Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment wi th dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)] . 5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)] ; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)] . 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ൒45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)] . One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B 12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administer ing NSAIDs concurren tly with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)] . 5.5 Required Laboratory Monitoring 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 [see Dosage and Administration (2.4)] . 5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embr yotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 88 5 becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)] . 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ൒20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ൒20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastati c NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B 12. Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ReactionbALIMTA/cisplatin (N=839)Gemcitabine/cisplatin (N=830) All Grades Toxicity (%)Grade 3-4 Toxicity (%)All Grades Toxicity (%)Grade 3-4 Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 Neurology Neuropath y-sensory 9 0 12 1 Taste disturbance 8 0c90c Dermatology/Skin Alopecia 12 0c21 1c Rash/Desquamation 7 0 8 1 aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. bRefer to NCI CTC Criteria version 2.0 for each Grade of toxicity. cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. No clinically relevant differences in adverse reactions were seen in patients based on histology.In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm. The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 89 6 Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Non-Small Cell Lung Cancer (NSCLC) - Maintenance Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B 12. Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa ReactionbALIMTA (N=438)Placebo (N=218) All Grades Toxicity (%)Grade 3-4 Toxicity (%)All Grades Toxicity (%)Grade 3-4 Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Leukopenia 6 2 1 1 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional Symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 52 20 Neurology Neuropath y-sensory 9 1 4 0 Dermatology/Skin Rash/Desquamation 10 0 3 0 aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. bRefer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity. No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucas ian patients compared to non-Caucasian patients (6.5% versus 0.6%). Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differen ces in Grade 3/4 adverse reactions were seen. Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 90 7 The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skin — alopecia, pruritis/itching Gastrointestinal — constipation General Disorders — edema, fever (in the absence of neutropenia) Hematologic — thrombocytopenia Renal — decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular — supraventricular arrhythmia Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity Neurology — motor neuropathy Renal — renal failure Non-Small Cell Lung Cancer (NSCLC) – After Prior Chemotherapy Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B 12supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy. Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa ReactionbALIMTA (N=265)Docetaxel (N=276) All Grades Toxicity (%)Grades 3-4 Toxicity (%)All Grades Toxicity (%)Grades 3-4 Toxicity (%) Laboratory Hematologic Anemia 19 4 22 4 Leukopenia 12 4 34 27 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/Pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional Symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/Desquamation 14 0 6 0 Pruritis 7 0 2 0 Alopecia 6 1c38 2c aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. bRefer to NCI CTC Criteria for lab values for each Grade of t oxicity (version 2.0).