h allucina tions or confusion ), nervous system disorders (e.g. s eizure, dysphasia, tremor, or headache ). Overall, in every grade of CRS, a vigilant supportive care including empiric treatment of concurrent bacterial infections and maintenance of adequate hydration and blo od pressure. Immunosuppression should be used in all patients with grade 3 or 4 CRS and instituted earlier in patients with extensive comorbidities or older age (Lee 2014) : • Grade 1 [defined per NCI CTCAE v5.0 as fever ± constitutional symptoms ]: vigilant support care, assess for infection (e.g. treat fever and neutropenia if present, monitor fluid balance, antipyretics, analgesics as needed) . • Grade 2 [defined per NCI CTCAE v5.0 as hypotension responds to fluid, hypoxia respond ing to <40% oxygen ]: vigilant supportive care, monitor cardiac and other organ function closely, consider corticosteroids or other specific therapy according to comorbidities and expected benefit vs. cancer treatment needs . • Grade 3 [defined per NCI CTCAE v5.0 as h ypotension managed with one pressor; hypoxia requiring ≥ 40% oxygen ] and Grade 4 [defined per NCI CTCAE v5.0 as life- threatening consequences, urgent intervention needed ]: vigilant supportive care and intensive care monitoring for Grade 4 events, adapted vasopressor support and oxygen; specific treatment required : corticosteroids and/or t ocilizumab (humanized monoclonal antibody against the interleukin -6 receptor (Actemra ®) which has been FDA -approved for grade 3 or grade 4 CRS induced by CAR -T cell therapy, although off -label in Europe and off -label for other indications than CAR -T cell ). OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 65 of 101 02 February 2022 • Decision to continue subsequent injections of OSE2101 shall be taken considering condition of the pati ent, response to therapy with OSE2101 and alternate anticancer treatment options and the severity of CRS. o In grade 1 and 2 CRS , continuation of OSE2101 may be considered under strict surveillance if patient is having benefit of OSE2101 therapy ; it has been reported that CRS did not systematically recur at subsequent injections in an instance where grade 2 CRS was reported with OSE 2101 o In grade 3 and 4 CRS , treatment with OSE2101 shall not be continued and alternate cancer therapy should be considered . Patie nt trial assessments shall continue as scheduled in the protocol. In case of reversible grade 3 CRS, if the investigator considers the patient to be experiencing clinical benefit with OSE2101 , continuation of OSE2101 may be considered under strict surveillance after discussion and approval of the Sponsor . In case of grade 4 CRS, OSE2101 will be permanently discontinued. Figure 3: Treatment algorithm for management of cy tokine release syndrome (per Lee, 2014) Anaphylactic and severe immunoallergic reactions Anaphylactic reaction should be treated with immediate adrenaline subcutaneous injection followed by intensive care management. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 66 of 101 02 February 2022 Immunoallergic reactions will require corticosteroids. In case of anaphylactic and severe (grade 3 and 4) immunoallergic react ions, OSE2101 will be permanently discontinued . OSE2101 dosing adaptation There will be no dose reduction of OSE210 1. Treatment administration of OSE2101 may be delayed allowing enough time for recovery from toxicity. Toxicities must have improved to NCI CTCAE Grade ≤ 1 prior to re -treatment or NCI CTCAE as of baseline . A patient who has not received any study drug(s) for > 16 weeks since last OSE2101 administration , should be permanently discontinued from study treatment . Pemetrexed Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepati c function. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum non -hematologic toxicity from the preceding cycle of therapy. Treatment may be delayed allowing suffici ent time for recovery. Upon recovery, patients should be retreated using the guidelines in Table 3, Table 4 and Table 5, which are suitable for using pemetrexed as a single -agent or in combination with cisplatin. Table 3: Dose Reduction for Pemetrexed – Hematologic Toxicities Nadir Absolute neutrophil count (ANC) <500/mm3 and nadir platelets ≥50,000/mm3 75% of previous dose Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC 75% of previous dose Nadir platelets <50,000/mm3 with bleeding, regardless of nadir ANC 50% of previous dose If patients develop non -hematologic toxicities (excluding neurotoxicity) ≥ Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre -therapy value. Treatment should be resumed according to guidelines in Table 4. Table 4: Dose Reduction for Pemetrexed – Non-hematologic Toxicities OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 67 of 101 02 February 2022 Dose of pemetrexed (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose In the event of neurotoxicity, the recommended dose adjustments for pemetrexed are described in Table 5. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 5: Dose Reduction for Pemetrexed - Neurotoxicity CTC Grade Dose of pemetrexed (mg/m2) 0-1 100% of previous dose 2 100% of previous dose Discontinuation Recommendation Pemetrexed therapy should be discontinued if a patient experiences any hematologic or non - hematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renal Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, pemetrexed should not be administered to patients whose creatin ine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m -DTPA serum clearance method: [140 - Age in years] × Actual Body Weight (kg) = mL/min Males: 72 × Serum Creatinine (mg/dL) Females: Estimated creatinine clearance for males × 0.85 Caution should be exercised when administering pemetrexed concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min. Docetaxel Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non -hematological toxicities during docetaxel treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection, USP treatment discontinued entirely . OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 68 of 101 02 February 2022 Pemetrexed and docetaxel adaptation Dose reduction of pemetrexed and docetaxel will follow the guidance’s as their respective SCPs. Treatment administration may be delayed allowing sufficient time for recovery from toxicity.