OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 2 of 101 02 February 2022 Signature page Sponsor Signatur e Date Coordinating investigators – Co-Chairs of the Steering Committee Date Signature Date Principal Investigator Signature Date As an investigator, I have read and approve this protocol. My signature, in conjunction with the signature of the sponsor, confirms the agreement of both parties that this clinical study will be conducted in accordance with the protocol and all related documents, and in accordance with all applicable laws and regulations including but not limited to the Guideline for Good Clinical Practice (GCP), the Code of Federal Regulations (CFR), Directive 2001/20/EC, the ethical principles of the Declaration of Helsinki and its amendments. Nothing in this document is intended to limit the authority of a physician to provide emergency medical care under applicable regulations. OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 4 of 101 02 February 2022 Revision History Study protocol version Summary of main changes Version 1.0 on 27-Jul-2015 Initial version submitted to Authorities (not applicable in countries) Version 1.2 on 02-Oct-2015 Exclusion criteria n°9 added to exclude patients treated with corticosteroids within 3 -weeks before inclusion (except if low dose) Version 2.0 on 30-Nov-2015 Exclusion criteria n°1 modified to exclude patients with Large Cell Carcinoma; Inclusion criterion n°5 clarified to authorize patients as 2nd line after failure of prior platinum -based chemotherapy or as 3rd line after failure of platinum -based chemotherapy then immune checkpoint inhibitor (ICI) Version 3.0 on 14-Feb-2017 Inclusion criterion n°5 modified to authorize patients as 2nd line o r 3rd line after failure of platinum -based chemotherapy and/or failure of ICI (sequential or combined with chemo) as ICIs may be used either as 1st or 2nd line therapy; PDL -1 expression on tumor biopsy not further mandatory for inclusion; clarification on inclusion criteria n°9 to authorize only patients with asymptomatic brain metastases Version 4.0 on 21-Dec-2017 and Version 4.1 on 28-Feb-2018 Inclusion criterion n°5 m odified to only authorize the subgroup of patients previously treated with ICI and who have progressed after ICI (as 2nd line after ICI + chemotherapy first line or as 3rd line after platinum -based chemotherapy in first line then ICI in second line); Study design modified for a Phase II (Step 1) / Phase III (Step 2) design with a first step Fleming non comparative Phase II design; First secondary criterion modified for disease control rate instead of progression -free survival; Clarification on population f or analysis for Step 1 and Step 2 (in version 4.1 per request after the voluntary harmoni zed procedure (VHP) in the European Union ); Per IDMC request, the recruitment was temporarily halted from June 2017 to November 2017 before the decision to restart the recruitment only in the subgroup of patients who progressed after ICI was taken based on the IDMC independent analysis of data (safety and death events) reported in the first 131 patients randomi zed until June 2017; This analysis was blinded from the investigators and the Sponsor. Version 5.0 on 29-Mar-2019 Implementation of the 8th edition of TNM instead of 7th edition leading to modify the study title with no modification of the target study po pulation; Inclusion criterion n°7 modified to authorize patient with progression during or within 12 months after the end of ICI as sequential or concomitant platinum -based chemotherapy ± radiation for locally advanced disease (stage III); Study design mod ified to remove the possibility of a sample size reassessment of Step 2 based on the Step 1 Phase II results, to continue with the 2:1 randomi zation ratio in Step 2 and, as a consequence, to increase the number of events in Step 2 from 250 to 278 and to i ncrease accordingly the number of patients, also to not consider for the final analysis the 38 patients with previous ICI treatment randomized before the recruitment hold; Implementation of NCI CTCAE version 5.0 instead of CTCAE version 4.0 leading to clar ifying the definition of cytokine release syndrome (CRS) as well as the management of CRS still per Lee recommendation; A translational study has been added for patients/sites who agreed, in order to assess immunogenicity before and under treatment. Version 6.0 on 02-Feb-2022 To notify the decision to early stop the recruitment in April 2020 per the IDMC recommendation due to the impact of the COVID -19 pandemic on the primary endpoint of the study (OS) and the risk on data integrity, and to harmoni ze the study protocol with the final Statistical Analysis Plan (SAP) completed on 23 -jul-21 before database lock . OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 5 of 101 02 February 2022 Main changes of the analysis plan compared to protocol v5.0 were to reorder the secondary endpoints and to a dd Post-Progression Survival (PPS) and Time to worsening of ECOG PS as first secondary endpoints to better reflect the efficacy of a cancer vaccine , to consider a Population of Interest (PoI) identified during Step -1 as the main population for the final analy sis, and to estimate the study power considering that half of patients have been finally included due to the early study discontinuation. Additional analysis of COVID -19 impact, and quality of life based on EORTC and FDA guidance’s were added . OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 6 of 101 02 February 2022 Protocol Summary Title A randomized parallel group Phase III trial of OSE2101 as 2nd or 3rd line compared with standard treatment (docetaxel or pemetrexed) in HLA -A2 positive patients with advanced Non -Small -Cell Lung Cancer with progressive disease after last treatment with immune checkpoint inhibitors (ICI) (OSE2101C301) Objectives Step 1 (Phase II ) 2:1 randomized non -comparative one stage Fleming Phase II Primary objective • To evaluate the overall survival (OS) rate at 12 months in HLA -A2 positive patients with advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint -inhibitor regimens Secondary objectives • To describe secondary measures of clinical efficacy including OS (median) , disease control rate (DCR) at 6 and 12 months, Health -related Quality of life (QoL) , progression free survival ( PFS), objective response rate (ORR) and evaluate duration of response (DR) • To assess the safety and tolerability • To de scribe patient reported outcomes (PRO) disease/treatment -related symptoms of lung cancer Step 2 (conditional Phase III ) 2:1 comparative randomized Phase III Primary objective • To demonstrate that OSE2101 is superior to control treatment with respect to OS in HLA -A2 positive patients with advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint -inhibitor regimens ; primary population will be the Population of Interest (PoI ) defined as patients with secondary resistance to ICI monotherapy with ICI given 2nd line; sensitivity analysis will be done in all patients Secondary objectives • To compare secondary measures of clinical efficacy including Post progression Survival (PPS), Time to worsening of ECOG PS, Health -related QoL, DCR at 6 and 12 months, and PFS • To assess the safety and toler ability of OSE2101 compared to the control treatment Exploratory objectives • To compare other efficacy criteria (ORR, DR), other QoL criteria , time to next lung cancer therapy and COVID -19 impact in both treatment arms . Design Open -label, multicenter, controlled, randomized, parallel group, 2 -step Phase II/III study ; Randomization 2:1 in experimental Arm A OSE2101 or Arm B Standard of Care (SoC ) docetaxel or pemetrexed using the following stratification factors: histology (squamous vs . non squamous), best response to first line treatment (objective response vs. no objective response), line rank of OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 7 of 101 02 February 2022 previous treatment with ICI (ICI first line vs. ICI second line) Study planned duration First subject First visit Q1 2016 Last subject Last visit ( Step 1) Last visit ( Step 2) ≈Q1 2020 Q1 2021 Centers / Country Approximately 80 to 125 centers in the European Union, North America and other countries. The study includes IND and non -IND centers (21 CFR 312.120 compliant). Subjects / Groups Step 1 (Phase II ) A total of 38 patients with previous ICI treatment have been recruited before protocol version 4.0. After implementation of protocol version 4.0, 1 08 new patients are to be randomized with a 2:1 randomization ratio in order to reach a total of 84 patients in arm A (OSE2101) evaluable at 12 months (death observed within 12 months or follow -up time of 12 months or more). Step 2 (Phase III ) After end of randomization in Step 1, the same 2:1 randomization ratio will be continued for patients entering Step 2 until a cumulated total of new 363 patients or a cumulated total of 278 deaths (both counts excluding the 38 patients enrolled before protocol 4.0) is reached. Step-1 analysis was reviewed by the independent data monitoring committee (IDMC) i n March 2020 . Step-1 data show ed that the pre defined thresholds of 12 months -OS rate in OSE2101 arm was achieved . At this time, the IDMC was concerned about the impact of the COVID -19 pandemic on the primary endpoint of the study (O S), on the risk on data integrity and recommended to stop accrual early. The Sponsor decided to stop the accrual in April 2020. At that date, 219 patients have been enrolled and planned to be followed for survival up to mid-January 2021 . From Step -1 analysis, a population of interest (PoI) consisting of patients from the 2d line ICI stratification factor with secondary resistance to ICI (duration of ICI ≥ 12 weeks) was identified as having a benefit over SoC and being proposed a s the main population for final analysis (Kluger et al., 2020) . N.B.: All patients included in the study will be monitored until de ath-events or termination of the study or decision to withdraw from the study, even after a change in therapy for progression, as the main criterion is OS and as all patients included in the post -ICI stratum will be kept for the final analysis. Patients in cluded within the subgroup "no previous treatment with ICI" before recruitment hold in this subgroup will continue treatment as planned. They will be described separately in the final analysis. OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 8 of 101 02 February 2022 Study periods The total study duration for an individual subject will depend on the survival of the subject, including the following periods: • Pre-screening: HLA -A2 testing (using PCR methods) can be done at any time before inclusion (a specific consent form is available). • Screening: 1 to 35 days befor e treatment administration. • Randomization: treatment allocation and baseline for OS calculations. • Treatment: − For OSE2101 (Arm A): Day 1 each 21 -day cycle for 6 cycles , then every 8 weeks for the remain der of year one and, finally every 12 weeks beyond year one ( see Figure 2: Schedule of OSE2101 administration ) − For docetaxel or pemetrexed (Arm B) : Day 1 each 21 -day cycle (i.e. every 3 weeks) − In both arms, t reatment cycles will be repeated until unequivocal RECIST 1.1 -defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal. Should pseudo progression or delayed response to treatment be suspected in arm A, investigator may continue treatment beyond the time of RECIST -defined progression, if the patient is perceived to be experiencing clinical benefit . • End of treatment: 4 weeks after the final treatment administration to obtain assessments from the 4 previous weeks. • Post-treatment f ollow -up: every 2 months after discontinuation of treatment for the post -treatment survival status . Inclusion criteria Protection of study subjects a nd compliance 1. Signed and dated informed consent document indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrollment 2. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Demography 3. Female or male, 18 years of age or older Cancer Diagnosis and treatment 4. Histologically or cytologically proven diagnosis of NSCLC that is locally advanced (stage III) unsuitable for radiotherapy or m etastatic (stage IV) according to the 8th edition of tumor, node, metastasis (TNM) in Lung Cancer published by the International Union Against Cancer and the American Joint Committee on Cancer 5. Subjects with disease recurrence or progression after therapy with an immune checkpoint inhibitor and platinum -based chemotherapy : OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 9 of 101 02 February 2022 • either 1st line chemotherapy followed by 2nd line checkpoint inhibitor • or 1st line combination of checkpoint inhibitor and chemotherapy Patients with progression during or within 12 months after the end of ICI as sequential or concomitant platinum -based chemotherapy ± radiation for locally advanced disease (stage III) are eligible 6. Subjects with measurable or non -measurable lesions 7. Subjects must express HLA -A2 phenotype as assessed serologically 8. Subjects must be considered suitable for chemotherapy with either single - agent pemetrexed or docetaxel 9. Subjects with brain metastases are eligible if treated (whole brain radiotherapy, stereotaxic radiotherapy, surgery) at least 3 weeks prior to initiation of study treatment and have no symptoms related to brain metastases for at least 2 weeks before initia tion of study treatment and are not taking any forbidden medications ( see Section 4.3.5 of the protocol ) 10. Any prior chemotherapy, immunotherapy, hormonal therapy, radiation therapy or surgeries must have been completed at least 3 weeks prior to initiation of study treatment 11. Any toxicity from prior therapy must have recovered to ≤ Grade 1 (except alopecia) Clinical status 12. ECOG performance status 0 -1 13. Adequate organ function as defined by all the following criteria: • Albuminemia > 25 g/L • Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 1.5 x upper limit of normal (ULN) with alkaline phosphat ase  2.5 x ULN, or AST and ALT  5 x ULN if liver function abnormalities are due to liver metastases • Total serum bilirubin  1.5 x ULN • Absolute neutrophil count (ANC)  1500/L • Platelets  100000/L • Hemoglobin  9.0 g/dL (in the absence of transfusion w ithin 2 weeks before randomization) • Creatinine clearance (based on modified Cockcroft -Gault formula) ≥ 45 ml/min Exclusion criteria Cancer Diagnosis and treatment 1. Small -cell lung cancer /mixed NSCLC with small cell component or other neuroendocrine lung cancers (typical and atypical carcinoids, large -cell neuroendocrine carcinomas) OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 10 of 101 02 February 2022 2.