| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic Pancreatic ductal adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic Pancreatic cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033605 |
| E.1.2 | Term | Pancreatic cancer metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the overall survival (OS) of OSE2101 alone or in combination with nivolumab followed by FOLFIRI reintroduction at progression, or FOLFIRI as maintenance therapy in patients with locally advanced or metastatic PDAC, HLA-A2 positive, having experienced 4-month induction chemotherapy with FOLFIRINOX without disease progression |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the progression-free survival (PFS)
- To assess the duration of disease control (DDC) of maintenance therapy with OSE2101 alone or in combination with nivolumab and FOLFIRI reintroduction at disease progression or unacceptable toxicity, or maintenance therapy with FOLFIRI until progression
- To assess the safety profile
- To assess objective response rate (ORR)
- To compare RECIST v1.1 to iRECIST criteria in the immune therapy arms (Arms B and C)
- To assess health-related Quality of life (HRQoL)
- To assess Q-TWiST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment)
- To assess predictive markers of response (biology, imaging)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated informed consent document, willing and able to comply with protocol requirements
2. Histologically or cytologically proven PDAC
3. Age ≥ 18 years
4. ECOG Performance Status (PS) 0-1
5. 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, CT-scan at C8 ± 2 weeks) 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 (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. Women of childbearing potential receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with women of childbearing potential will be instructed to adhere to contraception for a period of 7 months after the last dose of nivolumab. These durations have been calculated using the upper limit of the half-life for nivolumab (~25 days) and are based on the recommendation that women of childbearing potential use contraception for 5 half-lives plus 30 days, and men who are sexually active with women of childbearing potential use contraception for 5 half-lives plus 90 days after the last dose of nivolumab. Females should not breastfeed while receiving nivolumab and for any subsequent protocol-specified period.
13. Registration in a national health care system (PUMA included).
|
|
| E.4 | Principal exclusion criteria |
1. Obstructive jaundice (bilirubin > 1.5 ULN) without adequate biliary drainage
2. Any systemic steroid therapy (> 10 mg daily dose of prednisone or equivalent) whatever the duration of this corticotherapy
3. Allograft recipient
4. Active HBV, HCV, or HIV infection
Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive hepatitis B core antigen [HBc] 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).
5. 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
6. 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
7. Prior treatment with any immune checkpoint inhibitor, including anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody
8. 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 neurologic 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
9. Uncontrolled massive pleural effusion or massive ascites
10. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, that has required systemic treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
Note: Patients with vitiligo, alopecia, or any chronic skin condition that does not require systemic therapy are exception to this criterion.
Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
11. Evidence of interstitial lung disease, any active, non-infectious pneumonitis, or known active tuberculosis
12. Active uncontrolled infection, or current unstable or uncompensated respiratory or cardiac conditions, or bleeding
13. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
14. Live vaccine administration within 30 days prior to the first dose of study treatment
15. 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
16. Known or suspected drug hypersensitivity to OSE2101 vaccine or nivolumab
17. 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
18. 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.
19. Treatment with any investigational medicinal product within 28 days prior to study entry
20. Prior intolerance/severe toxicity with 5FU or irinotecan (including DPD and UGT1A1 deficiency)
21. Pregnancy/lactation
22. Tutelage or guardianship. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- PFS by centralized review of CT-scan imaging.
- SSR (strategy success rate) at 6 months - The SSR is derived from the DDC, which is defined as the PFS, or, if FOLFIRI is reintroduced and achieves partial response (PR) or stable disease (SD), as the addition of the initial PFS (PFS1) and the PFS of the reintroduction PFS (PFS2)
- Safety
- ORR
- Quality of life with EORTC QLQ-C30 questionnaire
- Q-TWIST analysis considers three health states, TOX, TWiST, and REL, and the duration of each state is calculated for every patient. TOX state : comprises the total number of days after randomisation and before strategy failure spent with toxicity, regardless of when the toxicity started or whether there were gaps between toxicities; TWIST state : is defined as DDC time minus time with toxicities; REL state : is defined as OS time minus DDC time, or the period of time from progression to death.
- Predictive biomarkers (blood and tumor tissue) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- The PFS is defined according to the DATECAN consensus as the time
from randomization to first progression or death for any reason, whichever occurs first.
- The SSR at 6 months
- Safety: until 100 days after randomization
- Response at baseline, every 8 weeks and end of treatment
- Quality of life: baseline, every 8 weeks and end of treatment
- Q-TWIST analysis considers three health states, TOX, TWiST, and REL, and the duration of each state is calculated for every patient.
- Predictive biomarkers at baseline, M2, M4 then every 4 months and end of treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 28 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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