Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 21 administration. Cyclophosphamide will be supplied by the institutional pharmacy. 4.1.2 Labeling Because the study is not blinded, the labeling will be that used on commercial vials of Cy, ALIMTA®, pemetrexed for injection, and cisplatin . The vials for CRS -207 will be labeled with the following: product name; volume; storage conditions; product lot number; sponsor name and address; fill date; and a caution statement (“Caution: New drug limited by Federal law to investigational use”). CRS -207 drug product is packaged in kit boxes that are also labeled with product name, number of vials, concentration, storage condition, a caution statement, sponsor name and address, expiration date, and kit lot number. 4.2 DOSING INSTRUCTIONS AND SCHEDULE 4.2.1 Cyclophosphamide Cohort 2 only: Cy will be administered to subjects by i.v. infusion at the immunomodulating dose of 200 mg/m2 in 100 m L normal saline over 30 minut es one day prior to each CRS -207 dose. For complete product information on dosage and administration, contraindications, warnings/precautions, adverse reactions, and drug interactions, see package insert for cyclophosphamide ( Appendix E). 4.2.2 C RS-207 CRS -207 will be administered by IV infusion (1 × 10 9 CFU in 100 mL sterile saline, USP, over approximately 1 hour ). CRS -207 is prepared by thawing one vial of drug product at room temperature. A total of 1 mL of product is drawn with a syringe and inserted into 1 bag of 100 mL saline solution for IV injection. Additional details for storage and preparation of CRS -207 are provided in the study Pharmacy Manual. CRS -207 will be administered to subjects by i.v. infusion on Day 1 of W eeks 1 and 3 for Cohort 1 or Day 2 of Weeks 1 and 3 for Cohort 2 prior to chemotherapy (prime vaccinations) and 3 and 6 weeks after the final chemotherapy cycle (boost vaccinations) . Subjects who continue to meet dosing eligibility will receive Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 22 additional CRS -207 maintenance vaccina tions at each follow- up visit . CRS -207 must not be administered via central venous catheters or infusion ports. Before each CRS -207 infusion, subjects will be premedicated with 650 mg acetaminophen. Subjects will receive a minimum of 500 mL of normal sal ine immediately before CRS -207 infusion and at least 500 mL after infusion (1 L is recommended for patients who can tolerate it, to mitigate infusion reactions) . Additional fluids may be given for persistent tachycardia, fever or hypotension based on investigator’s discretion. Subjects will be observed in the clinic for at least 4 hours after each infusion. Subjects who are not stable to be released at 4 hours after infusion should continue to be monitored until stable. Hospital admissions for overnight monitoring will not be considered an SAE unless the event meets criteria for seriousness other than hospitalization. Accumulating subject experience during and after CRS -207 infusions at 1 × 10 9 CFU have further demonstrated the following clinical obser vations which are to be expected : • Fevers . Despite the acetaminophen premedication, subjects can spike fevers up to 40°C starting at the end of the CRS -207 infusion generally through the next 24 hours. Oral Ibuprofen (400 to 800 mg) and acetaminophen (650 to 1000 mg) can be used in alternate sequence every 4 hours. • Rigors . Rigors (generally once or twice) have been observed starting during or at the end of the CRS -207 infusion through 24 hours. Intravenous narcotics such as morphine or meperidine can be administered per institutional policy. Oral morphine or non- steroidal anti- inflammatory drugs (NSAIDs) may be used as home treatment. • Blood pressure. Decreases in blood pressure have been observed necessitating additional IV fluids during the 4 hour observation period (up to 1 or 2 L). This may be the result of fever, compartmental shifts of fluid resulting from the CRS -207 infusion, and the use of narcotics. Some subjects have also been slightly hypotensive at 24 hours. Subjects are encouraged to hydrate themselves liberally at home with oral fluids. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 23 • Nausea and vomiting. Nausea and vomiting have been reported and observed within 24 hours after CRS -207 infusion. Subjects may be given anti-emetics as needed. 4.2.3 Pemetrexed The recommended dose of pemetrex ed is 500 mg/m2 body surface area ( BSA ) in 100 mL 0.9% sodium chloride administered over 10 minutes as an intravenous infusion on Day 1 of a 21- day cycle. Dose reductions may be required for subjects with hepatic or renal impairment or history of hematolo gic or non- hematologic toxicity to pemetrexed/cisplatin (see Appendix C , prescribing information for Alimta®). Subjects may receive pre- medications (e.g. folic acid and cyanocobalamin ) and pre - and post -infusion hydration per standard of care and investigator’s practice . For complete product information on dosage and administration, contraindications, warnings/precautions, adverse reactions, and drug interactions, see package insert for ALIMTA®, pemetrexed for injection (Appendix C ). 4.2.4 Cispla tin The recommended dose of cisplatin is 75 mg/m2 BSA in 1L 0.9% sodium chloride with mannitol 30g/L infused over 2 hours, beginning approximately 30 minutes after the end of pemetrexed administration on Day 1 of each 21 day cycle. Subjects may receive anti -emetics , e.g. dexamethasone, prior to cisplatin infusion per standard of care and investigator’s practice . Dose reductions may be required for subjects with hepatic or renal impairment or history of hematologic or non- hematologic toxicity to pemetre xed/cisplatin (see Appendix D , prescribing information for cisplatin). If a subject is determined to be intolerant to cisplatin after at least one dose, carboplatin may be substituted to be administered with pemetrexed per standard of care with the approval of the Sponsor. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 24 For complete product information on dosage and administration, contraindications, warnings/precautions, adverse reactions, and drug interactions, see the package insert for cisplatin (Appendix D ). 4.2.5 Delayed Dosing Dosing of CR S-207 with or without Cy (prime vaccination 2 [PV2], boost vaccination 1 [BV1], boost vaccination 2 [BV2] or maintenance vaccinations [MVs]) may be delayed up to 2 weeks. The medical monitor should be contacted for further instruction on continued dosing for any delay greater than 2 weeks. The total delay time during the prime vaccination period may not exceed 2 weeks , i.e. the first cycle of chemotherapy treatment should be administered no later than Week 7, after which the medical monitor should be contacted to discuss continued dosing. For subjects enrolled in Cohort 2, i f CRS -207 dosing is delayed more than 72 hours after administration of Cy for a particular dose, the dose will be delayed and Cy re-administered a minimum of 1 week after the original Cy dosing and CRS-207 administered according to schedule thereafter. Delayed chemotherapy dosing or missed chemotherapy doses due to the subject’s clinical status are at the discretion of the investigator, but the medical monitor may be contacted to discuss plans for continued dosing. The Sponsor should be notified of all modifications to the planned study schedule during the chemotherapy dosing period. If administration of CRS -207 doses (with or without Cy) or chemotherapy cycles are delayed, the subsequent dosing schedule will be adjusted according to the delayed dose(s). 4.3 STORAGE AND HANDLING OF CLINICAL TRIAL MATERIAL 4.3.1 Cyclophosphamide Cyclophosphamide powder should be kept at or below 25ºC. Cy reconstituted in normal saline is chemically and physically stable for 24 hours at room temperature and for 6 days when refrigerated. Guidelines outlining the procedures for proper handling and disposal of anticancer drugs should be followed when handlin g Cy (OSHA 1996). Protective gloves should be worn when handling Cy in both powder and reconstituted forms. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 25 4.3.2 CRS -207 CRS -207 must be stored at –60ºC or colder until just before use. The investigational site (s), per institutional guidelines, will des troy used CRS -207 vials after formulation for administration. The formulation of CRS -207 for administration and the destruction of each used vial will be carefully documented in the study Pharmacy Manual. The principal investigator is responsible for CRS - 207 accountability during on -site monitoring visits. Unused CRS -207 will be destroyed at the study site after final investigational product accountability and notification by Sponsor, unless otherwise directed by Sponsor. Wild -type Lm is classified by the Centers for Disease Control and Prevention for handling in the laboratory according to Biosafety Level 2 practices. Since CRS - 207 is attenuated by greater than 1,000- fold compared to wild- type Lm, individuals who prepare CRS 207 for injection should t ake appropriate precautions to avoid contamination or direct contact with the agent. Once it is prepared for infusion, CRS -207 can be handled with BSL 1 practices, including use of protective gloves, eye and face protection when handling and thorough hand washing after handling as the chance for direct exposure to CRS -207 by study personnel should be greatly diminished. Study personnel and staff should also adhere to the institutional guidelines for standard precautions. 4.3.3 Environmental Precautions Wild -type Lm is a common pathogen that is widely distributed in the environment and contaminates a variety of ready -to-eat foods. Despite the presence of Lm in diverse locations, clinically apparent human infection is not commonly reported in immunocompetent, normal individuals. Direct human- to-human spread of Lm is believed to be limited mainly to vertical transmission from mother to neonate. Standard isolation precautions are usually recommended for subjects infected with wild -type Lm. CRS -207 is a live -attenuated construct originating from wild - type Lm which contains deletion of 2 virulence genes that render it greater than 1,000- times less toxic than wild- type Lm. Preclinical studies demonstrated that virtually all CRS -207 was cleared from the body within 4 days of infusion and clinical studies with CRS -207 and similar live -attenuated Lm strains showed no shedding of the bacterium in urine or feces post -infusion. While the risk of infection with CRS -207 is unknown and expected to be low or none based on these data, p recautions should be exercised to avoid intimate contact between subjects and individuals who are at high risk of listeriosis (e.g. newborn infants, Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 26 pregnant women, HIV -positive individuals) for at least 7 days after each CRS -207 infusion. 4.4 PRODUCT ACCOUNTABILITY The investigator is responsible for the control of the investigational agent under study.