expansion) will be evaluated descriptively and may be used as covariates in sensitivity analyses of efficacy endpoints . 8.2.4 Efficacy Analysis Efficacy analysis will be conducted on full analysis and per protocol populations. Standard adjustments to analyses for pre -specified or baseline -suggested clinical covariates will be performed; these covariate -adjusted analyses will be considered secondary analyses. The primary endpoint is the change in IFN -γ production of mesothelin- specific T cells by ELISPOT assay from baseline to (1) immediately after CRS -207 (with or without Cy), (2) after receiving chemotherapy, and (3) after receiving two subsequent doses of CRS -207 (with or without Cy) following chemotherapy. Change from baseline will be compared via paired t -test of log - transformed post/pre ELISPOT values and assessed for statistical significance via Hochberg multiplicity alpha adjustment. T cell responses to mesothelin will be considered positive when the f requency of specific responses are ≥ 1 in 10 5 CD8+ peripheral blood lymphocytes (PBL) above the control sample and increased by at least 2 -fold compared to baseline. T cell responses to Lm (LLO) will be considered positive when specific T cell frequencies were ≥ 1 in 105 PBMCs and increased by at least 2 -fold compared to baseline. In addition, if change from baseline in the logarithmic scale is not normally distributed (that is, if p<0.05 by a Shapiro-Wilks test) then a Wilcoxon signed rank test will be performed instead. Analyses of other efficacy endpoints including changes in PFTs, objective tumor response, progression free survival, time to progression and overall survival will be conducted on the full analysis and per protocol populations. Time to event data will be analyzed using Kaplan -Meier methods and will be calculated from date of first dose of study treatment. Further details on the analyses including censoring strategies will be described in a statistical analysis plan. Exploratory analyses will be conducted to evaluate t he relationship between PFT improvement and tumor response, as well as to evaluate the relationship between overall survival and tumor response. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 65 8.2.5 Safety Analysis AE data will be listed individually and incidence of AEs summarized by system organ class and preferred terms within a system organ class for each treatment group. When calculating the incidence of AEs, each AE (based on preferred terminology defined by M edical Dictionary for Regulatory Activities, Version 13.1, or the most current version) will be counted only once for a given subject. In analyses of grade and causality, if the same AE occurs on multiple occasions, the highest grade and strongest relatio nship to study drug will be assumed. If two or more AEs are reported as a unit, the individual terms will be reported as separate experiences. Changes in vital signs, hematology, and clinical chemistry parameters from baseline to the end of the study wi ll be examined. Treatment -emergent changes from normal to abnormal values in key laboratory parameters will be identified. 8.2.6 Pharmacokinetic Analysis No formal pharmacokinetic or pharmacodynamic analyses are planned for the investigational agents used in this study. 8.2.7 Interim Analysis Safety data will be reviewed on an ongoing basis by Aduro, the investigator (s), and medical monitor. No formal interim analysis for this phase 1B study is planned. 8.2.8 Sample Size Up to 60 subjects in total may be enrolled, based on the original planned cohort of 16 subjects and an expansion cohort that may enroll up to an additional 44 subjects. At least 32 subjects will receive CRS -207 in combination with chemotherap y (Cohort 1) . Additional subjects (up to 28) will receive Cy one day prior to each CRS-207 administration combined with chemotherapy (Cohort 2). The originally planned sample size calculation was based on the primary endpoint of change in mesothelin- specific T cell responses as measured from ELISPOT. With one primary parameter (ELISPOT) to be measured with respect to a change from baseline at three post -baseline time points , the sample size will be selected to allow each test to be performed using a 0.017 two- tailed significanc e level, in Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 66 order to allow the overall set of three tests to be very conservatively performed as if at an overall 0.05 level using a Bonferroni adjustment. Assuming 14 subject s with complete measurements of the main parameter at baseline and the three subsequent time points, there would be 80% power to detect a change from baseline to each time point equal to 1.0 standard deviations of the change (1.0 effect size) using a two -tailed 0.017 level paired t -test. This stringent multiplicity adjustment is for p ower computation only. In practice, for analysis purposes, instead of requiring that each test achieve a 0.017 level in order to be declared significant, a less overly stringent Hochberg adjustment may be used . In order to allow for a small number of ine valuable subjects, up to 16 subjects could be enrolled . The expansion cohort of up to 44 additional subjects , including subjects receiving Cy one day prior to CRS -207 (Cohort 2) is intended to obtain additional safety , immune and efficacy data for future study planning . The expansion sample size is based on practical rather than statistical considerations. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 67 9.0 CLINICAL STUDY ADMINISTRAT ION 9.1 INFORMED CONSENT AND AUTHORIZATION FOR USE AND DISCLOSURE OF PHI Written informed consent and authorization of use and disclosure of PHI must be obtained from each subject (or the subject’s legally authorized representative) before performing any study -specific screening/baseline period evaluations. One copy of the signed ICF and authorization for use and disclosure of the PHI form will be given to the subject, and the investigator will retain the original. The ICF and authorization for use and disclosure of PHI, which is prepared by the investigator or the site, must be reviewed and approved by Aduro, the study monitor (if applicable), and the site’s IRB before the initiation of the study. The ICF must contain the 20 elements of informed consent described in ICH E6, Section 4.8. The authorization for use and disclosure of PHI must contain the elements required by Title 45 of the CFR, Section 164.508(b), for valid authorizations. 9.2 STUDY DOCUMENTATION 9.2.1 Investigator Information Investigator information is included in the SPM, which is updated as needed. 9.2.2 Investigator Study Files Documentation about the investigator and study staff, the IRB, and the institution, is required by the sponsor before study site initiation. Copies of these documents as well as supplemental information, such as the investigator’s obligations, IB, clinical study protocol and amendments, safety information, CTM, biological samples, laboratory, SPM and study logs, monitoring activities, sponsor/investigator/study monitor correspondence, will be kept on- site in study site-specific binders. Aduro will be responsible for maintaining backup of all CRF data. The investigator is responsible for maintaining backup of all electronic data systems used for primary documentation or source documentation. Backup of electronic data will be performed periodically as described in the site- specific SOPs. Backup records must be stored at a secure location on site, and backup and recovery logs must be maintained to facilitate data recovery. Finally, if an Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 68 electronic medical records system that is not supported by the sponsor (or is discontinued or decommissioned) is used, the investigator must maintain a system to retrieve these records or arrange for the transfer of these records to an alternate electronic format or to paper. Changes to any electronic records requires an audit trail, in accordance with 21 CFR 11.10(e), and should include who made the changes and when and why the changes were made. An audit trail is defined as a secure, computer -generated, time-stamped electronic record that will allow reconstruction of the course of events relating to the creation, modification, and deletion of an electronic record. Audit trails must be created incrementally, in chronological order, and in a manner that does not allow new audit trail information to overwrite existing data. Finally, audit trails should be in a readable format and readily available at the study site and any other location where electronic study records are maintained. Audit trails are generated automatically for electronic CRFs. The investigator is responsible for maintaining audit trails of all electronic data systems used for primary documentation or source documentation. 9.2.3 CRF s and Source Documentation The investigator must make study data accessible to the site monitor, to other authorized representatives of Aduro, and to the appropriate regulatory authority inspectors. The original CRF for each subject will be checked against source documents at the study site by the site monitor. 9.2.4 Retention of Study Documents According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and electronic documentation and administrative records, must be retained by the investigator for a minimum of 2 years after notification that the appropriate regulatory authority has approved the product for the indication under study, notification that the entire clinical investigation will not be used in support of a marketing application, or notification that the marketing application was not approved. No study documents will be destroyed or moved to a new location without prior written approval from Aduro. If the investigator relocates, retires, or withdraws from the clinical study for any reason, all records required to be maintained for the study should be transferred to an agreed -upon designee, such as another investigator at the institution where the study was conducted. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 69 Audit trails for electronic documents must be retained for a period at least as long as that required for the subject electronic records to which they pertain. The investigator must retain either the original or a certified copy of audit trails. 9.3 CONFIDENTIALITY 9.3.1 Data All information about the nature of the proposed investigation provided by Aduro or the study monitor to the investigator (with the exception of information required by law or regulations to be disclosed to the IRB, the subject, or the appropriate regulatory authority) must be kept in confidence by the investigator. 9.3.2 Subject Anonymity The anonymity of participating subjects must be maintained. Subjects will be identified by their initials and an assigned subject number on CRFs and other documents retrieved from the site or sent to the study monitor, Aduro, regulatory agencies, or central laboratories/reviewers. Documents that identify the subject (e.g. the signed ICF) must be maintained in strict confidence by the investigator, except to the extent necessary to allow auditing by the appropriate regulatory authority, the study monitor, or Aduro representatives. 9.4 PROTOCOL COMPLIANCE Substantive changes in the protocol include changes tha t affect the safety of subjects or changes that alter the scope of the investigation, the scientific quality of the study, the experimental design, dosages, assessment variable(s), the number of subjects treated, or the subject selection criteria. Such changes must be prepared as a protocol amendment by Aduro only upon joint approval of the changes by Aduro and the investigator. A protocol amendment must receive IRB approval before implementation. In parallel with the IRB approval process, the protocol amendment will be submitted to the appropriate regulatory authority as an amendment to the regulatory submission under which the study is being conducted. If a protocol amendment requires changes in the ICF, the revised ICF prepared by the investigator must also be approved by Aduro, the study monitor, and the IRB before implementation. Emergency departures from the protocol that eliminate an apparent immediate hazard to a particular subject and that are deemed crucial for the safety and Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 70 well-being of that subject may be instituted for that subject only. The investigator or the attending physician also will contact the medical monitor as soon as possible in the case of such a departure. These departures do not require preapproval by the IRB; however, the IRB and the medical monitor must be notified in writing as soon as possible after the departure has been made. In addition, the investigator will document in the subject’s CRF the reasons for the protocol deviation and the ensuing events. 9.5 STUDY MONITOR FUNCTIONS AND RESPONSIBILITY The study monitor, in accordance with Aduro’s requirements, will ensure that the study is conducted and documented properly by carrying out the relevant activities outlined in ICH E6, Section 5.18.4. 9.6 GENERAL INFORMATION The investigator should refer to the IB, product labels, and the SPM, any other information provided during the study initiation visit or by the study monitor, and the appendices of this protocol for further information about this investigational new product or details of the procedures to be followed during the course of this study. Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 71 10.0 REFERENCES 1. Walter S WT, Stenzl A, Zdrojowy R, Pluzanska A, et al. Multipeptide immune response to cancer vaccine IMA901 after single -dose cyclophosphamide associates with longer patient survival. Nat Med 2012;18:1254-61.