untitled h1
for patients with non-measurable disease

| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                                                             | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is  increasingly used as an endpoint for assessment of efficacy in some trials so to assign this  category when no lesions can be measured is not advised |               |                    |
untitled h1
6.3.5 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 the 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.
untitled h1
6.3.6 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. Please refer to **Appendix C** for further details.
untitled h1
6.3.7 progression-free survival

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
untitled h1
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 Adverse Events (CTCAE) version 4.3 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.3. A copy of the CTCAE version 4.3 can be downloaded from the CTEP web site (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_4.3). All appropriate treatment areas should have access to a copy of the CTEP Active Version of CTCAE.
untitled h1
7 nih reporting requirements /

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
untitled h1
7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies. 7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
untitled h1
7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
untitled h1
7.4 institutional biosafety committee (ibc)

The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-threatening experience associated with the use of Pexa-Vec oncolytic virus as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events that are unexpected and associated with the use of Pexa-Vec oncolytic virus, but are not fatal or lifethreatening, 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.
untitled h1
7.4.2 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, the NIH Intramural 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.
untitled h1
7.4.3 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 identifiers - participant population (such as disease indication and general age group, e.g. adult or pediatric)
- the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was 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.
7.4.4 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 the 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, including, for example, information about dose-response, information from controlled trials, and information about bioavailability.
untitled h1
7.5 nih required data and

The clinical research team will meet on a weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable 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. Events meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within the appropriate timelines.  
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.
untitled h1
7.5.2 safety monitoring committee (smc)

This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NIH Intramural 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.
untitled h1
8 sponsor protocol/safety reporting 8.1

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2)) 8.1.2 Serious Adverse Event (SAE) 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 event (see section **8.1.3**)
- Inpatient hospitalization or prolongation of existing hospitalization - Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- 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 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.
8.1.3 Life-threatening An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32) 8.1.4 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.3.
untitled h1
8.1.5 relationship to study product

All AEs will have their relationship to study product assessed using the terms: related or not related.  
- Related - There is a reasonable possibility that the study product caused the adverse event.  
Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
- Not Related - There is not a reasonable possibility that the administration of the study product caused the event.  
8.1.6 Adverse Events of Special Interest (AESI)
See Section 3.4.3.
untitled h1
8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution.  
SAEs will be:  
- Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
- Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
- Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor with the exception of any listed in section 8.4.
untitled h1
8.3 reporting of serious adverse

Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form.  
All SAE reporting must include the elements described in section 8.2.  
SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
untitled h1
8.4 waiver of expedited reporting

As death due to disease progression is part of the study objectives (OS) and captured as an endpoint in this study, death due to disease progression will not be reported in expedited manner to the Sponsor. However, if there is evidence suggesting a causal relationship between the study drug and the event, report the event in an expedited manner according to section **8.3.**
Hospitalization that is deemed to be due to disease progression, and not attributable to the intervention will not be reported as an SAE. The event, and the assessment that it was caused by disease progression will be documented in the medical records. The causality assessment of hospitalization will be re‐evaluated any time when new information is received. If the causality assessment changes from disease progression to related to the study intervention, SAE report will be sent to the Sponsor in an expedited manner according to section 8.3. If there is any uncertainty whether the intervention is a contributing factor to the event, the event should be reported as AE or SAE as appropriate.
untitled h1
8.5 safety reporting criteria to

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 Pexa-Vec, durvalumab + tremelimumab or until the initiation of alternative anticancer therapy. 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. Such reports must be forwarded to AstraZeneca and Sillajen concurrently with submission 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 and Sillajen at the above timepoints. A cover page should accompany the MedWatch or equivalent form indicating the following:  
- "Notification from NCI Center for Cancer Research" - NCI CCR 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 Send SAE report and accompanying cover page by way of email to Sillajen's designated mailbox:
safetyCRC027@sillajen.com If a non-serious AE becomes serious, this and other relevant follow-up information must also be provided to AstraZeneca, Sillajen and the FDA. 8.5.2 Overdose Any overdose of a study subject with 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. An overdose of a study subject with Pexa-Vec should be reported to the designated safety mailbox: safetyCRC027@sillajen.com. If the overdose results in an AE or SAE, these should be reported as such.  
8.5.3 Hepatic function abnormality Hepatic function abnormality (as defined in Section **3.4.3.4**) 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.
untitled h1
8.6 reporting pregnancy 8.6.1 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 no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (see section **8.1.2)** should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
untitled h1
8.6.2 paternal exposure

Male patients should refrain from fathering a child or donating sperm during the study and for 180 days after the last dose of durvalumab+ tremelimumab combined therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period. 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 180 days after the last dose of durvalumab+ tremelimumab combined therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period after the last dose should, if possible, be followed up and documented.
untitled h1
8.7 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
untitled h1
9 clinical monitoring

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 and secondary study endpoints; adherence to the protocol, regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
- Informed consent process  
- Eligibility confirmation
- Drug administration and accountability
- 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 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
untitled h1
10 statistical considerations

The primary objective of this study is to determine the response rate of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer based on investigator evaluation. Based on our analysis of data from previous trials of patients with similar eligibility requirements the typical response rate is much less than 10%. For Arm A2, provided that adequate safety has been demonstrated, a total of 10 evaluable patients will be enrolled and treated at DL2. The following table shows the probability of having 1 or more responses or 2 or more responses out of 10 patients as a function of the underlying true probability of a response:  
True response No. of responses Probability  
| True response   | No. of responses   | Probability   |
|-----------------|--------------------|---------------|
| 0.02            | 1+                 | 0.18          |
|                 | 2+                 | 0.016         |
| 0.05            | 1+                 | 0.40          |
|                 | 2+                 | 0.086         |
| 0.15            | 1+                 | 0.80          |
|                 | 2+                 | 0.46          |
| 0.25            | 1+                 | 0.94          |
|                 | 2+                 | 0.76          |
| 0.30            | 1+                 | 0.97          |
|                 | 2+                 | 0.85          |  
Thus, observing 2+ responses out of 10 evaluable patients would have 8.6% probability of occurring if the true probability of a response rate were 5% and would have 76-85% probability of occurring if the true probability of a response were 25-30%. As such, it would be desirable if 2 or more responses out of 10 could be noted to rule out 5% and demonstrate consistency with a 25% or greater response rate. However, in the context of this preliminary pilot trial, observing a single response in 10 patients would provide limited evidence of at least 15% true response probability and thus suggests that may be minimal evidence for benefit. As a further aid to interpretation, the exact two-tailed 80% confidence interval about 1/10 is 0.01 to 0.34, and the exact two-tailed 80% confidence interval about 2/10 is 0.05-0.45. Biopsies from patients treated at DL2 will be taken pre-treatment and then half the patients will receive a second biopsy at day 1 and the other half at day 29. Thus, within Arm A2, 5 patients will be expected to have paired results from biopsies based on day 1- baseline and 5 will be expected to have paired results from biopsies based on day 29-baseline. Any statistical evaluations made for the 5 patients within each set of paired biopsy results will be considered exploratory, and the results will not be adjusted for multiple comparisons. With 5 patients in a paired comparison, there would be 90% power to identify a change from baseline equal to 2.0 SD of the difference (effect size 2.0), or 71% power to identify a change with effect size 1.5, using a 0.05 significance level paired t-test. In practice, Wilcoxon signed rank tests may be used unless the differences are shown to be consistent with a normal distribution (p>0.05 by a Shapiro-Wilks test). After completion of Arm A2, a decision will be made - after review of all the clinical, safety and correlative data - whether to proceed with Arm B1 at that time. The same statistical considerations will apply to Arm B2 as in Arm A2. Formal comparison between the two arms will not be possible given patient numbers and will be considered hypothesis generating for future development. To address safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition, adverse events will be tabulated by grade according to CTCAE and analyzed and reported descriptively. In addition to evaluation of the proportion of patients that are progression-free at 5 months, the progression-free survival for patients will also be analyzed via a Kaplan-Meier curve. This curve will be compared informally to other published results in similar patients. As well, the overall response rate will be reported and the overall survival will be reported using a Kaplan-Meier curve. It is anticipated that up to 12 patients per year will be able to enroll onto this protocol. It is expected that accrual of up to 26 total patients will be required to complete this protocol, but up to 32 may be needed if DL1 requires 6 patients at each dose level. Thus, accrual is expected to be completed in approximately 2 to 3 years. In order to allow for a small number of unevaluable patients, the accrual ceiling will be set at 35 patients.
untitled h1
11 collaborative agreement 11.1 cooperative

11.1.1 Medimmune/Astrazeneca The CRADA (02853) for this protocol is finally executed between Thoracic & GI Malignancies Branch, NCI, NIH and Medimmune/Astrazeneca, the manufacturer of Tremelimumab and Durvalumab
untitled h1
11.1.2 sillajen inc.

The CRADA (03163) for this protocol is finally executed between Thoracic & GI Malignancies Branch, NCI, NIH and Sillajen Inc. the manufacturer of Pexastimogene Devacirepvec (Pexa-Vec)
untitled h1
11.2 material transfer agreement (mta)

An MTA with Adaptive Biotechnologies (40860-16) is in place to perform the studies on coded, linked samples indicated in sections 5.1 and **5.1.3**.
untitled h1
12 human subjects protections 12.1

Subjects treated on this study, will be individuals with metastatic colorectal cancer, which has recurred (or persisted) after appropriate standard treatment. Individuals of any gender, 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.
untitled h1
12.2 participation of children

Individuals under the age of 18 will not be eligible to participate in this study because they are unlikely to have colorectal carcinoma, and because of unknown toxicities in pediatric patients.
untitled h1
12.3 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 decisional impaired. For this reason and because there is a prospect of direct benefit from research participation (section **12.5**), 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 HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisional impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
untitled h1
12.4 evaluation of benefits and

Patients will receive evaluation of their disease at the National Cancer Institute's Clinical Center. This protocol may or may not benefit an individual, but the results may help the investigators learn more about the disease and develop new treatments for patients with this disease. Potential adverse reactions attributable to the administration of Pexa-Vec and the chemotherapeutic agents utilized in this trial are discussed in section 3.4. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. Patients will be examined and evaluated prior to enrollment. All evaluations to monitor the treatment of patients will be recorded in the patient chart. If patients suffer any physical injury as a result of the participation in this study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland. Although no compensation is available, any injury will be evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations. In all publications and presentations resulting from this trial, patients' anonymity will be protected to the maximum extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and Drug Administration (FDA) or other regulatory authorities may have access to research files in order to verify that patients' rights have been safeguarded. In addition, patient names will be given to the Central Registration to register and verify patients' eligibility.
untitled h1
12.5 risks/benefits analysis 12.5.1 risk

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. 12.5.2 Risks of exposure to ionizing radiation The study will involve radiation from the following sources:
- Up to 7 CT scans per year for disease assessment  
- Up to 3 CT scans for the collection of 2 mandatory and 1 optional biopsy
Subjects in this study may be exposed to approximately 10.1 rem per year. This amount is more than would be expected from everyday background radiation. Being exposed to excess radiation can increase the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 1 out of 100 (1%) and of getting a fatal cancer is 0.5 out of 100 (0.5%). 12.5.3 Risks of CT Scans In addition to the radiation risks discussed above, CT scans may include the risks of an allergic reaction to the contrast. Participants might experience hives, itching, headache, difficulty breathing, increased heartrate and swelling.
untitled h1
12.5.4 research blood collection risks

Risks of blood draws include pain and bruising in the area where the needle is placed, lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood cell count (anemia) can develop.
untitled h1
12.5.5 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.
untitled h1
12.5.6 risks/benefits analysis

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 colorectal cancer. Potential risks include the possible occurrence of any of a range of side effects listed above. The risks and benefits of participation for adults who become unable to consent, are no different than those described for patients who are less vulnerable.
untitled h1
12.6 consent process and documentation

The informed consent document will be provided to the participant for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the designated study investigator and with the agreement of the participant. Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed.
untitled h1
13 pharmaceutical information 13.1 tremelimumab

13.1.1 Source Tremelimumab will be supplied by AstraZeneca/MedImmune, Inc. 13.1.2 Toxicity See **Appendix B** for details.  
13.1.3 Formulation and preparation Tremelimumab is a human IgG2 anti-CTLA-4 mAb that is being developed as an immunotherapeutic agent for various cancers.  
| Investigational       | Manufacturer                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Concentration and Formulation as Supplied                |
|-----------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Product  Tremelimumab | AstraZeneca/                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Tremelimumab will be supplied by AstraZeneca either as a |
| MedImmune             | 400-mg or a 25-mg vial solution for infusion after dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM  histidine/histidine hydrochloride, 222 mM trehalose  dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02%  weight/volume (w/v) polysorbate 80; it has a pH of 5.5 and  density of 1.034 g/mL. The nominal fill volume is 20.0 mL  for the 400-mg vial and 1.25 mL for the 25-mg vial.  Investigational product vials are stored at 2°C to 8°C (36°F  to 46°F) and must not be frozen. Drug product should be  kept in original container until use to prevent prolonged  light exposure. |                                                          |  
The 20 mg/mL solution will be diluted into a 0.9% Sodium Chloride bag for IV infusion. Vials containing tremelimumab may be gently inverted for mixing but should not be shaken. For dose preparation steps, the following ancillary items are required:  
- IV infusion bags of 0.9% sodium chloride injection (250 mL size). 0.9% Sodium Chloride 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.  
- 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.  
Lines should contain a 0.22 or 0.2 μm in-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.  
- Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless steel and/or PVC components.  
- Syringes made of polypropylene and latex-free. Polycarbonate syringes should not be used with tremelimumab.  
- Needles made of stainless steel.  
13.1.4 Stability and Storage
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. 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. 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. Labels will be prepared in accordance with Good Manufacturing Practice (GMP). 13.1.5 Administration procedures Tremelimumab is to be administered as an IV solution at a rate of 250 mL/h. In the event that either preparation time or infusion time exceeds the time limits a new dose must be prepared from new vials. Tremelimumab does not contain preservatives, and any unused portion must be discarded. No incompatibilities between tremelimumab and polyvinylchloride or polyolefin have been observed. However, polycarbonate syringes and administration set containing cellulose-based filters should not be used with tremelimumab 13.1.5.1 Monitoring of dose administration See Section **3.2.4**.
untitled h1
13.2 durvalumab (17363)

13.2.1 Source Durvalumab will be supplied by AstraZeneca/MedImmune Inc. 13.2.2 Toxicity See **Appendix B** for details.  
13.2.3 Formulation and Preparation Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1κ) subclass.  
| Investigational Product   | Manufacturer   | Concentration   | and   |
|---------------------------|----------------|-----------------|-------|
| Formulation as Supplied   |                |                 |       |  
| Durvalumab   | Medimmune/AstraZeneca   | Durvalumab will be supplied  as a 500 mg vial solution for  infusion after dilution. The  solution contains 50 mg/mL  durvalumab, 26 mM  histidine/histidine  hydrochloride, 275 mM  trehalose dihydrate, and  0.02% (weight/volume)  polysorbate 80; it has a pH of  6.0. The nominal fill volume  is 10 mL. Investigational  product vials are stored at  2°C to 8°C (36°F to 46°F)  and must not be frozen.  Durvalumab must be used  within the individually  assigned expiry date on the  label.   |
|--------------|-------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
untitled h1
13.2.4 stability and storage

The dose of durvalumab for administration must be prepared by the Investigator's or site's designated IP manager using aseptic technique. Total time from needle puncture of the durvalumab vial to the start of administration should not exceed:
- 24 hours at 2°C to 8°C (36°F to 46°F)
untitled h1
- 4 hours at room

If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion solutions must be allowed to equilibrate to room temperature prior to commencement of administration. Protect from light.
untitled h1
13.2.5 administration procedures

No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an IV bag containing 0.9% (w/v) NaCl or dextrose, with a final durvalumab concentration ranging from 1 to 20 mg/mL and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. Remove 30.0 mL of IV solution from the IV bag prior to addition of durvalumab. Next, 30.0 mL of durvalumab (i.e., 1500 mg of durvalumab) is added to the IV bag such that final concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion via an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire contents of the IV bag should be administered as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. The IV line will be flushed with a volume of IV solution (0.9% [w/v] NaCl 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. In the event that either preparation time or infusion time exceeds the time limits a new dose must be prepared from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any unused portion must be discarded. 13.2.5.1 Monitoring of dose administration See Section **3.2.4**
13.2.5.2 Dose Calculation Note: The dosing for durvalumab will be a flat dosing of 1500mg. The corresponding volume of investigational product should be rounded to the nearest tenth of a mL (0.1 mL). Each vial contains a small amount of overage and the overage should be utilized as much as possible before using another vial. The number of vials required for dose preparation is the next greatest whole number of vials from the following formula: Number of vials = Dose (mL) ÷ 20 (mL/vial) 13.2.5.3 Investigational Product Preparation Steps (Durvalumab) 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) Labels will be prepared in accordance with Good Manufacturing Practice (GMP).
13.2.5.4 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 (**13.2.5.6**) 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. 13.2.5.5 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. 13.2.5.6 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
untitled h1
13.3 pexa-vec (17363)

13.3.1 Source Pexa-Vec will be supplied by Sillajen Inc. 13.3.2 Toxicity Toxicity of Pexa-Vec listed in Section **3.4.1**
13.3.3 Formulation and Preparation VACC-6.25.1, Recombinant Vaccinia/GM-CSF (VAC-6.25.1 [GM-CSF1]), VAC GM-CSF, Vaccinia/GM-CSF
Generic Name: Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (thymidine kinasedeactivated plus GM-CSF)
Pexa-Vec is a viral suspension supplied in individual 4-mL glass vials. Each vial contains Pexa-Vec diluted in 30 mM Tris 10% Sucrose buffer. The recoverable volume of Pexa-Vec in each vial is 2 mL with an infectious titer of 1 × 109 pfu (9.0 Log pfu). Each vial is intended for single use (i.e., 1 injection to 1 patient). 0.6 ml of viral suspension is to be removed for the 3 x 108 pfu dose 13.3.3.1 Packaging and Labeling of Pexa-Vec Each vial is packed in a cardboard box (secondary packaging) which constitutes a Pexa-Vec treatment kit (1-vial treatment kit). The primary labels on the vials as well as the secondary labels on the cardboard boxes are in the language of countries where the study is to be performed. Labels are compliant with local regulatory requirements and contain information including, but not limited to: Sponsor name, product code, lot number, concentration, volume, storage conditions, route of administration and a cautionary statement in proper language. 13.3.3.2 Biosafety/Containment Level Classification of Pexa-Vec Pharmacies, hospitals, and clinics routinely administer infectious organisms (e.g., live viral vaccines, and live BCG for bladder cancer) and Pexa-Vec preparation and administration handling recommendations are also based on CDC guidelines for preparation of the standard vaccinia vaccine (CDC 2009). Pexa-Vec is classified as a biohazard safety level 1 or 2 (BSL-1 or 2) agent based on the very low pathogenicity and the potential to spread only by direct physical contact
untitled h1
13.3.3.3 transport of pexa-vec 13.3.3.4

Pexa-Vec is shipped on dry-ice with the official transport designation as a "Biological Substance, Category B" in compliance with International Air Transportation Association and Department of Transportation regulations and other local regulations for air and road transport of infectious substances (UN 3373 regulations). 13.3.3.5 Transport within the Institution All transport of Pexa-Vec (in vial or IV bag) within the institution must be done using a leak-proof container/bag clearly-marked with a biohazard symbol.
untitled h1
13.3.4 stability and storage

Pexa-Vec must be stored at or below –60°C in an alarmed, temperature-monitored, secure freezer with restricted access. Pexa-Vec can be stored with other therapeutics but should be separate from lab samples.  
The study demonstrated that the diluted Pexa-Vec is stable for 24 hours at 20 to 80 and an additional 3 hours at room temperature. 13.3.4.1 Dispensing of Pexa-Vec Pexa-Vec will be dispensed only with the written authorization of the Investigator or a subInvestigator to staff that have been specifically designated and trained for this study.
untitled h1
13.3.5 handling of pexa-vec

All applicable institutional policies for preparation, transport, and disposal of viral vectors should be consulted and followed. During all Pexa-Vec manipulations gloves, gown, surgical mask and goggles (or safety glasses with side shields) must be worn. Headgear and overshoes are not mandatory. Regardless of the BSL classification, the following are recommended as conservative measures for Pexa-Vec preparation, decontamination and storage: 13.3.5.1 Individuals excluded from handling (preparation and administration):  
- pregnant or breastfeeding women
- immunocompromised individuals (e.g., organ transplant recipient, HIV-positive individual, or receiving chronic immunosuppressive medication)
- individuals with ongoing severe inflammatory skin condition requiring medical treatment or history of severe eczema requiring medical treatment.
13.3.5.2 Limit access:  
- place a biohazard sign in the preparation area - limit access to the designated area (e.g., the hood used to prepare Pexa-Vec) during preparation
13.3.5.3 Equipment The following are recommended as conservative measures for Pexa-Vec preparation, decontamination and storage:  
- Prepare in a Class IIA Biological Safety Cabinet (e.g., a standard chemotherapy hood equipped with a properly maintained high-efficiency particulate air [HEPA] filter)
- Wear standard PPE - gloves, goggles, mask, and gown while preparing the agent (e.g., as with standard chemotherapy precautions)
13.3.6 Preparation and administration of Pexa-Vec The Pexa-Vec dose of 3 x 108 pfu (DL 1) or 1 x 109 pfu (DL 2) will be administered via IV
infusion over 60 minutes (±5 minutes). Patients will receive 1 L 0.9% NaCl prior to infusion.  
This dose of Pexa-Vec will be suspended in a 255 mL infusion bag, containing 250 mL sterile 0.9% sodium chloride [NaCl] and 5 mL molar sodium bicarbonate (8.4% NaHCO3). The total amount of NaCl and NaHCO3 will approximately be 2.25 and 0.42 g/infusion, respectively.
untitled h1
13.3.7 cleaning / disinfection and

Standard institutional policies should be followed for cleaning and decontamination while handling vaccinia virus-based products. Hospital-grade chemical disinfectants containing: bleach (with at least 0.6% of active chlorine), alcohols (≥60%), aldehydes, hydrogen peroxide (3%), iodophor (75 ppm), phenols or quaternary ammonium compounds are adequate for routine cleaning and disinfection of work areas after Pexa-Vec handling. The manufacturer's instructions should be followed to ensure adequate contact time and confirm the ability of the equipment to withstand the disinfectant used. All contaminated material (e.g., syringes, catheters, needles, tubing, gloves, used or unused vials, containers, bandages, etc.) should be disposed of in a clearly-marked biomedical waste container and discarded according to regular institution procedure for infectious waste i.e., autoclaving, incineration, or treatment with sodium hypochlorite solution. Biomedical waste will not be left unattended in a public area; autoclaved medical waste must not be disposed of as regular trash. Textiles and fabrics can be laundered in hot water (71°C) with detergent and hot air drying.
untitled h1
13.3.8 spills or environmental contamination

In the event of a spill, people in the immediate area will be alerted and other institutional personnel will be notified as required by institutional policies. Vaccinia viruses, like most enveloped viruses, are sensitive to inactivation by standard physical and chemical methods of disinfection. A standard hospital-grade disinfectant should be used to clean non-critical patient care equipment or medical devices between each patient use (e.g., bedpans, commodes, blood pressure cuffs, oximeters, glucose meters.) Hospital-grade disinfectants include 3% hydrogen peroxide, ≥60% alcohol, hypochlorite (1000 ppm), 0.5% accelerated hydrogen peroxide, quaternary ammonium compounds, iodophors (75 ppm), phenolics, and aldehydes. The manufacturer's instructions should be followed to ensure adequate contact time and confirm the ability of the equipment to withstand the disinfectant used. Critical and semi-critical devices should be cleaned and reprocessed according to institutional guidelines. Spills and accidents that result in overt exposures to infectious material will be reported as required by institutional policies.
untitled h1
13.3.9 unused drug return or

During the course of the study and at termination of the study all unused Pexa-Vec patient kits will be destroyed locally or returned to the drug supply provider. For local destruction, the Investigator/Pharmacist or delegated person will ensure that all contaminated material should be disposed of in a clearly-marked biomedical waste container and discarded according to regular institution procedure for infectious waste and will not expose humans to any risks from Pexa-Vec. A certificate of destruction will be completed. The drug supply provider will coordinate the return of all unused Pexa-Vec patient kits. A certificate of return will be completed and provided to the drug supply provider (copy retained by the site).  
Upon completion or termination of the study at a site, the monitor will verify that all used Pexa-Vec patient kits have been decontaminated (if applicable) and disposed, all unused Pexa-Vec patient kits have been returned or destroyed, and no IP remains on site.
untitled h1
14 references

1. Mlecnik B, Tosolini M, Kirilovsky A et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011; 29: 610-618. 2. Pages F, Kirilovsky A, Mlecnik B et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009; 27: 5944-5951. 3. Zamarin D, Holmgaard RB, Subudhi SK et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 2014; 6: 226ra232. 4. Heo J, Reid T, Ruo L et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 2013; 19: 329-336. 5. Breitbach CJ, Burke J, Jonker D et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 2011; 477: 99-102. 6. Park SH, Breitbach CJ, Lee J et al. Phase 1b Trial of Biweekly Intravenous Pexa-Vec (JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus in Colorectal Cancer. Mol Ther 2015; 23: 1532-1540. 7. Kohlhapp FJ, Kaufman HL. Molecular Pathways: Mechanism of Action for Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy. Clin Cancer Res 2016; 22: 1048-1054. 8. Rajani KR, Vile RG. Harnessing the Power of Onco-Immunotherapy with Checkpoint Inhibitors. Viruses 2015; 7: 5889-5901. 9. Andtbacka RH, Kaufman HL, Collichio F et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 2015; 33: 27802788. 10. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252-264.  
11. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. New England Journal of Medicine 2015; 373: 123-135. 12. Wang E, Kang D, Bae KS et al. Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma. J Clin Pharmacol 2014; 54: 1108-1116. 13. Ng CM, Lum BL, Gimenez V et al. Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res 2006; 23: 1275-1284. 14. Wang DD, Zhang S, Zhao H et al. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009; 49: 1012-1024. 15. Zhang S, Shi R, Li C et al. Fixed dosing versus body size-based dosing of therapeutic peptides and proteins in adults. J Clin Pharmacol 2012; 52: 18-28.  
16. Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational anti-interferon-alpha monoclonal antibody, in systemic lupus erythematosus. Clin Pharmacokinet 2013; 52: 1017-1027.  
17. Brahmer JR. PD-1-targeted immunotherapy: recent clinical findings. Clin Adv Hematol Oncol 2012; 10: 674-675. 18. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 2009; 45: 228247.