neither progress nor die, the duration of objective response will be censored at the same time they were censored for the primary definition of PFS. |
| Overall survival (OS) | Maximum 3 years after randomization | OS with nivolumab plus FOLFOX with or without EXL01. OS is defined as the time between the date of randomization and the date of death from any cause. |
| 2-year and 3-year OS | At 2 years and 3 years | 2-year and 3-year OS rate of nivolumab plus FOLFOX with or without EXL01 |
| 1-year and 2-year PFS | At 1 year and at 2 years | 1-year and 2-year PFS rates per RECIST v 1.1 and iRECIST (immune RECIST) criteria with nivolumab plus FOLFOX with or without EXL01 |
| Objective response rate (ORR) | Maximum 3 years after randomization | ORR per RECIST v 1.1 criteria nivolumab plus FOLFOX with or without EXL01. ORR is defined as the number of patients with the best overall response (BOR) of CR or PR divided by the number of measurable patients with target lesion at baseline. BOR is defined as the best response designation, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1) or the date of subsequent anti-cancer therapy, whichever occurs first. |
Countries
France
Contacts
Primary ContactMarie-Line GARCIA LARNICOL, MD
Outcome results
None listed