Table 1. Dosing -Eligibility Requirements Hematologic Renal Hepatic ANC ≥1,500/ µL Platelets ≥ 100,000/ µl Hemoglobin ≥9 g/dL CD4 ≥ 0.2 ×109/L prior to 1st post- chemotherapy CRS -207 boost vaccination Creatinine ≤2.0 × ULN AST/ALT ≤2.5× ULN Bilirubin ≤1.5× ULN or Bilirubin ≤3.0 × ULN if due to Gilbert’s disease ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of normal; WBC = white blood cell. * Cockcroft -Gault formula: Creatinine Clearance = {[(140 -age) x weight in kilograms] x [0.85 if female] }/[72 x creatinine in mg/dL] Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 17 3.3 ENDPOINTS 3.3.1 Primary Endpoint The primary endpoints are as follows: • The induction of mesothelin- specific T cell responses as measured by IFN -γ ELISPOT assay prior to treatment and at different time points during treatment . T cell responses to mesothelin will be considered positive when the frequency of specific responses are > 1 in 105 CD8+ peripheral blood lymphocytes (PBL) above the control sample and increased by at least 2 -fold compared to baseline. • Safety assessed by evaluation of AEs and deaths, vital signs, physical examination findings, clinical chemistry and hematology laboratory findings in subjects treated with CRS -207 (with or without Cy) combined with pemetrexed and cisplatin 3.3.2 Secondary Endpoints The secondary endpoints are as follows: • Objective tumor response, progression free survival and time to progression assessed by modifi ed RECIST for assessment of response in MPM 4 and irRC47 • Overall survival • Measure of s erum mesothelin to assess predictive value for therapeutic response 3.3.3 Exploratory Endpoints Exploratory endpoints are as follows: • Immune subset analysis ( e.g. CD4, CD8 , Treg) by immunohistochemistry and gene expression pro filing of tumor tissue pre and post vaccination • Induction of anti-mesothelin humoral immune response by ELISA • Tumor marker kinetics measured by serum levels of mesothelin and CA -125 and plasma osteopontin; other markers may also be evaluated Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 18 • Pulmonary function tests (PFTs ) measured by forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and vital capacity (VC) 3.4 RANDOMIZATION AND BLINDING No randomization or blinding is planned. 3.5 REPLACEMENT OF DROPOUTS Subjects who withdraw consent or are removed from the study before completing at least 4 cycles of chemotherapy will be considered dropouts and may be replaced at the discretion of the lead investigator, sponsor and medical monitor. 3.6 DOSE -LIMITING TOX ICITIES Dose -limiting toxicities (DLTs) are defined as events that are determined by the investigator as related to CRS -207 that meet one of the following criteria : • A fever of >40°C that lasts for greater than 24 hours and does not respond to antipyretics • Clinically significant hypotension unresponsive to intravenous fluids ( e.g. systolic BP <90 mm Hg or mean arterial pressure <55 mm Hg as measured on two separate occasions at least 10 minutes apart) • Grade 3 or greater decreases in leukocytes, ANC , or pl atelets that persist for more than 4 days • Hemoglobin ≤ 7.0 g/dL • ALT, AST, or alkaline phosphatase elevations >5 times the ULN (Grade 3) that persist for more than 7 days • Initiation of antibiotic therapy, coincident with simultaneous isolation of CRS -207 from a normally sterile body site, other than blood (e.g. cerebrospinal fluid, joint fluid) • Unexpected Grade 3 laboratory abnormalities lasting >48 hours • Grade 3 or greater hypophosphatemia or lymphopenia that persist for more than 7 days Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 19 • Any other Grade 3 or greater event according to National Cancer Institute’s Common Terminology Criteria for AEs (CTCAE) Version 4.03 All unexpected Grade 3 events will be reviewed by the lead investigator, sponsor and medical monitor. If the event is determined to be related to CRS -207 dosing and clinically meaningful, it will be considered a dose- limiting toxicity. Grade 3 laboratory abnormalities should be repeated within 24- 72 hours if clinically indicated and monitored as necessary to determine if event meets DLT criteria. DLTs will be continuously monitored per cohort and across cohorts . If more than 33% of subjects (i.e. 1 in 3 subjects) experience a DLT at the starting dose of 1 × 109 CFU, the dose will be lowered to 3 × 108 CFU for all subsequent dosing with CRS -207. Subjects currently receiving treatment may continue to receive CRS - 207 dosing at the lower dose and all subsequent subjects will receive CRS -207 at the lower dose. DLTs will continue to be monitored at the lower dose. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 20 4.0 DRUGS AND DOSAGES 4.1 IDENTIFICATION AND DESCRIPTION OF CLINICAL TRIAL MATERIAL (CTM) 4.1.1 CTM CRS -207 is a formulated live -attenuated strain hMeso38 of Lm, derived by deletion of actA and inlB coding sequences from a Streptomycin- resistant , wild-type strain and insertion of the hMeso coding sequence. The CRS -207 drug product consists of attenuated Lm (1 × 109 CFU total ) suspended in 1.0 mL of Dulbecco’s phosphate buffered saline and 9% vol/vol glycerol, filled into a single -use 3 -mL glass vial with a gray butyl stopper and aluminum crimp seal with a flip -off cap, and stored frozen at –60ºC or colder until intravenous administration. CRS -207 is supplied by Aduro. ALIMTA®, pemetrexed for injection, is an antifolate antineoplastic agent that exerts its action by disrupting folate -dependent metabolic processes essential for cell replication. Pemetrexed disodium heptahydrate has the chemical name L - Glutamic acid, N-[4-[2-(2-amino -4,7-dihydro-4- oxo-1H-pyrrolo[2,3- d]pyrimidin - 5-yl)ethyl]benzoyl] -, disodium salt, heptahydrate. It is a white to almost- white solid with a molecular formula of C 20H19N5Na2O6•7H 2O and a molecular weight of 597.49. Pemetrexed is supplied as a sterile lyophilized powder for i.v. infusion available in single -dose vials. The product is a white to either light yellow or green -yellow lyophilized solid. Each 500- mg vial contains pemetrexed disodium equivalent to 500 mg pemetrexed and 500 mg of mannitol. Pemetrexed will be supplied by the institutional pharmacy. Cisplatin, USP ( cis-diamminedichloroplatinum) is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. It is a white powder with the molecular formula PtCl 2H6N2, and a molecular weight of 300.1. Cisplatin injection is a sterile aqueous solution for intravenous use, each mL containing 1 mg cisplatin and 9 mg sodium chloride. Cisplatin will be supplied by the institutional pharmacy. Cyclophosphamide ( Cy; active ingredient cyclophosphamide monohydrate) is a synthetic antineoplastic drug chemically related to the nitrogen mustards. It is commercially available in a sterile powder formulation for use in i.v.