It does not refer to an event that hypothetically might have caused death if it were more severe. • Requires inpatient hospitalization or prolongation of existing hospitalization; • Results in persistent or significant disability/incapacity; • Results in congenital anomaly/birth defect. • Important medical event . OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 61 of 101 02 February 2022 Medical judgment should be exercised in determining whether an event is an important medical event to be reported as a SAE. An important medical event may not be immediately life - threatening and/or result in death or hospitalization. However, if it is determined that the event may jeopardize the subject and/or may require medical or surgical intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are intensive treatment in an emergency room or at home f or allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse. 5.6.2 Hospitalization - Prolongation of existing hospitalization Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room. An additional overnight stay defines a prolongation of existing hospitalization. All AEs associated with hospitalization or prolongation of hospitalization are consi dered serious. Admission also includes transfer within the hospital to an acute/intensive care unit (e.g., from a medical floor to a coronary care unit). Hospitalization does not include the following: • Rehabilitation facilities. • Hospice facilities. • Nursing homes. • Routine emergency room admissions. • Same day surgeries (as outpatient/same day/ambulatory procedures). Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in itself a SAE. Exa mples include: • Planned hospitalization for a pre -existing disease or medical condition that did not worsen, e.g., hospitalization for chemotherapy for cancer, elective hip replacement for arthritis, coronary angiography for a patient with stable angina pe ctoris. • Admission for treatment of a preexisting condition not associated with the development of a new adverse event or with a worsening of the preexisting condition (e.g., for work -up of persistent pre -treatment lab abnormality); • Social admission (e.g., subject has no place to sleep). • Administrative admission (e.g., for yearly physical exam). • Optional admission not associated with a precipitating clinical adverse event (e.g., for elective cosmetic surgery); • Protocol -specified admission during a clinical t rial (e.g., for a procedure required by the trial protocol). 5.6.3 Serious Adverse Events related to study -mandated procedures They are defined as SAEs that appear to have a reasonable possibility of causal relationship (i.e., a relationship cannot be ruled o ut) to study -mandated procedures (excluding administration of OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 62 of 101 02 February 2022 study drug) such as an event related to the discontinuation of subject's previous treatment during a washout period, or complication of a mandated invasive procedure (e.g., blood sampling), or car accident on the way to the hospital for a study visit. 5.7 Reporting of serious and non -serious adverse events 5.7.1 Reporting requirements Each AE is to be assessed to determine if it meets the criteria for SAE. If a SAE occurs, expedited reporting will follo w local and international regulations, as appropriate. All SAEs must be recorded on SAE forms, irrespective of the study drug received by the subject, whether or not this event is considered by the investigator to be related to study drug. These SAE forms must be faxed or scanned to the Clinical Research Organisation (CRO) in charge of pharmacovigilance for OSE Immunotherapeutics : STRAGEN SERVICES fax: +33 (0) 4 78 42 55 71 or email: OsePV@stragen.fr All AEs will be reported on the AE page(s) of the CRF. The SAE form and the AE CRF page must be completed in a consistent manner (e.g., same AE date, terms and drug relationship). 5.7.2 Serious adverse even t reporting requirements All SAEs must be reported by the investigator to Stragen Services in charge of pharmacovigilance within 24 hours of awareness of the event by the investigator. If the SAE is fatal or life -threatening, notification to Stragen Services must be made immediately, irrespective of the extent of available AE information. This timeframe also applies to additional new information (follow -up) on previously forwarded SAE rep orts. Stragen Services acknowledges the receipt of the SAE information by email to the investigational site within one working day. In the absence of email acknowledging the receipt or in case of issue in sending the fax or email, the investigator shall co ntact Stragen Services by any means for ensuring the receipt of SAE information at the earliest opportunity. In the rare case that the investigator does not become aware of the occurrence of a SAE immediately (e.g., if an outpatient trial subject initially seeks treatment elsewhere), the investigator is to report the event within 24 hours after learning of it and document the time of his/her first awareness of the AE. For all SAEs, the investigator is obligated to pursue and provide information to Stragen S ervices in accordance with the timeframes for reporting specified above. In addition, an investigator may be requested by Stragen Services to obtain specific additional follow -up information in an expedited fashion. This information may be more detailed than that captured on the AE case report form. In general, this will include a description of the AE in sufficient detail to allow for a OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 63 of 101 02 February 2022 complete medical assessment of the case and independent determination of possible causality. Information on other poss ible causes of the event, such as concomitant medications and illnesses must be provided. In the case of a subject death, a summary of available autopsy findings must be submitted as soon as possible to Stragen Services . REFERENCE SAFETY INFORMATION The reference safety information (RSI) to guide for expedited reporting of Suspected Unexpected Serious Adverse Reaction is Investigator's Brochure for OSE2101 and the EU Summary of Product Characteristics for pemetrexed and docetaxel available at SUSAR proces sing date . 5.8 Management of adverse events, dosing adaptations and risk minimization strategy OSE2101 Skin/injection site reactions • If grade 1 local toxicity [defined per NCI CTCAE v5.0 as tenderness ± associated symptoms (e.g. warmth, erythema, itching) ] or grade 2 local toxicity [defined per NCI CTCAE v5.0 as pain, lipodystrophy, edema, phlebitis ]: o apply a hot or cold compress to the injection site and consider giving an analgesic or antipruritic medication. o It is intended that all injections be given at the same site : either the anterior thigh or deltoid region of the non -dominant arm (see section 4.3.3) . If pain or granuloma formation limit dosing in a patient despite measures such as pain medication or local hot or cold compresses, other areas may be used . If the 1 -mL injection cannot be given by a single injection, then it may be divided into two injections, pr eferably in the same lymph node drainage area . • If grade 3 local toxicity [defined per NCI CTCAE v5.0 as ulceration or necrosis; severe tissue damage; operative intervention indicated ] or grade 4 local toxicity (defined per NCI CTCAE v5.0 as life-threateni ng consequences; urgent intervention needed ], local toxicity shall be considered dose limiting , and the patient will not to receive further injections. Cytokine release syndrome (CRS) CRS has been reported in the completed Phase I and Phase II studies . In 88 pat ients exposed to OSE2101 in these completed studies, 2 cases of CRS (1 grade 2, 1 grade 3) have been reported in 2 patients ( 2.3%). Both adverse effects were resolutive. CRS caused by T cell -engaging therapies is related to elevation in effector cytokines, such as interferon gamma (Maude 2014, Lee 2014) and abnormal elevation in cytokines associated with macrophage activation and hemophagocytic syndrome, such as interleukin 6 and 10 (Lee 2014). CRS is a constellation of inflammatory symp toms resulting from cytokine elevations associated with T cell engagement and proliferation. In most patients, CRS symptoms are mild and flulike, with fevers and myalgias. However, some patients experience a severe inflammatory syndrome, OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 64 of 101 02 February 2022 including vascular leak, hypotension, pulmonary edema, and coagulopathy, resulting in multi - organ system failure. Serious adverse events that may be associated with CRS include pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased a spartate aminotransferase, and increased total bilirubin. These events may lead to treatment discontinuation. Disseminated intravascular coagulation, capillary leak syndrome, and hemophagocytic lympho - histiocytosis/macrophage activation syndrome have been reported in the setting of CRS. Patients will be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of OSE2101, corticosteroids and other symptomatic treatments. The risk minimization strategy of CRS consists of: • As a first step , patients should be monitored at least 4h after injection and be informed of possible later symptoms like flu-like syndrome, malaise, fever, low blood pressure which would need to make c ontact with the investigator. • Should symptom s occur, CRS should be classified according to CTCAE 5.0 or other adapted classification (Lee 2014) in order to adapt treatment strategy (Lee 2014) . Per NCI CTCAE v5.0 d efinition , CRS is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. Also consider reporting other organ dysfunctions including neurological toxicities such as psychiatric disorders (e.g.