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. Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 91 8 The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. Incidence 1% to 5% Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin — erythema multiforme Neurology — motor neuropathy, sensory neuropathy Renal — increased creatinine Incidence Less than 1% Cardiovascular — supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM) Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid an d vitamin B 12. Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa ReactionbALIMTA/cisplatin (N=168)Cisplatin (N=163) All Grades Toxicity (%)Grade 3-4 Toxicity (%)All Grades Toxicity (%)Grade 3-4 Toxicity (%) Laboratory Hematologic Neutropenia 56 23 13 3 Leukopenia 53 15 17 1 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Creatinine elevation 11 1 10 1 Creatinine clearance decreased 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/Pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Neuropath y-sensory 1001 01 Taste Disturbance 8 0c60c Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0c60c 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 except the term “creatinine clearance decreased” which is derive d from the CTC term “renal/genitourinary-other”. cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin. Incidence 1% to 5%Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 92 9 Body as a Whole — febrile neutropenia, infection, pyrexia Dermatology/Skin — urticaria General Disorders — chest pain Metabolism and Nutrition — increased AST, increased ALT, increased GGT Renal — renal failure Incidence Less than 1% Cardiovascular — arrhythmia Neurology — motor neuropathy Effects of Vitamin Supplementations Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B 12from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm. Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Adverse Eventa(%)Fully Supplemented Patients (N=168)Never Supplemented Patients (N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 aRefer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0). The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%). Subpopulations No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%). Additional Clinical Trials Experience Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients. Cases of esophagitis have been reported in clinical trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or est ablish a causal relationship to drug exposure. These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.Gastrointestinal — colitis General Disorders and Administration Site Conditions —e d e m a Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy. Respiratory — interstitial pneumonitis Skin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal. 7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ൒80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)] . Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethac in) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. 7.2 Nephrotoxic DrugsProtocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 93 10 ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incompl ete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. 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 use effec tive contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4 Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) an d a Phase 2 study (72 patients). All patients received pretreatment with vitamin B 12and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial.