7.1.4. Vital Signs and Physical Examination Participants will have a phy sical examination to include weight, vital signs, assessment of ECOG performance status and height; height will be measured at screening only . A complete ph ysical examination (PE) will be performed at Screening and at the End of Treatment visit for each participant and will include an assessment of all body systems. A neurologic examination must be conducted at Screening to look for potential signs of underly ing autoimmune disorders. Findings of all phy sical examinations should be recorded in the source documents, and an y change from baseline considered b y the investigator to be clinically significant should be recorded as an adverse event in the CRF. Abbreviated PEs should be performed as appropriate per the Schedule of Activities (SOA), and on an as needed basis for assessment of adverse events. Abbreviated exams should be targeted to specific s ymptoms or complaints and be consistent with local standard of care. However, a neurologic examination must be performed d uring each exam conducted during Cycle 1. Weight and bod y surface area (BSA) do not need to be performed at each visit; however participants should be monitored throughout the study for significant weight change. Vital signs should include measurements of blood pressure, pulse, and temperature (oral, temporal, ty mpanic or axillary ). On dosing day s, vital signs should be measured prior to administration of any of the study treatments. Sitting blood pressure (BP) and pulse after approximately 5 minutes res t should be measured with the participant’s arm supported at the level of the heart and recorded to the nearest mmHg. The same arm shouldbe used throughout the trial. A properl y-sized and calibrated blood pressure cuff should be used to measure blood pre ssure. The use of automated devices for measuring BP is acceptable. Vitals signs, including temperature, pulse, and BP to be recorded 1 -hour post- study drug administration during each Cy cle on Day s 1, 29, 57, and 85. Assessment of the skin and subcutaneo us tissue thickness at the eligible administration sites will be performed at screening as described in the TDS -IM V 2.0 Instructions for Use. The assessment procedure does not need to be repeated during the course of the study unless the participant expe riences a greater than 10% change in body mass relative to screening. PF-06936308 C3621001 Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 947.1.5. (12-Lead) Electrocardiogram Electrocardiogram machines to be utilized in this study will be supplied by a third part y vendor. At screening, a single 12 -lead ECG tracing (with a 10- second rhy thm strip) will be obtained. For C ycle 1 Day 1 and all subsequent specified time points (see Schedule of Activities), triplicate 12 -lead ECG tracings (with a 10 -second rhy thm strip) will be obtained. Generally , baseline a nd all corresponding time point ECGs should not be collected within 3hours after food or beverage consumption and should be performed after the participant has rested quietly for at least 10 minutes in a supine position. All 12 lead ECGs should be confir med b y a qualified person at the institution and will be reviewed b y a central laboratory . At each time point, (see the Schedule of Activities), three consecutive ECGs will be performed at approximately 2minutes apart to determine the mean QTcF interval. If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re -evaluated b y a qualified person at the institution for confirmation. If manual reading verifies a QTcF of >500 msec, immediate correction for reve rsible causes (including electroly te abnormalities, hypoxia and concomitant medications for drugs with the potential to prolong the QTcF interval) should be performed. I n addition, repeat ECGs should be immediately performed hourly for at least 3 hours un til the QTcF interval falls below 500 msec. If QTcF interval reverts to less than 500 msec, and in the judgment of the investigator(s) and sponsor it is determined to be due to cause(s) other than investigational product, treatment may be continued with r egular ECG monitoring. If in that timeframe the QTcF intervals rise above 500msec the investigational product will be held until the QTcF interval decreases to 500msec. Participants will then re -start the investigational product at the next lowest dose level. If the QTcF interval has still not decreased to 500 msec after 2 -weeks, or if at any time a participant has a QTcF interval >515 msec or becomes sy mptomatic, the participant will be removed from the stud y. Additional triplicate ECGs may be perfor med as clinically indicated. Prior to concluding that an episode of prolongation of the QTcF interval is due to investigational product, thorough consideration should be given to potential precipitating factors (eg, change in participant clinical conditio n, effect of concurrent medication, electrol yte disturbance) and possible evaluation by specialist. If the participant experiences a cardiac or neurologic AE (specificall y syncope, dizziness, seizures, or stroke), an ECG (triplicate) should be obtained at the time of the event. Prior to concluding that an episode of prolongation of the QTcF interval is due to investigational product, thorough consideration should be given to potential precipitating factors (eg, change in participant clinical condition, eff ect of concurrent medication, electrol yte disturbance) and possible evaluation by specialist. PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 95When matched with PK sampling, the ECG must be carried out before each PK sample drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK collections over rides the timing of the ECG collections). 7.1.6. Monitoring for Potential Immune Mediated Endocrinopathies Participants will be monitored for clinical si gns and symptoms of hypophysitis, adrenal insufficiency (including Addisonian crisis), and hyper- or hypothyroidism. Laboratory evaluation will be performed as clinically indicated based on symptoms. For example, the development of symptoms of adrenal insufficiency, such as unexplained nausea, vomiting and hypotension, would trigger prompt evaluation (Cosyntropin Stimulation Testing) and treatment (systemic glucocorticoids). Symptoms suggestive of an inflammatory pituitary process with mass effect, such as diplopia, visual field abnormalities and severe headache, call for urgent pituitary imaging and evaluation for hypopituitarism, with specific attention to the pituitary-adrenal axis. Symptoms of disordered thyroid metabolism, such as changes in bowel frequency, fatigue, unexplained weight loss or gain should prompt evaluation of thyroid function tests, with a focus on free thyroid hormone levels (T3 and T4) given the possibility that thyroid stimulating hormone levels may be unreliable due to immune-mediated pituitary dysfunction. 7.1.7. Acetylcholine Receptor Testing A blood sample will be collected at screening for central evaluation of acetylcholine receptor (AChR) antibodies. reatment decisions will be made based on the clinical diagnosis. The evaluation for AChR antibodies is included to exclude participants who test positive at screening as agreed upon with the US FDA and to confirm requirement for evaluation if myasthenia gravis is suspected. 99 7.1.8. Cardiac Safety Monitoring The algorithm for cardiac Safety Monitoring is shown in Figure 2 below. For participants undergoing screening, circulating levels of cardiac Troponin-I (cTnI) must be measured and found to be within the normal reference range within 28 days before study entry, preferably using the central laboratory kits provided. Dosing should not proceed until results within the normal reference range have been received by the Investigator. For any results above of the normal reference range (even if borderline), the participant should be referred to a cardiologist by the Investigator for complete cardiac workup and repeat cardiac troponin. The participant can only enter the study after cardiac evaluation, troponin findings within the normal reference range, cardiac clearance, and the Sponsor’s approval. For participants ongoing in the study, circulating levels of cardiac Troponin-I (cTnI) must be measured within 10 days of dosing on the days shown in the SOA (ie, C1D29, C1D57, C1D85, C2D29, month 9 and month 12) and found to within the normal reference range. No dosing of participants can occur unless the cTnI is within the normal reference range. For any results above the normal reference range (even if borderline) the participant must be referred by the Investigator to a cardiologist for complete work-up and repeat cTnI. Dosing CCI PF-06936308 C3621001 Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 96can onl y occur after cardiac evaluation, cTnI findings within the normal reference range, cardiac clearance, and the Sponsor’s approval. While central laboratory testing for cTnI is preferred, it requires a minimum of 3 day s to return results. Therefore, local laboratory testing of cTnI may be used, but only if the timing of measuring cTn I by the central laboratory test (minimum 3 day turnaroun d time) puts an undue burden or risk on the participant. The use of cardiac troponin -T is strongl y discouraged, but could be used in place of cTn I if the central laboratory test puts an undue burden or risk on the participant. Figure 2.Cardiac Safety Monitoring Algorithm 7.2.Pharmacokinetics Assessments 7.2.1. Serum for Assessment of Tremelimumab Pharmacokinetics Blood samples (approximately 3 mL whole blood) to provide a minimum of 1 mL of serum for measurement of serum tremelimumab concentrations will be collected from participants receiving tremelimumab. The samples will be collected into appropriately labeled tubes at time points outlined in the Schedule of Activities. The PK sampling schedule may be modified based on emerging PK data, but the total number of PK samples will remain the same. In addition to samples collected at the scheduled times, an additional blood sample for determination of serum tremelimumab concentration should be collected from participants experiencing unexpected and/or serious AEs and the date and time of blood sample collection and of last dosing prior to PK collection documented on the CRF. PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 97Where noted in the Schedule of Activities , blood samples for tremelimumab concentrations will be collected at approximately the same time as other assessments such as PD samples and ECGs (first ECG then PK collection), wherever possible. All efforts will be made to obtain the PK samples at the scheduled nominal time relative to dosing. However, samples obtained within the protocol specified time window will be considered compliant with the protocol, and the exact time of the sample collection will always be noted on the CRF. If a scheduled blood sample collection cannot be completed for any reason, the missed sample time may be re-scheduled with agreement of the clinical investigator, participant, and sponsor. PK samples will be assayed for tremelimumab using a validated analytical method at a central laboratory in compliance with Pfizer standard operating procedures (SOPs). The PK samples must be processed and shipped as indicated in the instructions provided to the investigator site to maintain sample integrity. Any deviations from the PK sample handling procedure (eg, sample collection and processing steps, interim storage or shipping conditions), including any actions taken, must be documented and reported to the sponsor. On a case-by-case basis, the sponsor may make a determination as to whether sample integrity has been compromised. Any deviation from the specified sample handling procedure resulting in compromised sample integrity will be considered a protocol deviation. As part of understanding the PK of the investigational product, samples may be used for evaluation of the bioanalytical method, These data will not be included in the Clinical Study Report (CSR). 7.2.2. Serum for Assessment of Sasanlimab Pharmacokinetics Blood samples (approximately 5 mL whole blood) to provide a minimum of 2 mL of serum for measurement of serum sasanlimab concentrations will be collected from participants receiving sasanlimab. The samples will be collected into appropriately labeled tubes at time points outlined in the Schedule of Activities . The PK sampling schedule may be modified based on emerging PK data, but the total number of PK samples will remain the same. In addition to samples collected at the scheduled times, an additional blood sample for determination of serum sasanlimab concentration should be collected from participants experiencing unexpected and/or serious AEs and the date and time of blood sample collection and of last dosing prior to PK collection documented on the CRF. Where noted in the Schedule of Activities , blood samples for sasanlimab concentrations will be collected at approximately the same time as other assessments such as ECGs (first ECG then PK collection), wherever possible. All efforts will be made to obtain the PK samples at the scheduled nominal time relative to dosing. However, samples obtained within the protocol specified time window will be considered compliant with the protocol, and the exact time of the sample collection will always be noted on the CRF. If a scheduled blood sample collection cannot be completed for CCI CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 98any reason, the missed sample time may be re-scheduled with agreement of the clinical investigator, participant, and sponsor. PK samples will be assayed for sasanlimab using a validated analytical method in compliance with Pfizer standard operating procedures (SOPs). The PK samples must be processed and shipped as indicated in the instructions provided to the investigator site to maintain sample integrity. Any deviations from the PK sample handling procedure (eg, sample collection and processing steps, interim storage or shipping conditions), including any actions taken, must be documented and reported to the sponsor. On a case-by-case basis, the sponsor may make a determination as to whether sample integrity has been compromised. Any deviation from the specified sample handling procedure resulting in compromised sample integrity will be considered a protocol deviation. As part of understanding the PK of the investigational product, samples may be used for evaluation of the bioanalytical method, These data will not be included in the Clinical Study Report (CSR). CCI CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 99CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 1007.4. Tumor Response Assessments Tumor assessments will include all known or suspected sites of disease. Screening images may be obtained within 5 weeks of registration. Imaging obtained as part of standard of care that are performed within 28 days (-7 days) of registration may be used for screening assessment. Imaging will include (a) CT scan (computerized tomography) of the chest, abdomen and pelvis, or magnetic resonance imaging (MRI) of these same areas, and (b) bone scan, for participants with known or suspected bone metastases. Baseline brain imaging (CT or MRI) is not required, except in the case of symptomatic participants to rule out brain metastases (see Section 4).CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 101The same imaging technique (CT scan or MRI) used to characterize lesions identified at baseline should be employed when performing on-study tumor assessments. As the intention of administration of VBIR-2 is to activate an anti-tumor immune response in the vaccine draining lymph nodes, the inguinal (limb) and axillary (arm) lymph nodes should not be used as target lesions, since injections of antigens may be given in the upper arm or thigh. It is possible that lymph nodes draining the upper arm or thigh may become enlarged following administration of the VBIR-2, and may not accurately reflect the status of underlying disease. Anti-tumor activity will be assessed through radiological tumor assessments conducted at baseline; during treatment as specified in the SOA ; whenever disease progression is suspected (eg, symptomatic deterioration); and at the time of withdrawal from treatment (if not done in the previous 6 weeks). Assessment of response will be made using RECIST version 1.1 ( Appendix 3 ). All participants’ files and radiologic images must be available for source verification and for potential peer review. In addition, historical images (collected up to one year prior to study entry) may be requested for potential peer review.