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6.4 modified immune-related response criteria

Modified immune-related response criteria (irRC) will also be employed in this study. This new classification is based on the recent learning from clinical studies with cancer immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. The irRC were created using bi-dimensional measurements (as previously widely used in the World Health Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC. 6.4.1 The modified irRC based on RECIST 1.1: New non-measurable lesions: Do not define progression but precludes (irCR). New measurable lesions: Incorporated into tumor burden. Overall irCR: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to 10 mm. Overall irPR: Sum of the longest diameters of target and new measurable lesions decreases Overall irSD: Sum of the longest diameters of target and new measurable lesions neither irCR, irPR, (compared to baseline) or irPD (compared to nadir). Overall irPD: Sum of the longest diameters of target and new measurable lesions increaseV (compared to nadir), confirmed by a repeat, consecutive observations at least 4 weeks (normally it should be done at 6 weeks) from the date first documented.
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please refer to appendix c.

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 Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_40).
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7 safety reporting requirements/data and

Any untoward medical occurrence in a human subject, including any 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 participation in the research.
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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.
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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 brochure 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 mentioned 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.
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7.1.4 serious

An Unanticipated Problem 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.
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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:
x Death, x A life-threatening adverse drug experience  
x Inpatient hospitalization or prolongation of existing hospitalization x Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions x A congenital anomaly/birth defect. x Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug 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.
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7.1.6 disability

A substantial disruption of a person's ability to conduct normal life functions.
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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 reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death.
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7.1.8 protocol deviation (nih definition)

Any change, divergence, or departure from the IRB approved research protocol. 7.1.9 Non-compliance (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:
x 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  
x Is related or possibly related to participation in the research; AND x Suggest that the research places subjects or others at a g*reater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized.
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7.2 nci-irb and clinical director

7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director:
x All deaths, except deaths due to progressive disease x All Protocol Deviations x All Unanticipated Problems x 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:
x All Grade 2 **unexpected** events that are possibly, probably or definitely related to the research; x All Grade 3 and 4 events that are possibly, probably or definitely related to the research;
x All Grade 5 events regardless of attribution;  
x All Serious Events regardless of attribution.
NOTE: Grade 1 events are not required to be reported.
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7.2.3 nci-irb reporting of ind

Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NCI IRB.
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7.3 ind sponsor reporting criteria

During the first 30 days after the subject receives investigational agent/intervention, the investigator must immediately report to the sponsor, using the mandatory MedWatch form 3500a or equivalent, 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 caused 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 for reporting per the above guideline:
x Deaths (except death due to progressive disease) must be reported via email within 24 hours. A complete report must be submitted within one business day.  
x Other serious adverse events including deaths due to progressive disease must be reported within one business day
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov and to the CCR PI and study coordinator.
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7.3.1 reporting pregnancy 7.3.1.1 maternal

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 an 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 perinatal 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 should 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, then 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 is 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 90 after the last dose of investigational drug. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 90 days after the last dose of investigational drug after the last dose should, if possible, be followed up and documented.
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7.4 safety reporting criteria to

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. 7.4.1 Reporting of serious adverse events All SAEs will be reported, whether or not considered causally related to the investigational product, or to the study procedure(s). The reporting period for SAEs is the period immediately following the time that written informed consent is obtained through 90 days after the last dose of durvalumab, or durvalumab + tremelimumab or until the initiation of alternative anticancer therapy. The investigator and/or Sponsor are responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE as per local requirements. The investigator and/or sponsor must inform the FDA, via a MedWatch or equivalent, of any serious or unexpected adverse events that occur in accordance with the reporting obligations of 21 CFR 312.32, and will concurrently forward all such reports to AstraZeneca. A copy of the MedWatch report must be send to AstraZeneca at the time the event is reported to the FDA. It is the responsibility of the sponsor to compile all necessary information and ensure that the FDA receives a report according to the FDA reporting requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the above timepoints. * A cover page should accompany the MedWatch form indicating the following: - "Notification from an Investigator Sponsored Study"  
- The investigator IND number assigned by the FDA - The investigator's name and address
- The trial name/title and AstraZeneca ISS reference number (ESR-16-11987) (AstraZeneca only) * Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in relation to all study medications and if the SAE is related to disease progression, as determined by the principal investigator. * Send SAE report and accompanying cover page by way of email to AstraZeneca's designated mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com If a non-serious AE becomes serious, this and other relevant follow-up information must also be provided to AstraZeneca and the FDA.
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7.4.2 overdose

Any overdose of a study subject with durvalumab or durvalumab + tremelimumab, with or without associated AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com. If the overdose results in an AE, the AE must also be recorded as an AE. Overdose does not automatically make an AE serious, but if the consequences of the overdose are serious, for example death or hospitalization, the event is serious and must be recorded and reported as an SAE. There is currently no specific treatment in the event of an overdose of durvalumab or tremelimumab. The investigator will use clinical judgment to treat any overdose. If the overdose results in an AE or SAE, these should be reported as such.
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7.4.3 hepatic function abnormality

Hepatic function abnormality in a study subject, with or without associated clinical manifestations, is required to be reported as "hepatic function abnormal" within 24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com, unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to investigational product has been confirmed. If the definitive underlying diagnosis for the abnormality has been established and is unrelated to investigational product, the decision to continue dosing of the study subject will be based on the clinical judgment of the investigator. If no definitive underlying diagnosis for the abnormality is established, dosing of the study subject must be interrupted immediately. Follow-up investigations and inquiries must be initiated by the investigational site without delay. Each reported event of hepatic function abnormality will be followed by the investigator and evaluated by the sponsor and AstraZeneca/MedImmune
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7.4.4 reporting removal from protocol

The study drug manufacturer should be notified of any ongoing AE that may delay treatment or necessitate permanent discontinuation of treatment.
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7.5 data and safety monitoring

The clinical research team will meet on a regular basis when patients are being actively treated on the trial to discuss each patient. Decisions about radiation dose and schedule will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead 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.
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7.5.2 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 interpretation 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:
x Informed consent process  
x Eligibility confirmation x Drug administration and accountability x Adverse events monitoring x 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 CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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8 statistical considerations

The primary objective of this trial is to conduct a pilot study of immune checkpoint inhibition in combination with Stereotactic Body Radiation Therapy (SBRT) in patients with advanced pancreatic cancer. As such, the main goal is to determine the safety of the proposed combinations of checkpoint inhibitors and SBRT as well as to evaluate if there may be any evidence of acceptable efficacy for any of the treatment combinations as well as whether one approach may be considered preferable over the others for use in future trials.  
With an amendment A the decision has been made to not proceed with Arms B1 and B2 and move directly from Arms A1 and A2 to Arms C1 and C2. Unfortunately, we have not seen any evidence of clinical activity as of yet. At the time of study design we did not have any supportive safety data for the combination of tremelimumab and durvalumab and that is why a staggered approach was conceived. We now have safety data for the combination of durvalumab and tremelimumab and the company has a recommended dose and schedule for the combination of these agents which they are moving forward across all their studies. We originally thought that Arms B1 and B2 (Tremelimumab 10mg/kg + SBRT) would provide some safety data to inform Arms C1 and C2, but this is no longer the case as the recommended dosing of Tremelimumab for Arms C1 and C2 is 10mg/kg (i.e., 10% of the dose in Arms B1 and B2). With amendment I, an additional secondary objective has been added to more precisely estimate the survival in patients enrolled in Arm C2. Safety will be evaluated as follows: the trial will be conducted in a sequential manner with patients enrolled in the following order: A1, A2, C1, and C2. The goal will be to evaluate 10 patients in A1 and then 10 in A2, provided that no more than 1 of the first 6 in A1 or A2 has a DLT, and that no more than 3 of 10 patients in either A1 or A2 has a DLT. If either of these is exceeded, then no further patients would be enrolled in that particular arm. The same rules apply to C1 and C2, but with all 10 in C1 and the first 10 in C2. Thus, if no safety concerns arise (0-1 of the first 6; 0-3 of 10 have a DLT in each of the 4 arms), then a total of 50 evaluable patients will be enrolled. To allow for a moderate number (30-40%) of inevaluable patients - based on disease progression - we will set the accrual ceiling at 70 patients. Among the initial patients enrolled in C2, there were two patients who have survived to approximately one year and beyond. It will be desirable to have additional patients enrolled in this arm to more precisely estimate its survival. Thus, in amendment I, the accrual to arm C2 will be expanded to a total of 20 evaluable patients to provide a more precise estimate of the patients' survival in that arm. The survival of the 20 patients will be determined by a Kaplan-Meier curve with 95% two-sided confidence intervals reported primarily at the median, and secondarily at 6 and 12 months. In addition, as a secondary analysis, the survival of the initial 10 patients treated on that arm will be reported separately from that of the second 10 patients treated on that arm, and the results will be informally compared to establish the degree of similarity of survival in the earlier and later treated patients. The median survival in second-line studies in this patient population is approximately 4 months. An important efficacy endpoint will be reached if a given patient is able to survive for 6 months or longer. The fraction of such patients will also be evaluated in the following manner, for purposes of making decisions about future directions, in addition to the new secondary endpoint focusing on C2, which demonstrated some survival advantage based on the first 10 patients:
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8.1 cross-arm comparison

Evaluation will be performed in combination of arms: A1+A2 and C1+C2. Within each of arm combinations A1+A2 and C1+C2, the 20 total patients who are treated in the combination of arms (A1+A2) and the total of 30 who are treated in the combination of arms (C1+C2) will be evaluated as a single group and the following objective will be evaluated: For the combination of A1+A2 (n=20), if 3 or more patients out of 20 are able to survive to 6 months, this would be a desirable goal, since the probability of observing 3 or more surviving to 6 months is 7.5% if the true underlying probability of surviving 6 months is 5% and the probability is 90.9% if the true underlying probability of surviving 6 months is 25%. Thus, 3 or more surviving 6 months or longer is a meaningful goal in a combination of arms of 20 patients. For the combination of C1+C2 (n=30), if 4 or more patients out of 30 can survive to 6 months, this would be a desirable goal, since the probability of observing 4 or more surviving to 6 months is 6.1% if the true underlying probability of surviving 6 months is 5% and the probability is 96.3% if the true underlying probability of surviving 6 months is 25%. Thus, 4 or more surviving 6 months or longer is a meaningful goal in a combination of arms of 30 patients. Given that there are 2 combination of treatment arms to be evaluated (A1+A2 and C1+C2), the one with the greatest fraction of 6-month survivors, provided that the surviving number is 3 or more of 20 patients in A1+A2 or 4 or more of 30 patients in C1+C2, will be considered for further evaluation. The numbers of patients in each combination of arms who live to or beyond 6 months who receive 1 day of SBRT or receive 5 days of SBRT will also be reported and compared informally, and will help guide future decisions.
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8.2 duration of radiation

In addition, the 20 patients who receive 1 day of SBRT and the 30 patients who receive 5 days of SBRT will be evaluated via a selection design, although with the caveat that lack of randomization and uneven numbers of patients should be considered when interpreting the results. The 20 or 30-patient SBRT combination of arms with the greatest fraction of survivors to 6 months would be preferentially chosen for further study. If there are 20-30 patients in the two groups and assuming the true rates are 15% and 25% in the two groups, the probability of correct selection is at least 78%.. Given that the two groups of 20 or 30 patients each have subsets of 10 (or 20) patients treated homogeneously, this would also need to be explored within the arms. Secondary endpoints include evaluation of clinical endpoints such as response rate, duration of response, progression free survival, and overall survival. These will be estimated using confidence intervals for response rates, descriptive statistic for duration of response and KaplanMeier curves for PFS and OS. PK parameters will be obtained and results will be estimated and described using standard exploratory and descriptive statistical techniques. Any statistical comparisons which may be undertaken will be done using non-parametric tests, without formal correction for multiple comparisons, but interpreted in the context of the secondary nature of the tests and the number of such tests performed.
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8.3 analysis of immunogenicity

Only subjects who receive at least one dose of both Durvalumab and/or tremelimumab, and provide the baseline and at least one post-treatment sample, will be evaluated. Immunogenicity results will be analyzed descriptively by summarizing the number and percentage of subjects who develop detectable anti-Durvalumab or anti-tremelimumab antibodies. The immunogenicity titer will be reported for samples confirmed positive for the presence of anti-Durvalumab or antitremelimumab antibodies. The impact of ADAs on PK will also be assessed if data allow.  
Samples confirmed positive for ADAs may also be evaluated for neutralizing antibody activity.
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8.4 analysis of pharmacokinetics

Only subjects who receive at least one dose of Durvalumab and/or tremelimumab, and provide the baseline and at least one post-treatment sample, will be evaluated. Individual Durvalumab and tremelimumab concentrations will be tabulated by dose arm along with descriptive statistics. The PK of Durvalumab and tremelimumab will be assessed using parameters including Cmax, trough concentration (Cmin), time to peak concentration (Tmax) and AUC after the first dose. Durvalumab and tremelimumab steady-state PK parameters including peak concentration (Cmax,ss), trough concentration (Cmin,ss), and time to peak concentration (Tmax,ss) will be estimated. Accumulation to steady state will be assessed as the ratio of Cmax,ss:Cmax and Cmin,ss:Cmin. All PK parameters will be estimated by non-compartmental analysis. Descriptive statistics of non-compartmental PK parameters will be provided.
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9 collaborative agreements 9.1 agreement

A CRADA, 02908, is in place between MedImmune, Inc. and CCR, NCI.
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10 human subjects protections 10.1

Subjects treated on this study, will be individuals with advanced pancreatic adenocarcinoma, which is not amenable to potentially curative resection. Individuals of any sex, race or ethnic group will be eligible for this study. Eligibility assessment will be based solely on the patient's medical status. Recruitment of patients onto this study will be through standard CCR mechanisms. No special recruitment efforts will be conducted.
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10.2 participation of children

Individuals under the age of 18 will not be eligible to participate in this study because they are unlikely to have pancreatic adenocarcinoma, and because of unknown toxicities in pediatric patients.
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10.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **10.5**), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH Policy 87-4 and NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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10.4 evaluation of benefits and

This research study involves exposure to radiation from 2 CT guided biopsies. This radiation exposure is not required for medical care and is for research purposes only. The amount of radiation received in this study is 1.6 rem which is below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation Safety Committee. The average person in the United States receives a radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the earth's air and soil. More information about radiation is available in the pamphlet, An Introduction to Radiation for NIH Research Subjects.
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10.4.2 risk of baseline biopsy

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent.
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10.4.3 other risks/benefits

The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor which may or may not have favorable impact on symptoms and/or survival. Potential risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis as described.
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10.5 risks/benefits analysis

For patients with pancreatic adenocarcinoma cancer, median survival is in the range between 6 and 10 months. It is possible that treatment on this protocol may reduce tumor burden or lessen symptoms caused by the cancer. While treatment on this protocol may not individually benefit subjects. The knowledge gained from this study may help others in the future who have pancreatic adenocarcinoma. Potential risks include the possible occurrence of any of a range of side effects listed. If patients suffer any physical injury as a result of the biopsies, immediate medical treatment is available at the NIH's Clinical Center in Bethesda, Maryland. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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10.6 consent process and documentation

Patients will meet with an associate or principal investigator on the trial in the GI oncology Clinic, during the initial evaluation for this study. During that meeting, the investigator will inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of this trial. The investigator will then provide a copy of the IRB-approved informed consent document that is included in this protocol. The patient will be allowed to take as much time as he wishes, in deciding whether or not he wishes to participate. If a prolonged period of time expires during the decision making process (several weeks, as an example), it may be necessary to reassess the patient for protocol eligibility. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on the study.
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10.6.1 reconsent via telephone

The informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. A witness to the subject's signature-- -will sign and date the consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented on a progress note by the consenting investigator. 10.6.2 Informed Consent of non-English Speaking Subjects If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative and the signed original will be filed in the medical record.  
Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible). We request prospective IRB approval of the use of the short form process for non-English speaking subjects and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form.
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11 pharmaceutical information 11.1 tremelimumab

11.1.1 Source Tremelimumab will be supplied by Medimmune, Inc. 11.1.2 Formulation and Preparation Tremelimumab is a human IgG2 anti-CTLA-4 mAb.  
| Investigational Product                                                                                                                                                                   | Manufacturer   | Concentration   | and   |    |         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|-----------------|-------|----|---------|
| Formulation as Supplied                                                                                                                                                                   |                |                 |       |    |         |
| Tremelimumab                                                                                                                                                                              | MedImmune      | Formulated      | at    | a  | nominal |
| concentration of 20 mg/mL in  20 mM histidine/histidine  hydrochloride, 222 mM  trehalose dihydrate, 0.02%  (w/v) polysorbate 80, and 0.27 mM disodium edetate dihydrate  (EDTA), pH 5.5. |                |                 |       |    |         |  
Tremelimumab is supplied as a sterile IV solution, filled in 20 mL clear glass vials with a rubber stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal fill of 20 mL accounting to 400 mg/vial) of Tremelimumab, in an isotonic solution at pH 5.5. Vials containing Tremelimumab must be stored in the refrigerator at 2-8C. The 20 mg/mL solution will be diluted into a saline bag for IV infusion.  
For dose preparation steps, the following ancillary items are required:  
x IV infusion bags of 0.9% sodium chloride injection (250 mL size). Saline bags must be latex-free and can be made of polyvinyl chloride (PVC) or polyolefins (e.g., polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free.  
x IV infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or polyethylene or polyurethane. All DEHP-containing or DEHP-free lines are acceptable. /LQHV VKRXOG FRQWDLQ D  RU  ȝP LQ-line filter. The in-line filter can be made of polyethersulfone (PES) or polyvinylidine fluoride DRF (PVDF). Lines containing cellulose-based filters should not be used with Tremelimumab.  
x Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless steel and/or PVC components.  
x Syringes made of polypropylene and latex-free. Polycarbonate syringes should not be used with Tremelimumab.  
x Needles made of stainless steel.
Tremelimumab does not contain preservatives and any unused portion must be discarded. Preparation of Tremelimumab and preparation of the IV bag are to be performed aseptically. Total in-use storage time for the prepared final IV bag should not exceed 24 hours at 2-8°C or 4 hours at room temperature (25°C). However, it is recommended that the prepared final IV bag be stored in the dark at 2-8°C until needed. The refrigerated infusion solutions in the prepared final IV bag should be equilibrated at room temperature for about 2 hours prior to administration. If storage time exceeds these limits, a new dose must be prepared from new vials.
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11.1.3 stability and storage

Tremelimumab must be stored in the refrigerator at 2-80C. The 20 mg/mL solution will be diluted into a saline bag for IV infusion. Vials containing Tremelimumab may be gently inverted for mixing, but should not be shaken.
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11.1.4 administration procedures

Tremelimumab will be administered as an IV infusion (250 mL) over approximately 1 hour. When an IV bag is used for the infusion, the IV line will be flushed with a volume of normal saline equal to the priming volume of the infusion set used after the contents of the IV bag are fully administered (unless prohibited by institutional practice).
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11.1.5 dose calculation

The subject's weight (in kilograms) must be measured prior to each dosing for dose calculation. Measurements can be taken in street clothes without shoes and a calibrated scale must be used for all measurements. The dose will be calculated at each dosing visit using the following formula: Tremelimumab: The tremelimumab dose will be calculated using the following formula: Arms A1 and A2 only: By weight: Dose (mL) = [subject weight (kg) × dose (mg/kg)]/ 20
(mg/mL) where 20 mg/mL is tremelimumab concentration.  
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). Dose adjustments for each cycle only needed for greater than 10% change in weight. Each vial contains a small amount of overage and the overage should be utilized as much as possible before using another vial. Arms C1 and C2: Following amendment B, Tremelimumab will be dosed at a flat dose of 75 mg via IV infusion q4w for up to 4 doses/cycles). Flat weight dosing will be used for all other patients including those who are greater than 75Kg e.g. 100-110Kg.
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11.2 durvalumab

11.2.1 Source Durvalumab will be supplied by Meddimmune, Inc. 11.2.2 Formulation and Preparation Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (Ig*ț subclass.  
| Investigational Product   | Manufacturer   | Concentration                                                                                                                                | and   |
|---------------------------|----------------|----------------------------------------------------------------------------------------------------------------------------------------------|-------|
| Formulation as Supplied   |                |                                                                                                                                              |       |
| Durvalumab                | MedImmune      | Formulated at 50 mg/mL in 26  mM histidine/histidine-HCl,  275 mM trehalose dihydrate, 0.02%  (weight/volume [w/v])  polysorbate 80, pH 6.0. |       |  
Durvalumab is supplied is supplied as a white to off-white lyophilized powder in clear 10R glass vials closed with an elastomeric stopper and a flip-off cap overseal. Each vial contains 200 mg (nominal) of active investigational product.  
For dose preparation steps, the following ancillary items are required:  
x IV infusion bags of 0.9% sodium chloride injection. x IV infusion lines. All DEHP-containing or DEHP-free lines are acceptable. x Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless steel and/or PVC components.  
| 11.2.3 Stability Manufacturer                                                                                                                                                                                                                      | MedImmune                                                                                                                                                                                                               |           |                |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|----------------|
| Expiration/Retest Date                                                                                                                                                                                                                             | Expiration/retest dates are documented on the Certificate of                                                                                                                                                            |           |                |
| Container Description                                                                                                                                                                                                                              | Type:                                                                                                                                                                                                                   | Material: | Size:          |
| Formulation                                                                                                                                                                                                                                        | Lyophilized powder containing 200 mg Durvalumab. When reconstituted with 4 mL of WFI, the solution contains 50 mg/mL Durvalumab, 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) |           |                |
| Active Ingredient Content                                                                                                                                                                                                                          | Mass/Weight:                                                                                                                                                                                                            | Volume:   | Concentration: |
| Storage Conditions                                                                                                                                                                                                                                 | +2°C to +8°C                                                                                                                                                                                                            |           |                |
| Stability after reconstitution24h at +2-8°C and 6h at +25°C/ambient Labeling Product name, lot number, route of administration, and storage conditions If Durvalumab administration has to be delayed, temporally interrupted or the infusion rate |                                                                                                                                                                                                                         |           |                |  
If Durvalumab administration has to be delayed, temporally interrupted or the infusion rate decreased, the total time between reconstitution and completion of the infusion should not exceed 6 hours at room temperature or Total in-use storage time from reconstitution of Durvalumab to start of administration should not exceed 4 hours at room temperature or 24 hours at 2-8 C. If administration time exceeds these limits, a new dose must be prepared from new vials. Durvalumab does not contain preservatives and any unused portion must be discarded.
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11.2.4 storage

Unopened vials of Durvalumab lyophilized Drug Product must be stored at 2°C to 8°C (36°F to 46°F). Protect from light. 11.2.5 Administration procedures Durvalumab is to be administered as an IV solution of 10 mg/kg over approximately 1 hour. When an IV bag is used for the infusion, the IV line will be flushed with a volume of normal saline equal to the priming volume of the infusion set used after the contents of the IV bag are fully administered (unless prohibited by institutional practice). Since the compatibility of Durvalumab with other IV medications and solutions, other than normal saline (0.9% [w/v] sodium chloride for injection), is not known, the Durvalumab solution should not be infused through an IV line in which other solutions or medications are being administered. The date, start time, interruption, and completion time of Durvalumab administration must be recorded in the source documents. For arms C1 and C2 Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion.  
11.2.5.1 Dose Calculation
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11.2.5.1.1 arms a1 and a2

The subject's weight (in kilograms) must be measured prior to each dosing for dose calculation. Measurements can be taken in street clothes without shoes and a calibrated scale must be used for all measurements. The dose of MEDI 4736 will be calculated at each dosing visit using the following formula: By weight: Dose (mL) = [subject weight (kg) × dose (mg/kg)]/ 50 (mg/mL) where 50 mg/mL is Durvalumab concentration after reconstitution. The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). Dose adjustments for each cycle only needed for greater than 10% change in weight. Each vial contains a small amount of overage and the overage should be utilized as much as possible before using another vial.
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11.2.5.1.2 arms c1 and c2

Following amendment B, MEDI 4736 (now called Durvalumab) will be dosed at a flat dose of 1500 mg via IV infusion q4w for up to 4 doses/cycles (in combination with 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles), and then continue 1500 mg durvalumab q4w (see Figure 3). Patients with a body weight less than or equal to 30 kg should be dosed using a weight-based dosing schedule (i.e. 1mg/kg for tremelimumab and 20mg/kg for durvalumab). Flat weight dosing will be used for all other patients including those who are greater than 75Kg e.g. 100-110Kg.  
11.2.6 Durvalumab Dose Preparation Steps 11.2.6.1 Durvalumab is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM
trehalose dihydrate, 0.02% (w/v) polysorbate 80 and is supplied as a lyophilized powder in 10R vials 11.2.6.2 Durvalumab should be reconstituted using aseptic techniques with 4.0 mL sterile water for injection (WFI) with the liquid added gently to the side of the vial to minimize product foaming, to give a final concentration of 50 mg/mL. The reconstituted solution will be diluted with 0.9% (w/v) saline for IV infusion using syringes or bags.  
11.2.6.3 In arms C1 and C2 Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion using a 0.2-ȝPLQ-line filter.  
11.2.6.4 Flush the IV line with a volume of normal saline equal to the priming volume of the infusion set used after the contents of the IV bag are fully administered, or complete the infusion according to institutional policy to ensure the full dose is administered and document if the line was not flushed.
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11.3 investigational product preparation steps

The investigational product manager or qualified personnel will be responsible for preparing the IV doses using the following steps:
1) Select the IXRS-assigned number of vials of investigational product required to prepare the subject's dose.  
2) All investigational product vials should be equilibrated to room temperature for 30 minutes prior to dose preparation.  
3) To prepare the IV bag, first, calculate the dose volume of investigational product required. Second, remove the volume of 0.9% sodium chloride IV solution equivalent to the calculated dose volume of investigational product from the IV bag.  
4) Lastly, add the calculated dose volume of investigational product to the IV bag. Gently mix the solution in the bag by inverting up and down. Avoid shaking the IV bag to prevent foaming.  
5) Example: A subject weighing 85 kg will require 42.5 mL (3 vials) of investigational product. Remove 42.5 mL of saline from the commercial IV bag. Add the 42.5 mL of investigational product to the IV bag and gently mix by inverting up and down.  
6) Labels will be prepared in accordance with Good Manufacturing Practice (GMP).
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11.4 investigational product inspection

Each vial selected for dose preparation should be inspected. If there are any defects noted with the investigational product, the investigator and site monitor should be notified immediately. Refer to the Product Complaint section (**11.5.1)** for further instructions. During the inspection if the solution is not clear or any turbidity, discoloration or particulates are observed, notify your site monitor and store the vial(s) in QUARANTINE at refrigerated (2-8ºC) temperature for drug accountability and potential future inspection. Notify the IXRS that the unusable vials are damaged. The IXRS will indicate the replacement vials. Select appropriate replacement vials for the preparation of the subject's dose, and perform the same inspection on the newly selected vials. For accountability, record the total number of vials removed from site inventory. Used vials should be held for accountability purposes at ambient storage temperature.
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11.5 investigational product accountability

The investigator's or site's designated investigational product manager is required to maintain accurate investigational product accountability records. Upon completion of the study, copies of investigational product accountability records will be returned to MedImmune. All unused investigational product will be returned to a MedImmune-authorized depot or disposed of upon authorization by MedImmune.
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11.5.1 reporting product complaints

Any defects with the investigational product must be reported *immediately* to the MedImmune Product Complaint Department by the site with further notification to the site monitor. All defects will be communicated to MedImmune and investigated further with the Product  
Complaint Department. During the investigation of the product complaint, all investigational products must be stored at labeled conditions unless otherwise instructed. Product defects may be related to component, product, or packaging and labeling issues. The list below includes, but is not limited to, descriptions of product complaints that should be reported.  
Component Issue: Defect in container or dosing mechanism of the investigational product. The component defect may be damaged, missing, or broken. Component examples include vials, stoppers, caps, spray barrels, spray nozzles, or plungers. Product Issue: Defect in the product itself. The product appearance has visual imperfections such as foreign particles, crystallization, discoloration, turbidity, insufficient volume, or anything that does not apply to the product description.  
Packaging/Labeling Issue: Defect in the packaging or labeling of the product. The packaging or labeling defects may be damaged or unreadable, or the label may be missing. When reporting a product complaint, site staff must be prepared to provide the following information: 1) Customer information: reporter name, address, contact number, and date of complaint 2) Product information: product name, packaging kit number or lot number, expiry date, and clinical protocol number 3) Complaint information: complaint issue category and description MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com Phone: +1-301-398-2105 +1-877-MEDI-411 (+1-877-633-4411) Fax: +1-301-398-8800 Mail: MedImmune, LLC Attn: Product Complaint Department One MedImmune Way, Gaithersburg, MD USA 20878
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13 appendices

| 13.1                                                                                                                                                                                       | APPENDIX A: PERFORMANCE STATUS CRITERIA                            |                                                              |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|--------------------------------------------------------------|-------------|
| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                        |                                                              |             |
| Grade                                                                                                                                                                                      | Descriptions                                                       | Percent                                                      | Description |
| 100                                                                                                                                                                                        | Normal, no complaints, no  evidence of disease.                    |                                                              |             |
| Normal activity. Fully active,                                                                                                                                                             |                                                                    |                                                              |             |
| 0                                                                                                                                                                                          | able to carry on all pre-disease  performance without restriction. | Able to carry on normal activity;                            |             |
| 90                                                                                                                                                                                         | minor signs or symptoms of  disease. Normal activity with effort;  |                                                              |             |
| 80                                                                                                                                                                                         | some signs or symptoms of  disease.                                |                                                              |             |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). |                                                                    |                                                              |             |
| 1                                                                                                                                                                                          | Cares for self, unable to carry on                                 |                                                              |             |
| 70                                                                                                                                                                                         | normal activity or to do active  work.                             |                                                              |             |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and  about more than 50% of waking  hours.                            | Requires occasional assistance,                                    |                                                              |             |
| 60                                                                                                                                                                                         | but is able to care for most of  his/her needs.                    |                                                              |             |
| 2                                                                                                                                                                                          | 50                                                                 | Requires considerable assistance  and frequent medical care. |             |
| 40                                                                                                                                                                                         | Disabled, requires special care  and assistance.                   |                                                              |             |
| In bed >50% of the time.  Capable of only limited self-care,  confined to bed or chair more  than 50% of waking hours.                                                                     |                                                                    |                                                              |             |
| 3                                                                                                                                                                                          | Severely disabled,                                                 |                                                              |             |
| 30                                                                                                                                                                                         | hospitalization indicated. Death  not imminent.                    |                                                              |             |
| 20                                                                                                                                                                                         | Very sick, hospitalization  indicated. Death not imminent.         |                                                              |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   |                                                                    |                                                              |             |
| 4                                                                                                                                                                                          | 10                                                                 | Moribund, fatal processes  progressing rapidly.              |             |
| 5                                                                                                                                                                                          | Dead.                                                              | 0                                                            | Dead.       |  
13.2 APPENDIX B: MEDIMMUNE SAMPLE PREPARATION PROCEDURES **SERUM- SST TUBE** 1. Draw maximum volume of blood into gold top SST tube (s). Record time of collection. 2. Gently invert 5 times. 3. Allow the blood to clot for 30 minutes at room temperature. 4. Centrifuge within 2 hours of collection at 1100 -1300 g for 15 minutes. 5. Transfer serum into labeled cryovials. 6. Immediately freeze the cryovials upright at -20ºC or colder. 7. Store at -20ºC or colder until shipment on dry ice.
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plasma- k2 edta tube

1. Draw maximum volume of blood into lavender top K2 EDTA tube(s). Record time of collection 2. Gently invert 8 to 10 times. 3. Centrifuge within 2 hours of collection at 1100 -1300 g for 10 minutes. 4. Transfer plasma into labeled cryovials. 5. Immediately freeze the cryovials upright at -20ºC or colder. 6. Store at -20ºC or colder until shipment on dry ice. Tube Label should include: 1. Patient Identifier 2. Sample ID (Serum 1, Cycle 1, Day 1etc.) 3. Sample type (plasma, serum) 4. Sample volume 5. Collection time 6. Barcode (if this system is available)