• At the time of publication or shortly thereafter. 6.3 EFFICACY ASSESSMENTS 6.3.1 Antitumor Response Tumo r assessments will be done at week 6 and then every 8 weeks thereafter and may include the following evaluations: ph ysical examination (with photograph and measurement of skin lesions, as applicabl e); cross-sectional imaging using computed tomography ( CT) or magneti c resonanc e imagin g (MRI) scan of the chest, abdomen, and pelvis (pelvis scan is optional unless known pelvic disease is present at baseline); nuc lear bone scan for subjects with known/suspected bone lesions; and CT or M RI scan of the brain (only as clinically warranted based on symptoms/findings). The preferred method of disease assessment is CT with contrast. If CT with contrast is contraindicated , CT of the chest without contrast and MRI scan of the abdomen/pelvis with contrast is preferred. At baseline, tumor lesions will be selected and categorized as target (measurable disease) or non - target lesions (non-measurable disease) . 6.3.2 Disease Parameter s Measurable disease . Measurable lesions are defined as those lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as : • By chest x -ray: >20 mm ; • By CT scan: o Scan slice thickness 5 mm or under: as >10 mm o Scan slice thickness >5 mm: double the slice thickness • With calipers on clinical exam: >10 mm. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Malignant lymph no des. To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm) . At baseline and in follow -up, only the short axis will b e measured and followed. Non-measurable disease . All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, l eptomeningeal disease, ascites, pleural/pericardial Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 44 effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non -measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non -measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non -cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions . All measurable lesions u p to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (those with the longest diameter) , be representative of all involved organs, but in addition should be those that lend themselves to reproducible and repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which cir cumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non -nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diamet ers. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions . All other lesions (or sites of disease) including any measurable lesions above the 5 target lesions should be identified as non -target lesions and should be recorded at baseline. Measurements of these lesions are not required, but the pre sence, absence, or in rare cases unequivocal progression of each should be noted throughout follow -up. 6.3.3 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline ev aluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and re ported lesion at baseline and during follow -up. Imaging -based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. The same mode of assessment (e.g., CT) use d to identify/evaluate lesions at baseline should be used throughout the course of the study unless subject safety necessitates a change (e.g., allergic reaction to contrast media). Clinical lesions: Clinical lesions will only be considered measurable whe n they are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion , is recommended. Chest x -ray: Lesions on chest x -ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 45 Conventional CT and MRI: This guideline has defined measurability of le sions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situatio ns (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow -up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence paramete rs for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath -hold scanning techniqu es, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET -CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part o f a PET -CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET -CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from o ne assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA -125 response (in recurrent ovarian cancer) and PSA response (in recurrent prosta te cancer) have been published. (75-77) In addition, the Gynecologic Cancer Intergroup has developed CA -125 progression criteria which are to be integrated with objective tumor assessment for use in first -line trials in ovarian cancer. (78) Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 46 Cytology, Histology: These techniques can be used t o differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and pro gressive disease. FDG -PET: While FDG -PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG -PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New l esions on the basis of FDG -PET imaging can be identified according to the following algorithm: a. Negative FDG -PET at baseline, with a positive FDG -PET at follow -up is a sign of PD based on a new lesion. b. No FDG -PET at baseline and a positive FDG -PET at follow -up: If the positive FDG -PET at follow -up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG -PET at follow -up is not confirmed as a new site of disease on CT, additional follow -up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG - PET scan). If the positive FDG -PET at follow -up corresponds to a pre -existing site of disease on CT that is not progressing on the ba sis of the anatomic images, this is not PD. c. FDG -PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG -PET in this ci rcumstance should be prospectively described in the protocol and supported by disease -specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG -PET and bio psy resolution/sensitivity. Note: A ‘positive’ FDG -PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image. 6.3.4 RECIST Response Criteria Antitumor activity will be evaluat ed with target and/or non -target lesions according to RECIST Version 1.1 (79) as summarized below. 6.3.5 Target Response Percentage change in target lesion size will be evaluated by the following formulae: 1. When determining complete response or partial response: [(Post value – Baseline value)/Baseline value] x 100 2. When determining progressive disease: [(Post value – Smallest value since treatment started)/(Smallest value since treatment started)] x 100 Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 47 Target response will be classified according to the RECIST Version 1.1 Target Lesion Response Criteria in Table 5. Table 5: RECIST Target Response Criteria Target Response Criteria Definition Complete Response (CR) Disappearance of all target lesions. Any pathological lymph nodes (whether target or non - target) must have reduction in short axis to < 10 mm. Partial Response (PR) At least a 30% decrease in the sum of diameters of target lesions, taking as reference th e baseline sum diameters. Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study . Progressive Disease (PD) At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum diameters while on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of 5 mm. (Note: the appearance of one or more lesions is also considered progression). Non-target response will be classified according to the RECIST Version 1.1 Non -Target Lesion Response Criteria in Table 6. Table 6: RECIST Non -Target Response Criteria Non-Target Response Criteria Definition CR Disappearance of all non -target lesions and normalization of tumor marker level. All lymph nodes must be non -pathological in size (< 10 mm short axis). Non-CR / Non -PD Persistence of one or more non -target lesion(s) and/or maintenance of tumor marker level above the normal limits. PD Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression). Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 48 Overall response will be classified according to the RECIST Version 1.1 Overall Response Criteria in Table 7. Table 7: RECIST Overall Response Criteria 6.3.6 Duration of Response Duration of overall response : The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from t he time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease : Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. 6.3.7 Progression -Free Survival (PFS) PFS is defined as the duration of time from start of treatment to time of progression or death, which ever occurs first. 6.4 TOXICITY CRITERIA The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adve rse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site : Target Lesions Non-Target Lesions New Lesions Overall Response CR CR No CR CR Non-CR / Non -PD No PR CR Not Evaluated No PR PR Non-PD or not all evaluated No PR SD Non-PD or not all evaluated No SD Not all evaluated Non-PD No Inevaluable PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 49 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 7 SAFETY REPORTING REQ UIREMENTS/DATA AND S AFETY MONITORING PLAN 7.1 DEFINITIONS 7.1.1 Adverse Event Any untoward medical occur rence in a human subject, including a ny abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in research, whether or not considered related to the subject’s p articipation in the research . 7.1.2 Suspected adverse reaction Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. 7.1.3 Unexpected adverse reaction An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator bro chure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected” also refers to adverse events or suspected adverse reactions that are mentio ned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation. 7.1.4 Serious An Unanticipated P roblem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 7.1.5 Serious Adverse Event An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following: • Death, • A life -threatening adverse drug experience • Inpatient hospitalization or prolongation of existing hospitalization • Persistent or significant inca pacity or substantial disruption of the ability to conduct normal life functions Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 50 • A congenital anomaly/birth defect. • Important medical events that may not result in death, be life -threatening, or require hospitalization may be considered a serious adverse d rug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 7.1.6 Disability A substantial disruption of a per son’s ability to conduct normal life functions. 7.1.7 Life-threatening adverse drug experience Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the rea ction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 7.1.8 Protocol Deviation (NIH Definition) Any change, divergence, or departure from the IRB -approved research protocol. 7.1.9 Non-complian ce (NIH Definition) The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects. 7.1.10 Unanticipated Problem Any incident, experience, or outcome that: • Is unexpected in terms of nature, severity, or frequency in relation to (a) the research risks that are described in the IRB -approved research protocol and informed consent document; Investigator’s Brochure or other study documents, and (b) the characteristics of the subject population being studied; AND • Is related or possibly related to participation in the research; AND • Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, econo mic, or social harm) than was previously known or recognized. 7.2 NCI-IRB AND CLINICAL DIRECTOR (CD) REPORTING 7.2.1 NCI-IRB and CD Expedited Reporting of Unanticipated Problems and Deaths The Protocol PI will report in the NIH Problem Form to the NCI -IRB and NCI CD: • All deaths, except deaths due to progressive disease • All Protocol Deviations • All Unanticipated Problems Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 51 • All non -compliance Reports must be received within 7 days of PI awareness via iRIS. 7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review The protocol PI will report to the NCI -IRB: 1. A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action. 2. A summary of any instances of non -compliance 3. A tabular summary of the following adverse events: • All Grade 2 unexpected events that are possibly, probably or definitely related to the research; • All Grade 3 and 4 events that are possibly, probably or definitely related to the research; • All Grade 5 events regardless of attribution; • All Serious Events regardless of attribution. NOTE : Grade 1 events are not required to be reported. 7.2.3 NCI-IRB Reporting of IND Safety Reports Only IND Safety Reports that meet the definition of an unanticipat ed problem will need to be reported to the NCI IRB. 7.3 IND SPONSOR REPORTING CRITERIA During the first 30 da ys after the subject receives investigational agent/intervention, the investigator must report within 1 business day to the sponsor, using the mandatory MedWatch form 3500a, any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caus ed the event . For serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention, only report those that have an attribution of at least possibly related to the agent/intervention. Required timing fo r reporting per the above guideline: • Deaths (except death due to progressive disease) must be reported via ema il within 24 hours. A complete report must be submitted within one business day. • Other serious adverse events as well as deaths due to progressive disease must be reported within one business day Events will be submitted to the Center for Cancer Researc h (CCR) at: CCRsafety@mail.nih.go v. 7.3.1 Reporting Pregnancy 7.3.1.1 Maternal Exposure Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 52 If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be documented in box B5 of the MedWatch form “Describe Event or Problem”. Pregnancy itself is not regarded as a n SAE. However, as patients who become pregnant on study risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, puerperium and perina tal conditions - Other (pregnancy )” under the Pregnancy, puerperium and perinatal conditions SOC. Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without complications shoul d not be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented. If any pregnancy occurs in the course of the study, th en the investigator should inform the Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes aware of it. The designated Sponsor representative will work with the investigator to ensure that all relevant information i s provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies. The same timelines apply when outcome information is available. 7.3.1.2 Paternal exposure Male patients should refrain from fathering a child or donating sperm during the study and for one month after the last dose of combination ETBX -011, ETBX -051, ETBX -061 . Pregnancy of the patient’s partner is not considered to be an AE. However, the outcom e of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until one month after the last dose should, if possible, be followed up and documente d. 7.4 SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 7.4.1 Etubics Corporation All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov . The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below. In the event of any new SAE (of any Grade) occurring during the reporting period (from first dose until decision made to discontinue treatment) , the investigator must within 2 business day s inform the Manufacturer (Etubics Corporation) or designee by telephone, by fax, or by email. When an event (or follow -up information) is reported by telephone, a written report must be sent immediately thereafter by fax or email. Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 53 Reportin g procedures and timelines are the same for any new information on a previously reported SAE (=follow -up). Any new SAE is reported to: Jelena Berglund, PhD VP Operations 401 West Harrison Street, Seattle, WA 98119 Telephone: 206-838-5110 Cell: 919-265-7089 (primary number) Fax: 206-838-2978 Email: jelena@etubics.co m All Medwatch 3500a forms and written reports should be transmitted, whic h must be completed by the investigator following specific completion instructions. Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant drugs). In all cases, the information provided in the SAE Report Form must be c onsistent with the data on the event that is recorded in the corresponding sections of the CRF. 7.5 INSTITUTIONAL BIOSAFETY COMMI TTEE (IBC) REPORTING CRITERIA 7.5.1 Serious Adverse Event Reports to IBC The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life -threatening experience associated with the use of ETBX vaccine s as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events that are unexpecte d and associated with the use of the ETBX vaccine s, but are not fatal or life -threatening, much be reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator’s initial receipt of the information. Adverse events may be reported by using the FDA Form 3500a. 7.5.2 Annual Reports to IBC Within 60 days after the one -year anniversary of the date on which the IBC approved the initial protocol , and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, IRB continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC protocol number on the report. 7.5.2.1 Clinical Trial Information A brief summary of the status of the trial in progress or completed during the previous year. The summary is required to include the following information: • the title and purpose of the trial • clinical site • the Principal Investigator • clinical protocol identi fiers; • participant population (such as disease indication and general age group, e.g., adult or pediatric); Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 54 • the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial wa s completed; and the number who dropped out of the trial with a brief description of the reasons • the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed, • if the trial has been completed, a brief description of any study results. 7.5.2.2 Progress Report and Data Analysis Information obtained during the previous year's clinical and non -clinical investigations, including: • a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system • a summary of all serious adverse events submitted during the past year • a summary of serious adverse events that were expected or considered to have causes not associated with the use of th e gene transfer product such as disease progression or concurrent medications • if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death • a brief description of any information obtained that is pertinent to an understanding of the gene transfer product’s actions, in cluding, for example, information about dose -response, information from controlled trials, and information about bioavailability. 7.6 DATA AND SAFETY MONITORING PLAN 7.6.1 Princip al Investigator/Research Team The clinical research team will meet on a weekly basis when patients are being actively treated on the trial to discuss each patient, enrollment and data management issues. Decisions about dose level enrollment and dose escalation will be made based on the toxicity data from prior patients. All data will be c ollected in a timely manner and reviewed by the principal investigator or associate investigator. Adverse events will be reported as required above. Any safety concerns, new information that might affect either the ethical and or scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff. 7.6.2 Sponsor Monitoring Plan As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR’s program allows for confirmation of: study data, specifically data that could affect the int erpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on: Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 55 • Informed consent process • Eligibility confirmation • Drug administration and accountabil ity • Adverse events monitoring • Response assessment. The monitoring program also extends to multi -site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by a n CCR contractor. Monitors are qualified by train ing and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct. 7.6.3 Safety Monitoring Committee (SMC) This protocol will require oversight from the Safety Monitoring Commit tee (SMC). Initial review will occur as soon as possible after the annual NCI -IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 8 STATISTICAL METHODS 8.1 STATISTICAL HYPOTHESIS This is a Phase I trial in subjects with advanced cancer. A combination ETBX -011, ETBX -051, ETBX -061 vaccine regimen using the same modified Adenovirus vector backbone, separately encoding three well -studied TAA s will be assessed. The vaccine will be tested at standard dose level, and a dose de -escalation (if requ ired) design will be employed. The primary endpoint will be to determine the overall safety of combined ETBX -011/ETBX -061/ETBX -051 vaccine when administe red SC to subjects with advanced solid tumors and establish a recommended phase 2 dose of vaccine. This will be reported when an MTD is determined (expected to be less than 1 year from trial start). A secondary endpoint will be to obtain preliminary data o n ORR, DCR, duration of response, PFS, and OS in treated subjects (preliminary data will be assessed around two years following trial start) . An exploratory hypothesis (objective) will be to evaluate the immunogenicity of the combined ETBX -011/ETBX -061/ETB X-051 vaccine. 8.2 SAMPLE SIZE DETERMINATION Up to six patients will be enrolled in an initial dose level 1 . If ≤1 of 6 patients experience a DLT, then the MTD will be declared, and initiation of the dose expansion phase will occur. If ≥2 of 6 experience DLT in the initial dose level 1 , then dose de -escalation will occur. Up to six patients will be enrolle d at the lower dose level ( -1) (1x1011 VP). If ≤1 of 6 patients experience a DLT, then the maximum tolerated (MTD) will be declared at this dose, and initiation of the dose expansion phase will occur. If ≥2 of 6 (or >=2 of the first 3) experience DLT in this second dose level -1, then a n amen dment may be written to further evaluate dose de -escalation . Once the MTD is identified, the dose expansion component will commence. An additional 4 subjects will be Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 56 enrolled at the MTD for a total of 10 subjects to gain additional safety data and explorat ory data on vaccine immunogenicity. We assume 16 patients will have screen failure. Therefore, up to 32 subjects will be enrolled in the study. Initial dose evaluation and or dose finding will require 6 -12 subjects, followed by 4 additional subjects treate d at a defined dose . 8.3 POPULATION FOR ANALYSES Evaluable for toxicity : All patients will be evaluable for toxicity from the time of their first treatment with the combination ETBX -011, ETBX -051, ETBX -061 vaccine regimen . Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re -evaluated will be considered evaluable for response. These patients will have their response classifi ed according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non -Target Disease Response : Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re -evaluated will be considered evaluable for non -target disease. The response assessment is based on the pre sence, absence, or unequivocal progression of the lesions. 8.4 STATISTICAL ANALYSES 8.4.1 General Approach Descriptive analyses of toxicity results and exploratory description of time-to-event and response based results. The planned analyses for each objective is described in the subsections below. 8.4.2 Analysis of Primary Efficacy Endpoint s Not applicable in this Phase 1 Study. The primary objective of evaluating safety is described in Section 8.4.4 below. 8.4.3 Analyses of Secondary Endpoint Analyses of secondary endpoint to obtain preliminary data on objective response rate (ORR), disease control rate (DCR), duration of response, progressio n-free survival (PFS), and overall survival (OS) in treated subjects. Since this is a Phase I trial, only preliminary data will be obtained for evidence of vaccine efficacy. Preliminary analyses of vaccine efficacy are described in the Sections 8.4.3.1 to 8.4.3.4 below. 8.4.3.1 Objective Tumor Response and Disease Control Rate The percentage of subjects that achieve an objective confirmed complete or partial overall tumor response using RECIST Version 1.1 will be evaluated by dose level and overall enrollment. If anti - tumor responses are observed, the 95% confidence interval of the response rate will be evaluated. Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 57 Disease control (confirmed response or SD lasting for at least 6 months) will be analyzed in a similar manner. 8.4.3.2 Duration of Response The duration of overall response will be evaluated by dose level and overall enrollment. Th e duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or PD is objectively documented (taking as reference for PD the smallest measurements recor ded since the treatment started). 8.4.3.3 Progression -Free Survival PFS will be evaluated by dose level and overall using Kaplan -Meier methods. PFS will be defined as the time from the date of first treatment to the date of disease progression or death (any cause ) whichever occurs first. Subjects who do not have disease progression or have not died at the end of follow up will be censored at the last known date the subject was progression free. 8.4.3.4 Overall Survival OS will be evaluated by dose level and overall using Kaplan -Meier methods. OS will be defined as the time from the date of first treatment to the date of death (any cause). Subjects who are alive at the end of follow up will be censored at the last known date alive. 8.4.4 Safety Analysis DLTs will be evaluated co ntinuously in a dose level . An overall assessment of whether to de- escalate to the next dose level will be made at least 1 week after the last subject in the previous dose level has received their first injection. A dose level will be considered safe if < 33% of subjects treated at a dose level experience a DLT (i.e., 0 of 3, ≤ 1 of 6, ≤ 2 of 9, ≤ 3 of 10) . Safety will be evaluated in 3 or 6 subjects at each dose level in the dose escalation component of the study. Safety will continue to be monitored amon g additional subjects treated at the MTD or HTD in the dose expansion component of the study. A subject will be considered evaluable for safety if treated with at least one injection. DLTs will be observed for 1 week. Safety endpoints will be analyzed as summary statistics during treatment and/or as change scores from baseline assessments. AEs will be coded as defined in the Medical Dictionary for Regulatory Activities (MedDRA). All AEs will be recorded and tabulated following each treatment (vaccine injection). AEs will be recorded by severity, frequency, and relationship to the study intervention and will be presented by System Organ Class (SOC) designations and preferred term groupings. Information on each AE will include start date, stop date, severit y, relationship, expectedness, outcome, and duration. Adverse events leading to premature discontinuation from the study intervention and serious treatment -emergent AEs will be presented either in a Table or a Listing. In addition, o verall safety will be assessed by descriptive analyses using tabulated frequencies of AEs by grade using CTCAE Version 5.0 within dose levels and for the overall study population in terms of treatment -emergent AEs, SAEs, and clinically significant changes in safety laboratory tests, physical examinations, ECGs, and vital signs. The safety events listed in section 8.4.6.2 will trigger a temporary suspension of the study injections .: Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 58 8.4.5 Baseline Descriptive Statistics Not applicable for this Phase I study. 8.4.6 Planned Interim Analyses and Halting Guidelines 8.4.6.1 Planned in terim analysis Not applicable for this Phase I study. 8.4.6.2 Halting guidelines The following safety events will trigger a temporary suspension of the study injections: • Death possibly related to the study agent. • Two Grade 4 toxicity events that are possibly related to the study agent. • At any time during the expansion phase > 33% of subjects experience a Grade 3 or 4 major organ toxicity possibly related to study injections. Assessment of these halting rules is a review of cumulative events for all st udy participants and should not be confused with reasons for delaying or terminating the treatment schedule of any individual subject. Treatment may also be suspended for safety concerns other than those described above if, in the judgment of the Investiga tor, participant safety is threatened 8.4.7 Sub-Group Analyses None will be performed because of the small size of the study . 8.4.8 Tabulation of Individual Participant Data No individual participant data will be tabulated. 8.4.9 Exploratory Analyses (Immune Responses) Exploratory immune analyses will be conducted to evaluate anti -tumor immune responses induced by vaccine injections . Immune response will be assessed among all subjects treated in each dose level . The magnitude of immune responses will also be d escribed. A subject will be considered evaluable for immune response if they receive at least three vaccine injections. The percentage of subjects with a positive immune response will be evaluated by dose level s and overall enrollment. A positive immune re sponse is defined by CMI reactivity in ex vivo stimulation using a flow cytometric readout (cytokine production or CD107 expression). Antigen -specific peptide challenge assays require a readout of >250 reactive T -cells/million cells above the background (35). If more than one dose level of patients is enrolled and at least three patients are treated in the dose level , Statistical analyses of data will be performed. For flow cytometry analyses on PBMC samp les, Student T tests will be performed on percentages of TNF - and/or IFN - expressing cells among the different dose levels to determine any significant differences in cell populations. Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 59 9 COLLABORATIVE AGREEM ENTS 9.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) A CRADA is in place between the Laboratory of Tumor Immunology and Biology (LTIB), CCR NCI and Etubics Corporation , the manufacturer of ETBX -011 (adenoviral CEA vaccine ); ETBX - 061 (adenoviral MUC1 vaccine ); and ETBX -051 (adeno viral brachyury vaccine ), CRADA # 02997 . 10 HUMAN SUBJECTS PROTE CTIONS 10.1 RATIONALE FOR SUBJECT SELECTION 10.1.1 Selection Based on Gender, Ethnicity, and Race Subjects from all genders and racial/ethnic groups are eligible for this study if they meet the eligibility criteria.