Maintenance With OSE2101 Plus FOLFIRI, or FOLFIRI After FOLFIRINOX-based Induction Therapy in Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma

TEDOPAM is a randomized (1.1.1) non-comparative phase II study. This study will assess the efficacy and safety of OSE2101 alone or in combination with nivolumab followed by FOLFIRI reintroduction, versus FOLFIRI as maintenance therapy in patients with advanced PDAC after induction therapy with FOLFIRINOX.

Current standard of care for patients with advanced pancreatic ductal adenocarcinoma (PDAC) is chemotherapy, preferential regimen being FOLFIRINOX (5FU, leucovorin, irinotecan, and oxaliplatin) in fit patients (PS 0-1, bilirubin \< 1.5 ULN). The question of how and when the FOLFIRINOX regimen and doses can be deescalated after a period of disease control (i.e. maintenance therapy) remains unanswered. In routine practice, oxaliplatin is usually stopped after 6-8 cycles due to limiting neuropathy, and the fluoropyrimidine is continued, either alone or, more frequently, in combination with irinotecan (FOLFIRI regimen), until disease progression.

Immune therapies have opened new opportunities in cancer therapy. However, results of immunotherapy in PDAC have been disappointing so far, with failure of checkpoint inhibitor monotherapies (anti-CTLA4 and anti-PD-L1 monoclonal antibodies \[mAb\]) in progressive advanced PDAC, while monovalent vaccines were demonstrated to be safe but with limited activity.

Eligibility Criteria:
Inclusion Criteria:

1. Signed and dated informed consent document, willing and able to comply with protocol requirements,
2. Histologically or cytologically proven pancreatic ductal adenocarcinoma,
3. Age ≥ 18 years,
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1,
5. Human Leukocyte Antigen (HLA-A2) genotype,
6. Recurrent or advanced disease not amenable to surgery with curative intent (previous resection of primary tumor allowed),
7. Measurable or evaluable (radiologically detectable disease which does not fulfill RECIST criteria for measurable disease) lesions according to RECIST v1.1 criteria (CT-scan \< 4 weeks),
8. Stable disease or tumor response according to RECIST v1.1 after a 4-month (8 cycles) course of first-line FOLFIRINOX or modified FOLFIRINOX induction chemotherapy,
9. Have archival tissue sample that has been identified and confirmed as available for study, or newly obtained core or excisional biopsy of a tumor lesion,
10. Adequate organ function, as defined by the following:

    * Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) \< 3 x upper limit of normal (ULN),
    * Total serum bilirubin \< 1.5 ULN,
    * Prothrombin ratio \> 70%,
    * Serum albumin ≥ 2.8 g/dL,
    * Hemoglobin ≥ 10,0 g/dl,
    * White blood cell count (WBC) ≥ 3,000/μL,
    * Absolute neutrophil count (ANC) ≥ 1,500/μL,
    * Platelets ≥ 100,000/μL,
    * Serum creatinine ≤ 1.5 ULN or creatinine clearance \> 50 mL/min (Modification of diet in renal disease \[MDRD\]),
11. Life expectancy ≥ 3 months,
12. Women participants of childbearing potential must have a negative serum pregnancy test within the 3 days prior to the first treatment administration. Both women participants of childbearing potential and men participants who are sexually active with women of childbearing potential must agree to use a reliable method of birth control (i.e. pregnancy rate \< 1% per year) until 6 months after the last dose of FOLFIRI, and 90 days after the last dose of OSE2101,
13. Registration in a national health care system (PUMA included).

Exclusion Criteria:

1. Obstructive jaundice (bilirubin \> 1.5 ULN) without adequate biliary drainage,
2. Allograft recipient,
3. Active HBV (hepatitis B virus), HCV (hepatitis C virus ), or HIV infection, Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive HBc (hepatitis B core antigen) antibody test are eligible.

   Note: Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
4. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri,
5. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of neuropathy, alopecia, and the laboratory values defined in the inclusion criteria,
6. Known active central nervous system metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurological symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids at a dose \> 10 mg/day of prednisone or equivalent for at least 14 days prior to trial treatment,
7. Uncontrolled massive pleural effusion or massive ascites,
8. Evidence of interstitial lung disease, any active, non-infectious pneumonitis, or known active tuberculosis,
9. Active uncontrolled infection, or current unstable or uncompensated respiratory or cardiac conditions, or bleeding,
10. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study,
11. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator,
12. Known or suspected drug hypersensitivity to OSE2101 vaccine,
13. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug,
14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational product, Note: Local surgery of isolated lesions for palliative intent is acceptable.
15. Treatment with any investigational medicinal product within 28 days prior to study entry,
16. Prior intolerance/severe toxicity with 5-fluorouracil (5-FU) or irinotecan (including dihydropyrimidinedehydrogenase \[DPD\] and UGT1A1 deficiency),
17. Pregnancy/lactation,
18. Tutelage or guardianship.