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9.1.4 merck requirements for evaluating

An investigator who is a qualified physician will evaluate all adverse events according to the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which changes CTCAE grade over the course of a given episode will have each change of grade recorded on the adverse event case report forms/worksheets. All adverse events regardless of CTCAE grade must also be evaluated for seriousness.  
An investigator who is a qualified physician, will evaluate all adverse events as to:  
| V4.0 CTCAE   | Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention   |
|--------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|
| Grading      | not indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                              |
| Grade 2      | Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate  instrumental ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                              |
| Grade 3      | Severe or medically significant but not immediately life-threatening; hospitalization or  prolongation or hospitalization indicated; disabling; limiting self-care ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                              |
| Grade 4      | Life threatening consequences; urgent intervention indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                              |
| Grade 5      | Death related to AE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                              |
| Seriousness  | A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: †Results in death; or †Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event  as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have  caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct  normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission,  regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note:  Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not  worsened does not constitute a serious adverse event.); or †Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or Is a new cancer; (that is not a condition of the study) or Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a  serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of  clinical interest and must be reported within 24 hours. Other important medical events that may not result in death, not be life threatening, or not require hospitalization  may be considered a serious adverse event when, based upon appropriate medical judgment, the event may  jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed  previously (designated above by a †). |                                                                                              |
| Duration     | Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and  units                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                              |
| Action taken | Did the adverse event cause the Merck product to be discontinued?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                              |
| Relationship | Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                              |
| to test drug | the adverse event will be provided by an investigator who is a qualified physician. The investigator's signed/dated  initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a  medically qualified assessment of causality was done. This initialed document must be retained for the required                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                              |  
CCCWFU \# 88215  
| regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing  the likelihood of a relationship between the test drug and the adverse event based upon the available information.  The following components are to be used to assess the relationship between the Merck product and the AE;  the greater the correlation with the components and their respective elements (in number and/or intensity), the more  likely the Merck product caused the adverse event (AE): Exposure Is there evidence that the subject was actually exposed to the Merck product such as: reliable history,  acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or  measurement of drug/metabolite in bodily specimen? Time  Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  Course Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with  investigational medicinal product)? Likely  Is the AE not reasonably explained by another etiology such as underlying disease, other  Cause drug(s)/vaccine(s), or other host or environmental factors   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Relationship                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | The following components are to be used to assess the relationship between the test drug and the AE: (continued)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| to                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Merck                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| product (continued)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Dechallenge                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Was the Merck product discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. If no, this is a negative dechallenge. (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the  AE resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug  trial); or (4) Merck product(s) is/are only used one time.) |
| Rechallenge                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Was the subject re-exposed to the Merck product in this study? If yes, did the AE recur or worsen? If yes, this is a positive rechallenge. If no, this is a negative rechallenge. (Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or  (2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time). NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS  SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF  REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT  RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE  BY THE U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE  PROTOCOL. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Consistency  with Trial  Treatment  Profile                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the  Merck product or drug class pharmacology or toxicology?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician  according to his/her best clinical judgment, including consideration of the above elements. Record one of the following Use the following scale of criteria as guidance (not all criteria must be present to be indicative of  a Merck product relationship). Yes, there is a reasonable  possibility of Merck  product relationship. There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative  to the administration of the Merck product is reasonable. The AE is more likely explained by the  Merck product than by another cause. No, there is not a reasonable  possibility Merck product  relationship Subject did not receive the Merck product OR temporal sequence of the AE onset relative to  administration of the Merck product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
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9.2 adverse event characteristics

- **CTCAE term (AE description) and grade:** 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  
CCCWFU \# 88215 copy of the CTCAE version 4.0 can be downloaded from the CTEP web site
(http://ctep.cancer.gov).  
- **'Expectedness'**: AEs can be 'Unexpected' or 'Expected' (see Section 7.1 above) for expedited reporting purposes only.
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- attribution of the ae

- Definite - The AE is clearly **related** to the study treatment. - Probable - The AE is likely **related** to the study treatment.  
- Possible - The AE may be **related** to the study treatment.  
- Unlikely - The AE **is doubtfully related** to the study treatment. - Unrelated - The AE **is clearly NOT related** to the study treatment.
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9.3 strc sae reporting requirements

The Safety and Toxicity Reporting Committee (STRC) is responsible for reviewing SAEs for CCCWFU Institutional studies as outlined in Appendix B. STRC currently requires that all unexpected 4 and all grade 5 SAEs on these trials be reported to them for review. All CCCWFU Clinical Research Management (CRM) staff members assisting a Principal Investigator in investigating, documenting and reporting an SAE qualifying for STRC
reporting are responsible for informing a clinical member of the STRC as well as the entire committee via the email notification procedure of the occurrence of an SAE.
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9.4 wfuhs irb ae reporting

Any unanticipated problems involving risks to subjects or others and adverse events shall be promptly reported to the IRB, according to institutional policy. Reporting to the IRB is required regardless of the funding source, study sponsor, or whether the event involves an investigational or marketed drug, biologic or device. Reportable events are not limited to physical injury, but include psychological, economic and social harm. Reportable events may arise as a result of drugs, biological agents, devices, procedures or other interventions, or as a result of questionnaires, surveys, observations or other interactions with research subjects. All members of the research team are responsible for the appropriate reporting to the IRB and other applicable parties of unanticipated problems involving risk to subjects or others. The Principal Investigator, however, is ultimately responsible for ensuring the prompt reporting of unanticipated problems involving risk to subjects or others to the IRB. The Principal Investigator is also responsible for ensuring that all reported unanticipated risks to subjects and others which they receive are reviewed to determine whether the report represents a change in the risks and/or benefits to study participants, and whether any changes in the informed consent, protocol or other study-related documents are required.  
Any unanticipated problems involving risks to subjects or others occurring at a site where the study has been approved by the WFUHS IRB (internal events) must be reported to the WFUHS IRB within 7 calendar days of the investigator or other members of the study team becoming aware of the event.  
CCCWFU \# 88215 Any unanticipated problems involving risks to subjects or others occurring at another site conducting the same study that has been approved by the WFUHS IRB (external events)
must be reported to the WFUHS IRB within 7 calendar days of the investigator or other members of the study team becoming aware of the event. Any event, incident, experience, or outcome that alters the risk versus potential benefit of the research and as a result warrants a substantive change in the research protocol or informed consent process/document in order to insure the safety, rights or welfare of research subjects.
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9.5 merck reporting requirements 9.5.1

Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them), including the pregnancy of a male subject's female partner that occurs during the trial or within 120 days of completing the trial completing the trial, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All subjects and female partners of male subjects who become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported.  
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)
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9.5.2 reporting of saes and

Any serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the cancer under study that occurs to any subject from the time the consent is signed through 90 days following cessation of treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to Merck product that is brought to the  
CCCWFU \# 88215 attention of the investigator at any time outside of the time period specified in the previous paragraph also must be reported immediately to the Sponsor and to Merck.
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sae reports and any other

A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. Investigators will cross reference this submission according to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. All subjects with serious adverse events must be followed up for outcome.
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10.0 pharmaceutical information

A list of the adverse events and potential risks associated with the investigational or commercial agents administered in this study can be found in Section 9.0.
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10.1 pharmaceutical accountability

Drug accountability logs will be maintained for all investigative agents used under this protocol. These logs shall record quantities of study drug received and quantities dispensed to patients, including lot number, date dispensed, patient identifier number, patient initials, protocol number, dose, quantity returned, balance remaining, and the initials of the person dispensing the medication.
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10.2 pembrolizumab

Clinical Supplies will be provided by Merck as summarized below.  
| Product Name & Potency    | Dosage Form                      |
|---------------------------|----------------------------------|
| Pembrolizumab 50 mg       | Lyophilized Powder for Injection |
| Pembrolizumab 100 mg/ 4mL | Solution for Injection           |  
Packaging and Labeling Information Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.  
CCCWFU \# 88215
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clinical supplies disclosure

This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided.  
Marketed Packs: When Study Drug is provided in the marketed package, Merck will not supply any Chemistry, Manufacturing, Control (CMC) information. Institution's regulatory submission should reference the Merck Marketing Authorization. If any additional labelling of containers is required, e.g. to add Study Protocol number, and it has not been agreed for Merck to perform the additional labelling, it is Institution's responsibility to arrange for this action to be done in accordance with U.S. regulations.
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storage and handling requirements

The lyophilized drug product after reconstitution with sterile water for injection, and the liquid drug product are a clear to opalescent solutions, essentially free of visible particles. The reconstituted lyophilized product and the liquid product are intended for IV administration. The reconstituted drug product solution or the liquid drug product can be further diluted with normal saline or 5% dextrose in the concentration range of 1 to 10 mg/mL in intravenous (IV) containers made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be immediately used to prepare the infusion solution in the IV bag and the infusion solution should be immediately administered. Diluted pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 hours. This includes room temperature storage of admixture solutions in the IV bags and the duration of infusion. In addition, IV bags can be stored at 2 to 8°C for up to a cumulative time of 20 hours. This recommendation is based on up to 24 hours of room temperature and up to 24 hours of refrigerated stability data of diluted MK3475 solutions in the IV bags.  
Clinical supplies must be stored in a secure, limited-access location. The drug product is to be stored as a stable lyophilized powder or liquid solution under refrigerated conditions (2 to 8°C). Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol.
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returns and reconciliation

The investigator is responsible for keeping accurate records of the clinical supplies received from Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining at the conclusion of the trial. Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to  
CCCWFU \# 88215 applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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10.3 paclitaxel

Product description: Supplied as:  
| NDC 0015-3475-30   | 30 mg/5 mL multidose vial individually packaged in a  carton     |
|--------------------|------------------------------------------------------------------|
| NDC 0015-3476-30   | 100 mg/16.7 mL multidose vial individually packaged in a  carton |
| NDC 0015-3479-11   | 300 mg/50 mL multidose vial individually packaged in a  carton   |  
Solution preparation: Paclitaxel Injection must be diluted prior to infusion.  
Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/mL.  
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.  
Storage requirements: Store the vials in original cartons between 20°–25° C
(68°–77° F). Retain in the original package to protect from light.  
Stability: Unopened vials of paclitaxel injection are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Prepared solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25° C) and room lighting conditions.  
Route of administration: Paclitaxel should be administered as an intravenous infusion through an in-line filter with a microporous membrane not greater than 0.22 microns. Monitor infusion site for possible infiltration during drug administration.  
Disposal: To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed  
CCCWFU \# 88215 thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.
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11.0 correlative/special studies 11.1 laboratory

Peripheral blood will be obtained from each patient prior to initiation of treatment, on cycle 4 day 1, cycle 8 day 1, and at the end-of-treatment visit. A total of six
(6)
10mL EDTA tubes will be drawn at each time point.  
Changes from baseline and in responding versus nonresponding patients will be assessed.  
(1) **Activated T-cells:** The goal is to calculate the number and percentage of IFNγ+CD8+ T cells in peripheral blood pre-, on-, and post-treatment.  
i. *Sample collection.* Peripheral blood will be obtained from each patient prior to initiation of treatment, on cycle 4 day 1, cycle 8 day 1, and at the end-oftreatment visit. The lymphocyte fraction will be isolated on a Percoll gradient.  
ii. *T-cell processing.* Cells will be stimulated overnight with plate-bound antiCD3 (1ug/mL) and soluble anti-CD28 (1ug/mL) in the presence of protein transport inhibitors Brefeldin A and monensin. Following stimulation, cells will be stained with anti-CD8-FITC antibody, fixed and permeabilized using the BD Cytofix/Cytoperm staining kit. Following permeabilization the cells will be stained with anti-IFNg, anti-IL-12, anti-IL2. Stained cells will be run on a FACS Canto and analyzed using manufacturer provided software. The proportion of IFNg+CD8+ T cells will be quantified, with expression of IL12 considered further evidence of activated effector function.  
(2) **MDSC and Tregs:** The goal is to determine whether combination treatment changes the number and proportion of MDSC and Tregs in peripheral blood.  
i. *Sample collection.* Peripheral blood will be obtained from each patient prior to initiation of treatment, on cycle 4 day 1, cycle 8 day 1, and at the end-oftreatment visit. The lymphocyte fraction will be isolated on a Percoll gradient.  
ii. *MDSC and T-reg processing*. Tregs will be quantified using the human Treg staining kit (eBioscience) and established methods.  
(3) **MicroRNAs:** The goal is to explore changes in circulating and urinary immuneregulatory microRNAs during treatment, using quantitative real time PCR.  
i. *Sample collection.* Blood and urine will be collected each patient prior to initiation of treatment, on cycle 4 day 1, cycle 8 day 1, and at the end-oftreatment visit. 10 mL of blood will be drawn into EDTA tubes. Peripheral blood mononuclear cells (PBMC) and plasma will be separated by gradient  
CCCWFU \# 88215 centrifugation. Urine is centrifuged at 1000 g for 10 minutes to pellet cellular debris. All samples are aliquoted and stored at −80°C until further use.  
ii. miRs *processing.* Total RNA will be isolated from plasma and urine using the miRNeasy Mini Kit (Qiagen) collected pre-, on-, and post-therapy. Pools of plasma samples collected from healthy donors will be tested as controls. Plasma levels of selected miRs will be measured with qRT-PCR, normalized to spiked-in synthetic miR, in all patients pre- and post-therapy. Reverse transcription reactions are performed using a TaqMan MicroRNA Reverse Transcription Kit (Applied Biosystems) according to the manufacturer's instructions. qRT-PCR will be performed using the reverse transcription reaction product, TaqMan MicroRNA Assay kits, and TaqMan Universal PCR Master Mix (Applied Biosystems. The ΔΔCT method is used to determine relative levels (RQ). Data are normalized to a *C. elegans* synthetic miR sequence, cel-miR-39 (Qiagen), which is spiked in as a control during RNA isolation.
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11.2 pathology correlative studies

When feasible, a metastatic biopsy will be performed. Archived tumor TURBT and cystectomy specimens will also be accessed. The goal will be to determine PD-L1 expression and to analyze cytotoxic T-cell number and function, MDSC, and Treg cells in tumor tissue.  
(1) **Tumor PD-L1 expression**: Biopsy samples will be stored and batched for PD-L1 immunohistochemistry. This will be done with QualTek per Merck's guidelines. Five
(5) unstained slides per patient, cut from a formalin-fixed, paraffin-embedded (FFPE) tissue block, will be sent to QualTek for PD-L1 staining. Positively charged ProbeOn Plus slides must be used for tissue sections. Samples may be held as blocks indefinitely at the site and then cut in batches. Slides must be shipped to QualTek immediately after sectioning to comply with the protocol's testing requirements.  
Sectioned slides must be shipped cold (2-8°C) and in the dark using the shipping materials provided by QualTek. Sectioned slides provided should contain tumor specimen sufficient for pathology review and analysis of tumor sample. If available, greater than 50% tumor content is preferred. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, lavage specimen, frozen sample, plastic embedded sample, or formalin fixed sample that was frozen at any point will not be accepted for IHC analysis. Needle core biopsies that are formalin-fixed and paraffinembedded are acceptable. The slides will be evaluated by a Qualtek-associated pathologist for review of biomarker staining expression levels.  
(2) **Tumor immune cells**: Cytotoxic T-cell number and function, MDSC, and Treg cells in tumor tissue will be evaluated in both archival tissue and in fresh biopsy specimens. Tumor tissue will be digested with DNase and Collagenase using standard protocols, and CD8+ T cells will be isolated by flow sorting. Sorted T cells will be stimulated with  
CCCWFU \# 88215 anti-CD3/anti-CD28, and expression of IFNg and IL-12 will be quantified by flow cytometry to determine proportion of functional T-cells. For detection of Tregs in biopsy samples, CD4+CD25+ T cells will be isolated by flow sorting, and post-stained for FoxP3. To detect MDSC, Gr+ and CD11b+ cells will be sorted and confirmed by Wright-Giemsa staining of sorted cells. Concordance of immune cell frequency between archival and fresh specimens and the peripheral blood from the same patient will be informative.
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12.0 data management

| Informed consent document          | ORIS   |
|------------------------------------|--------|
| Protocol registration form         | ORIS   |
| Adverse Events                     | ORIS   |
| Baseline Data Collection Form      | REDCap |
| Follow-Up Data Collection Form     | REDCap |
| Treatment Evaluation Response Form | REDCap |
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13.0 statistical considerations 13.1 power

Simon's minimax two-stage design37 will be used. The null hypothesis that the true response rate is 24% will be tested against a one-sided alternative. In the first stage, 15 patients will be accrued. If there are 3 or fewer responses in these 15 patients, the study will be stopped. Otherwise, 12 additional patients will be accrued for a total of 27. The null hypothesis will be rejected if 10 or more responses are observed in 27 patients. This design yields a type I error rate of .09 and power of 90% when the true response rate is 48%. We anticipate an accrual rate of 1-2 patients per month or 12-24 patients per year.
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13.2 analysis of primary objective

The primary endpoint will be overall response rate. The analysis will be performed in all patients that are evaluable for efficacy and will have one interim analysis. In this phase 2 trial, we will calculate the overall response rate (primary outcome) and 6-month PFS. For the overall response rate, if 10 or more responses are observed in the 27 patients, we will reject the null hypothesis that the response rate is 24% or less.
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13.3 analysis of secondary objectives

The secondary endpoints include PFS and safety. We will estimate PFS at 6months using the Kaplan-Meier method on all evaluable patients. All AEs will be  
CCCWFU \# 88215 tabulated and presented by preferred term and/or system organ class and grade.  
All deaths and SAEs will be tabulated. The 6-month PFS will be compared to historical rates using a chi-square test.
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13.4 analysis of correlative objectives

The correlative endpoints include immune effects. They will be analyzed in exploratory analyses to associate their levels with tumor response. Categorical endpoints will be analyzed using chi-square or Fisher's exact tests, and continuous measures will be compared using t-tests to compare response groups.
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references

1. *Cancer Facts & Figures 2015.* Atlanta: American Cancer Society. 2. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. *Journal of clinical oncology : official journal of the American Society* of Clinical Oncology. Jul 20 2005;23(21):4602-4608.  
3. Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. *Cancer research.* Feb 1 2004;64(3):1140-1145.  
4. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clinical cancer research : an official journal of the American Association for Cancer Research. Dec 15 2012;18(24):6580-6587.  
5. Plimack E, Gupta S, Bellmunt J, et al. A phase 1b study of pembrolizumab in patients with advanced urothelial tract cancer. *ESMO annual meeting.* 2014;LBA23.  
6. Eruslanov E, Neuberger M, Daurkin I, et al. Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. *International journal of cancer. Journal international du cancer.* Mar 1 2012;130(5):1109-1119.  
7. Brandau S, Trellakis S, Bruderek K, et al. Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. *Journal of leukocyte biology.* Feb 2011;89(2):311-317.  
8. Loskog A, Ninalga C, Paul-Wetterberg G, de la Torre M, Malmstrom PU, Totterman TH. Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. *The Journal of* urology. Jan 2007;177(1):353-358.  
9. Horn T, Grab J, Schusdziarra J, et al. Antitumor T cell responses in bladder cancer are directed against a limited set of antigens and are modulated by regulatory T cells and routine treatment approaches. *International journal of cancer. Journal international du cancer.* Nov 2013;133(9):2145-2156.  
10. Chikamatsu K, Sakakura K, Toyoda M, Takahashi K, Yamamoto T, Masuyama K.  
Immunosuppressive activity of CD14+ HLA-DR- cells in squamous cell carcinoma of the head and neck. *Cancer science.* Jun 2012;103(6):976-983.  
11. Kim K, Skora AD, Li Z, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. *Proceedings of the National* Academy of Sciences of the United States of America. Aug 12 2014;111(32):11774-11779.  
12. Mangsbo SM, Sandin LC, Anger K, Korman AJ, Loskog A, Totterman TH. Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy. *Journal of immunotherapy.* Apr 2010;33(3):225-235.  
13. Albers P, Park SI, Niegisch G, et al. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. *Annals of oncology*
: official journal of the European Society for Medical Oncology / ESMO. Feb 2011;22(2):288-294.
untitled h1
cccwfu # 88215

14. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Feb 15 2002;20(4):937-940.  
15. McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. *Journal of clinical oncology : official journal of the* American Society of Clinical Oncology. May 1997;15(5):1853-1857.  
16. Yuan L, Wu L, Chen J, Wu Q, Hu S. Paclitaxel acts as an adjuvant to promote both Th1 and Th2 immune responses induced by ovalbumin in mice. *Vaccine.* Jun 17 2010;28(27):4402-4410.  
17. Huang X, Huang G, Song H, Chen L. Preconditioning chemotherapy with paclitaxel and cisplatin enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model.  
International journal of cancer. Journal international du cancer. Aug 1 2011;129(3):648-658.  
18. Sevko A, Michels T, Vrohlings M, et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model.  
Journal of immunology. Mar 1 2013;190(5):2464-2471.  
19. Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. *Journal of translational medicine.* 2014;12:36.  
20. Wei H, Zhao L, Li W, et al. Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin. *PloS one.* 2013;8(12):e84927.  
21. Alizadeh D, Larmonier N. Chemotherapeutic targeting of cancer-induced immunosuppressive cells. *Cancer research.* May 15 2014;74(10):2663-2668.  
22. Daud AI, Hamid O, Ribas A, et al. Antitumor activity of the anti-PD-1 monoclonal antibody MK3475 in melanoma: Correlation of tumor PD-L1 expression with outcome. *AACR Annual Meeting.*
2014;Abstract CT104.  
23. Gandhi L, Balmanoukian A, Hui R, et al. MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression. *AACR* Annual Meeting. 2014; Abstract CT105.  
24. Bellmunt J, Mullane SA, Werner L, et al. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. Jan 18 2015.  
25. Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research.  
Feb 15 2015;21(4):712-720.  
26. Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Dec 1 2013;31(34):4311-4318.  
27. Miah S, Dudziec E, Drayton RM, et al. An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer. *British journal of cancer.* Jun 26 2012;107(1):123-128.  
28. Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. *Urologic* oncology. Nov-Dec 2010;28(6):655-661.  
29. Adam L, Wszolek MF, Liu CG, et al. Plasma microRNA profiles for bladder cancer detection.  
Urologic oncology. Nov 2013;31(8):1701-1708.  
30. Achberger S, Aldrich W, Tubbs R, Crabb JW, Singh AD, Triozzi PL. Circulating immune cell and microRNA in patients with uveal melanoma developing metastatic disease. *Molecular* immunology. Apr 2014;58(2):182-186.  
31. Triozzi PL, Achberger S, Aldrich W, Elson P, Garcia J, Dreicer R. Differential immunologic and microRNA effects of 2 dosing regimens of recombinant human granulocyte/macrophage colony stimulating factor. *Journal of immunotherapy.* Sep 2012;35(7):587-594.  
32. Dreicer R, Gustin DM, See WA, Williams RD. Paclitaxel in advanced urothelial carcinoma: its role in patients with renal insufficiency and as salvage therapy. *The Journal of urology.* Nov 1996;156(5):1606-1608.  
CCCWFU \# 88215 33. Papamichael D, Gallagher CJ, Oliver RT, Johnson PW, Waxman J. Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. *British* journal of cancer. 1997;75(4):606-607.  
34. Seidman AD, Hudis CA, Albanell J, et al. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Oct 1998;16(10):3353-3361.  
35. Friedland DM, Dakhil S, Hollen C, Gregurich MA, Asmar L. A phase II evaluation of weekly paclitaxel plus carboplatin in advanced urothelial cancer. *Cancer investigation.* 2004;22(3):374382.  
36. 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 (Oxford, England : 1990).* Jan 2009;45(2):228-247.  
37. Simon R. Optimal two-stage designs for phase II clinical trials. *Controlled clinical trials.* Mar 1989;10(1):1-10.  
CCCWFU \# 88215
appendix a - protocol registration
cccwfu # 88215

DEMOGRAPHICS  
  
| Non-Hispanic      |                   |
|--------------------|-------------------|
|  PACIFIC ISLANDER |  NATIVE AMERICAN |  
  
PROTOCOL INFORMATION Informed written consent: (consent must be signed prior to registration)
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday - Friday.  
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or e-mailed to the registrar at 336-7136772 or registra@wakehealth.edu.  
Date of Registration: ___ ___ / ___ ___ / ___ ___
MD Name (last) : ______________________
Date protocol treatment started: ___ ___ / ___ ___ / ___ ___  
  
Date Consent Signed: ___ ___ / ___ ___ / ___ ___
PID # (to be assigned by ORIS): ___ ___ ___ ___ ___ ___ ___ ___
Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory urothelial carcinoma Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 88215
appendix b - subject eligibility
irb protocol no. cccwfu protocol

Study Title: Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory urothelial carcinoma Principal Investigator: Rhonda Bitting, MD  
| Inclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Criteria      | Criteria is   | Source Used to Confirm *                |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|---------------|-----------------------------------------|
| (as outlined in study protocol)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | is met        | NOT met       | (Please document dates and lab results) |
| Patients diagnosed with platinum-refractory  metastatic urothelial cancer that is measureable  based on Response Evaluation Criteria in Solid  Tumors (RECIST) criteria 1.1. Platinum-refractory  disease is defined as progressive disease on  cisplatin or carboplatin therapy or within 12 months of prior platinum treatment (last dose.)                                                                                                                                                                                                                                                     | □             | □             |                                         |
| At least 1 prior chemotherapy regimen containing  cisplatin or carboplatin.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | □             | □             |                                         |
| Be willing to provide tissue from a newly obtained  core or excisional biopsy of a tumor lesion.  Newly-obtained is defined as a specimen  obtained up to 6 months (168 days) prior to  initiation of treatment on Day 1. Archived  specimen can be used for subjects, if available.                                                                                                                                                                                                                                                                                                              | □             | □             |                                         |
| Age >18 years.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | □             | □             |                                         |
| Performance status of 0 or 1 on the ECOG  Performance Scale.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | □             | □             |                                         |
| Adequate organ function as defined below: ANC ≥ 1,500/mcL Platelets ≥ 80,000/mcL Hemoglobin ≥9 g/dL without transfusion dependency. Serum Creatinine OR  Measured or Calculated Creatinine Clearance   (GFR can also be used in place of creatinine or CrCl)  ≤1.5x upper limit of normal (ULN) OR  ≥35 mL/min for subject with creatinine levels >1.5x institutional ULN Serum Total bilirubin ≤ 1.5x ULN OR  Direct bilirubin ≤ ULN for subjects with total bilirubin  levels > 1.5x ULN AST (SGOT) and ALT (SGPT) ≤ 2.5x ULN OR ≤ 5x ULN for subjects with liver metastases Albumin >2.5 mg/dL | □             | □             |                                         |
| Female subjects of childbearing potential should  have a negative urine or serum pregnancy within  72 hours prior to receiving the first dose of study  medication. If the urine test is positive or cannot  be confirmed as negative, a serum pregnancy test  will be required.                                                                                                                                                                                                                                                                                                                  | □             | □             |                                         |
| Protocol version date 03/10/2020                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Page 63 of 85 |               |                                         |  
Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory urothelial carcinoma Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 88215  
| CCCWFU # 88215                                                                                                                                                                                                                                                                                                                                                                                 |                                         |                          |                                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|--------------------------|-----------------------------------------|
| Inclusion Criteria                                                                                                                                                                                                                                                                                                                                                                             | Criteria                                | Criteria is              | Source Used to Confirm *                |
| (as outlined in study protocol)                                                                                                                                                                                                                                                                                                                                                                | is met                                  | NOT met                  | (Please document dates and lab results) |
| Female subjects of childbearing potential should  be willing to use 2 methods of birth control or be  surgically sterile, or abstain from heterosexual  activity for the course of the study through 120  days after the last dose of study medication.  Subjects of childbearing potential are those who  have not been surgically sterilized or have not  been free from menses for >1 year. | □                                       | □                        |                                         |
| Male subjects should agree to use an adequate  method of contraception starting with the first                                                                                                                                                                                                                                                                                                 | □                                       | □                        |                                         |
| dose of study therapy through 120 days after the  last dose of study therapy. Ability to understand and the willingness to sign  an IRB-approved informed consent document.                                                                                                                                                                                                                    | □                                       | □                        |                                         |
| Criteria  NOT  present                                                                                                                                                                                                                                                                                                                                                                         |                                         |                          |                                         |
| Exclusion Criteria                                                                                                                                                                                                                                                                                                                                                                             |                                         |                          |                                         |
| (as outlined in study protocol)                                                                                                                                                                                                                                                                                                                                                                | Criteria is                             | Source Used to Confirm * |                                         |
| present                                                                                                                                                                                                                                                                                                                                                                                        | (Please document dates and lab results) |                          |                                         |
| Currently receiving or has had treatment with an  investigational agent or used an investigational                                                                                                                                                                                                                                                                                             | □                                       | □                        |                                         |
| device within 4 weeks of study Day 1. Anti-cancer monoclonal antibody (mAb) within 4  weeks prior to study Day 1 or who has not  recovered (i.e., ≤ Grade 1 or at baseline) from  adverse events due to agents administered more  than 4 weeks earlier.                                                                                                                                        | □                                       | □                        |                                         |
| Chemotherapy, targeted small molecule therapy,  or radiation therapy within 2 weeks prior to study  Day 1 or who has not recovered (i.e., ≤ Grade 1  or at baseline) from adverse events due to a  previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an  exception to this criterion and may qualify for the  study.                                                 | □                                       | □                        |                                         |
| Note: If subject received major surgery, they  must have recovered adequately from the toxicity  and/or complications from the intervention prior to  starting therapy. Prior therapy with an anti-PD-1, anti-PD-L1, or                                                                                                                                                                        | □                                       | □                        |                                         |
| anti-PD-L2 agent. Prior therapy with paclitaxel or  docitaxel. Hypersensitivity to pembrolizumab, any of its  excipients, paclitaxel, or any of its excipients.                                                                                                                                                                                                                                | □                                       | □                        |                                         |
| Diagnosis of immunodeficiency or is receiving  systemic steroid therapy or any other form of                                                                                                                                                                                                                                                                                                   | □                                       | □                        |                                         |
| immunosuppressive therapy within 7 days prior to  the first dose of trial treatment. Known history of active TB (Bacillus  Tuberculosis).                                                                                                                                                                                                                                                      | □                                       | □                        |                                         |  
Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory urothelial carcinoma Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 88215  
| CCCWFU # 88215                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |          |             |                                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|-------------|-----------------------------------------|
| Inclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Criteria | Criteria is | Source Used to Confirm *                |
| (as outlined in study protocol)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | is met   | NOT met     | (Please document dates and lab results) |
| Known additional malignancy that is progressing  or requires active treatment. Exceptions include  basal cell carcinoma of the skin or squamous cell  carcinoma of the skin that has undergone  potentially curative therapy or in situ cervical  cancer.                                                                                                                                                                                                                                                                                                                                                        | □        | □           |                                         |
| Known active central nervous system (CNS)  metastases and/or carcinomatous meningitis.  Subjects with previously treated brain metastases  may participate provided they are stable (without  evidence of progression by imaging for at least  four weeks prior to the first dose of trial treatment  and any neurologic symptoms have returned to  baseline), have no evidence of new or enlarging  brain metastases, and are not using steroids for at  least 7 days prior to trial treatment. This  exception does not include carcinomatous  meningitis which is excluded regardless of clinical  stability. | □        | □           |                                         |
| Active autoimmune disease that has required  systemic treatment in the past 2 years (i.e. with  use of disease modifying agents, corticosteroids  or immunosuppressive drugs). Replacement  therapy (eg., thyroxine, insulin, or physiologic  corticosteroid replacement therapy for adrenal or  pituitary insufficiency, etc.) is not considered a  form of systemic treatment.                                                                                                                                                                                                                                 | □        | □           |                                         |
| Known history of, or any evidence of active, noninfectious pneumonitis.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | □        | □           |                                         |
| Active infection requiring systemic therapy.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | □        | □           |                                         |
| History or current evidence of any condition,  therapy, or laboratory abnormality that might  confound the results of the trial, interfere with the  subject's participation for the full duration of the  trial, or is not in the best interest of the subject to  participate, in the opinion of the treating  investigator.                                                                                                                                                                                                                                                                                   | □        | □           |                                         |
| Known psychiatric or substance abuse disorders  that would interfere with cooperation with the                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | □        | □           |                                         |
| requirements of the trial. Pregnancy or breastfeeding, or expecting to  conceive or father children within the projected  duration of the trial, starting with the pre-screening  or screening visit through 120 days after the last  dose of trial treatment.                                                                                                                                                                                                                                                                                                                                                   | □        | □           |                                         |
| Known history of Human Immunodeficiency Virus  (HIV) (HIV 1/2 antibodies).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | □        | □           |                                         |
| Known active Hepatitis B (e.g., HBsAg reactive)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | □        | □           |                                         |
| or Hepatitis C (e.g., HCV RNA [qualitative] is  detected).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |          |             |                                         |  
Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory urothelial carcinoma Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 88215  
| Inclusion Criteria                                                                                                                                                                                                                                                                                | Criteria   | Criteria is   | Source Used to Confirm *                |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|---------------|-----------------------------------------|
| (as outlined in study protocol)                                                                                                                                                                                                                                                                   | is met     | NOT met       | (Please document dates and lab results) |
| Received a live vaccine within 30 days of planned  start of study therapy. Note: Seasonal influenza vaccines for injection  are generally inactivated flu vaccines and are  allowed; however intranasal influenza vaccines  (e.g., Flu-Mist®) are live attenuated vaccines, and  are not allowed. | □          | □             |                                         |  
This subject is eligible / ineligible for participation in this study.  
ORIS Assigned PID: __________________  
| Signature of research professional confirming eligibility:_______________________ Date: _______________ Signature of Treating Physician**: _____________________________________ Date: _______________   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, specifically state which document in the medical record was used to assess eligibility. Also include the date on the document. Example: "Pathology report, 01/01/14" or "Clinic note, 01/01/14" **Principal Investigator signature can be obtained following registration if needed Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory urothelial carcinoma Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 88215
appendix b - subject eligibility
appendix c - race &

Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our information. As a brief reminder, the information you provide today will be kept confidential.  
1. Are you:
Hispanic or Latino/a Not Hispanic or Latino/a 2. What is your race? One or more categories may be selected.  
White or Caucasian Black or African American American Indian or Alaskan Native Asian Native Hawaiian or Other Pacific Islander Other, Please Specify: ___________________________
appendix b - subject eligibility
internal use only

Name: *____________________* MRN\#: *____________________*
Was the self-reported race and ethnicity of the participant verified at the time of consent?  
Yes No Was a discrepancy found? **Yes No**
*If yes, please provide what is currently indicated in the EMR:*
Ethnicity: *____________________* Race: *____________________*
Additional comments: __________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________  
CCCWFU \# 88215
appendix b - subject eligibility
appendix d - mandatory strc

Date: 07/10/2019 Safety and Toxicity Review Committee (STRC) Serious Adverse Event (SAE) Notification SOP
Mandatory STRC SAE Reporting Requirements in **WISER**
This document describes reporting requirements of adverse events from WFBCCC Investigator Initiated interventional trials to the Safety and Toxicity Review Committee (STRC). A trial is considered a **WFBCCC Investigator Initiated interventional trial** if the following criteria are met:
1. The Principal Investigator (PI) of the trial is a member of a department at the Wake Forest University Baptist Medical Center.  
2. WFBCCC is considered as the primary contributor to the design, implementation and/or monitoring of the trial. 3. The trial is designated as "Interventional" using the Clinical Research Categories definitions provided by the NCI in the Data Table 4 documentation. (https://cancercenters.cancer.gov/GrantsFunding/DataGuide\#dt4)
There are two distinct types of WFBCCC Investigator Initiated interventional trials based on where patient enrollment occurs. These include:
1. Local WFBCCC Investigator Initiated interventional trials defined as trials where all **patients are enrolled from one of the WFBCCC sites.** These include the main outpatient Cancer Center clinics (located in Winston-Salem) as well as WFBCCC affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons, Lexington, High Point, or Wilkesboro.  
2. Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials where patients are enrolled from other sites in addition to WFBCCC sites.  
There are three types of trials that are included in this category:
a. Trials sponsored by the NCI Community Oncology Research Program (NCORP)
that are conducted at multiple sites where the PI is a member of a department at the Wake Forest University Baptist Medical Center. b. Trials sponsored by Industry that are conducted at multiple sites and the PI is a member of a department at the Wake Forest University Baptist Medical Center. c. Trials sponsored by WFBCCC that are conducted at multiple sites and the PI is a member of a department at the Wake Forest University Baptist Medical Center.  
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients enrolled on WFBCCC Investigator Initiated Interventional trials must be entered into the WISER system. The only exception to this requirement is for patients enrolled on NCORP trials at non- WFBCCC sites.  
CCCWFU \# 88215 AEs and SAEs for NCORP patients enrolled at WFBCCC sites must be entered into the WISER system. Once these AEs and SAEs are entered in WISER, certain actions must be taken regarding the reporting of specific Adverse Events to the STRC.  
All Adverse Events that occur during protocol intervention (defined below) and are coded as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours **(regardless of**
grade), or **grade 5 (death)** must be reported to the STRC using the using the SAE console in WISER.  
A research nurse or clinical research coordinator when made aware that an adverse event meets one of the above criteria has occurred on a WFBCCC Investigator Initiated interventional trial, is responsible for informing a clinical member of the STRC by phone (or in-person) about the adverse event. The nurse/coordinator should contact the treating physician prior to calling the STRC clinical member to obtain all details of the SAE, as well as all associated toxicities to be recorded along with the SAE. In addition, this nurse or coordinator is responsible for entering the adverse event information into the SAE console in WISER. Once the adverse event has been entered into the SAE
console an email informing the entire STRC committee will be generated.
appendix b - subject eligibility
these reporting requirements apply to

Institutional Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE identification, documentation, grading and assignment of attribution to the investigational agent/intervention. However, when an AE event as described above is observed, it is the responsibility of the person who observed the event to be sure that it is reported to the STRC.
appendix b - subject eligibility
what is considered during protocol

During protocol intervention is considered to be the time period while a patient is on study treatment or during the time period within 30 days of last study treatment (even if patient begins a new (nonstudy) treatment during the 30 days). This window of 30 days should be the standard window to be used in all protocols unless a specific scientific rationale is presented to suggest that a shorter window can be used to identify events. If it is a trial sponsored by Industry and the sponsor requires a longer window for monitoring of SAEs, then the longer window of time specified by the sponsor should be followed.
appendix b - subject eligibility
what is considered as an

Any grade 4 event that was not specifically listed as an expected adverse event in the protocol should be considered as unexpected. A grade 4 adverse event can be considered to be unexpected if it is an event that would not be expected based on the treatment being received or if it is unexpected based on the health of the patient. In either case, if there is any uncertainty about whether a grade 4 adverse event is expected or unexpected it should be reported to STRC.  
CCCWFU \# 88215
appendix b - subject eligibility
strc notification responsibilities of the

1. Make a phone call (or speak in person) to the appropriate clinical member of the STRC as listed below (page if necessary) 2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in WISER
WITHIN 24 HOURS of first knowledge of the event. Information can be entered and saved, but the STRC members will not be notified until a date is entered into the STRC Notification Date Field. This will ensure that all persons that need to be made aware of the event (i.e., study team members and STRC members) will be notified; remember to file a copy of the confirmation. 3. Document that the appropriate person(s) on the STRC has been contacted. Indicate the name of the STRC clinician that was contacted in the Event Narrative field in the SAE console of the particular subject.  
4. Document whether or not the protocol should be suspended based on the discussion with the STRC clinician. This is the major function of the email notification. Enter whether the protocol should be suspended in the Event Narrative Field.  
5. Follow up/update the clinical member(s) of STRC regarding any new developments or information obtained during the course of the SAE investigation and reporting process.
appendix b - subject eligibility
elements needed to complete the

2. Reported Date 3. Reported by 4. If Grade 5, enter Death Date 5. If Grade 5, enter Death occurred: within 30 days 6. Event Narrative: Brief description (include brief clinical history relevant to this event, including therapies believed related to event). Begin narrative with the STRC clinician who was notified and Date/Time notified. In addition, state attribution by STRC clinician as either "Unrelated", "Unlikely",
"Possibly", "Probably", or "Definitely". Always include the following here:
i.STRC clinician name and comments ii.Date of last dose before the event iii.Is suspension of the protocol needed? Y/N
7. Treating Physician comments 8. PI comments, if available 9. Protocol Attribution after discussion with STRC clinician 10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not Resolved, Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, Recovering and Resolving)
11. Consent form Change Required? Y/N 12. SAE Classification *This is required in order for the email notification to be sent* 13. Adverse Event Details - Enter all details for each AE associated with the SAE.  
CCCWFU \# 88215 a. Course start date b. Category c. AE Detail d. Comments e. Grade/Severity f. Unexpected Y/N
g. DLT Y/N
h. Attributions i. Action j. Therapy k. Click ADD to attach the AE Detail to the SAE.  
14. Enter Date Notified STRC -- *This is required for the email notification to be sent* 15. Click Submit. The auto-generated notification email will disseminate within 5 minutes. If you do not receive an email within 5 minutes, check that you have entered the "Date Notified STRC" and the "SAE Classification". If these have been entered and the email still has not been received, take a screen shot of the SAE in WISER and immediately email it out to all of the STRC
members listed in this SOP. In the subject line, indicate that this is a manual transmission of the SAE in lieu of the auto-generated email. It is required that a notification goes to the STRC members immediately so that their assessment can be obtained within the 24 hour time frame requirement. Contact the Cancer Center Programmer/Analyst to alert that there is an issue with the auto-generated email.
appendix b - subject eligibility
the clinical members of strc

Bayard Powell, MD - Director-at-Large, WFBCCC; Section Head, Hematology/Oncology 6-
Glenn Lesser, MD - Hematology Oncology 6- Stefan Grant, MD, JD-Hematology Oncology 3-
Jimmy Ruiz, MD-Hematology Oncology 6-
Mercedes **Porosnicu, MD**- Hematology Oncology 6-
**Michael Farris, MD** - Radiation Oncology 3-
appendix b - subject eligibility
definition of unavailable

As a general guideline if the first clinician that is contacted does not respond to the phone call or page within 30 minutes, then initiate contact with a different STRC clinician. Allow up to 30 minutes for the new STRC clinician to respond to a phone call or page before contacting another member. These times (30 minutes) are a general guideline. Best judgment as a clinical research professional should be used giving considerations of the time of day, severity of the SAE, and other circumstances as to when it is appropriate to contact backup clinicians. If the event occurs near the end of day, then leave messages (voice or email) as appropriate and proceed with submitting the STRC notification form. It is important to take reasonable steps and to document that some type of contact has been initiated to one or more of the clinical members of STRC.  
CCCWFU \# 88215
appendix b - subject eligibility
strc clinican responsibility

It is the responsibility of the STRC clinician to review all reported events, evaluate the events as they are reported; and communicate a response to the Investigator, event reporter and the members of STRC. The review will include but not be limited to the information reported; there may be times when additional information is needed in order for an assessment to be made and further communication directly with the investigator may be warranted. STRC reserves the right to disagree with the Investigator's assessment. If STRC does not agree with the Investigator, STRC reserves the right to suspend the trial pending further investigation. If there is any immediate danger or harm that could be present for a future patient based on the information provided in the STRC report then an immediate suspension of enrollment should be considered.
appendix b - subject eligibility
amendments to previous reports

If all pertinent information is unavailable with the initial submission, once the additional information is available **do not submit a new report**. Rather, go to the original email that was sent to the STRC
and using that email "reply to all". Entitle this new email "**Amendment** for (list date of event and patient ID)" this will avoid duplications of the same event. List the additional information being reported. This information needs to be entered into WISER as well. To do this, go to the Subject console and click SAEs on the left column. Click on the appropriate SAE number that needs updating. Then click update. This will allow additional informatio n to be added
appendix b - subject eligibility
acronyms

AE - Adverse Event STRC-Safety and Toxicity Review Committee SAE-Serious Adverse Event WFBCCC - Wake Forest Baptist Comprehensive Cancer Center NCI-National Cancer Institute WISER –Wake Integrated Solution for Enterprise Research Screen **Shots:** The following screen shots come from the SAE Console within the Subject Console in WISER. Screen Shot 1:  
  
CCCWFU \# 88215  
  
Screen Shot 3:
Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinumrefractory urothelial carcinoma Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 88215  
  
  
| Appendix E - TUMOR RESPONSE WORKSHEET (RECIST v1.1) Target Lesions Nodal/Nonnodal (measure shortest  diameter for  nodal) Baseline Date: Cycle_____ Cycle_____ Cycle_____                                                                                                                                                                             | Cycle_____                 | Cycle_____   |            |          |            |            |            |            |            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|--------------|------------|----------|------------|------------|------------|------------|------------|
| Date:                                                                                                                                                                       | Date:                      | Date:        | Date:      | Date:    |            |            |            |            |            |
| Imaging (ie,CT, MRI)                                                                                                                                                        |                            |              |            |          |            |            |            |            |            |
| Lesion                                                                                                                                                                      | Site                       |              |            |          |            |            |            |            |            |
| 01                                                                                                                                                                          | mm                         | mm           | mm         | mm       | mm         | mm         |            |            |            |
| TARGET Lesions                                                                                                                                                              | 02                         | mm           | mm         | mm       | mm         | mm         | mm         |            |            |
| 03                                                                                                                                                                          | mm                         | mm           | mm         | mm       | mm         | mm         |            |            |            |
| 04                                                                                                                                                                          | mm                         | mm           | mm         | mm       | mm         | mm         |            |            |            |
| 05                                                                                                                                                                          | mm                         | mm           | mm         | mm       | mm         | mm         |            |            |            |
| Sum of Diameters                                                                                                                                                            | mm                         | mm           | mm         | mm       | mm         | mm         |            |            |            |
| % Change (% ∆) from Baseline or Nadir* & absolute value (AbV)                                                                                                               | NA                         | NA           | % ∆    AbV |          |            |            |            |            |            |
| Target Lesion Response                                                                                                                                                      |                            | N/A          |            |          |            |            |            |            |            |
| Non-Target Lesions                                                                                                                                                          |                            |              |            |          |            |            |            |            |            |
| Lesion                                                                                                                                                                      | Site                       | Nodal/Nonnodal              | Imaging    | Baseline | Cycle_____ | Cycle_____ | Cycle_____ | Cycle_____ | Cycle_____ |
| 01 02 03 04 05 06 07 08 09 10                                                                                                                                               | Non-Target Lesion Response | N/A          |            |          |            |            |            |            |            |
| NON-TARGET Lesions                                                                                                                                                          | New Lesions                |              |            |          |            |            |            |            |            |
| 1                                                                                                                                                                           | N/A                        |              |            |          |            |            |            |            |            |
| New                                                                                                                                                                         | 2                          | N/A          |            |          |            |            |            |            |            |
| 3                                                                                                                                                                           | N/A                        |              |            |          |            |            |            |            |            |
| Overall Tumor Response                                                                                                                                                      | Cycle___                   | Cycle___     | Cycle___   | Cycle___ | Cycle___   |            |            |            |            |
|                                                                                                                                                                             |                            |              |            |          |            |            |            |            |            |
| Radiologist Signature: Treating Physician Signature: PI Signature: *Terms & Calculations Baseline: The set of data collected prior to randomization Nadir: The lowest point |                            |              |            |          |            |            |            |            |            |  
| WEEK / CYCLE #   | INVESTIGATOR PRINTED NAME   | INVESTIGATOR SIGNATURE   | DATE   |
|------------------|-----------------------------|--------------------------|--------|  
| TARGET AND NON-TARGET LESIONS   |                   |            |                  |
|---------------------------------|-------------------|------------|------------------|
| TARGET LESION                   | NON-TARGET LESION | NEW LESION | OVERALL RESPONSE |
| CR                              | CR                | NO         | CR               |
| CR                              | NON-CR/NON-PD     | NO         | PR               |
| CR                              | NOT EVALUATED     | NO         | PR               |
| PR                              | NON-PD OR NOT ALL | NO         | PR               |
| EVALUATED                       |                   |            |                  |
| SD                              | NON-PD OR NOT ALL | NO         | SD               |
| EVALUATED                       |                   |            |                  |
| NOT ALL                         | NON-PD            | NO         | NE               |
| EVALUATED PD                    | ANY               | YES OR NO  | PD               |
| ANY                             | PD                | YES OR NO  | PD               |  
| ANY   | ANY   | YES   | PD   |
|-------|-------|-------|------|  
| Non-Target Disease Only   |             |                  |
|---------------------------|-------------|------------------|
| Non-Target Lesions        | New Lesions | Overall Response |
| CR                        | No          | CR               |
| Non-CR/Non-PD             | No          | Non-Cr/Non-PD    |
| Not All Evaluated         | No          | NE               |
| Unequivocal PD            | Yes or No   | PD               |
| Any                       | Any         | PD               |  
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evluated
appendix b - subject eligibility
target lesion timepoint assessment

| Target Lesion Response   | Definition Disappearance of all target lesions. Pathological lymph nodes  (whether target or non-target) must have reduction in short axis                                                                                                                                                          |
|--------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Complete Response (CR)   | to < 10 mm                                                                                                                                                                                                                                                                                          |
| Partial Response (PR)    | At least a 30% decrease in sum of diameters, taking as reference  the baseline sum diameters At least a 20% increase in the sum of diameters of target lesions,  taking as reference the smallest sum on study based on all target  lesions recorded since the treatment started. The sum must also |
| Progressive Disease (PD) | demonstrate an absolute increase of at least 5 mm. (Note: the  appearance of one or more new lesions is also considered  progression) Neither sufficient shrinkage to qualify for PR nor sufficient                                                                                                 |
| Stable Disease (SD)      | increase to qualify for PD, taking as reference smallest sum  diameters while on study Any target lesion present at baseline which was not assessed or  was unable to be evaluated leading to an inability to determine                                                                             |
| Not Evaluated (NE)       | the status of that particular tumor for that time point                                                                                                                                                                                                                                             |
| Not Applicable (NA)      | No target lesions were identified at baseline                                                                                                                                                                                                                                                       |
appendix b - subject eligibility
non-target lesions timepoint assessment

Complete Response (CR)  
Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (< 10 mm short axis)  
| Non-Target Lesion Response   | Definition   |
|------------------------------|--------------|
| Complete Response (CR)       |              |  
Non-Complete Response/Non- Persistence of one or more non-target lesions not qualifying for  
| Progressive Disease                                                                                                        | either CR or PD  Unequivocal progression of existing non-target lesions.  - subjects with measurable non-target disease - Substantial worsening such that the overall tumor  burden has increased sufficiently to merit   |
|----------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Progressive Disease (PD)                                                                                                   | discontinuation of therapy.                                                                                                                                                                                               |
| -                                                                                                                          | subjects with non-measurable disease - Increase in  overall tumor burden comparable in magnitude to the  increase required to declare PD for measurable disease.                                                          |
| Any non-target lesion present at baseline which was not  assessed or was unable to be evaluated leading to an inability to |                                                                                                                                                                                                                           |
| Not Evaluable (NE)                                                                                                         | determine status                                                                                                                                                                                                          |
| Not Applicable (NA)                                                                                                        | No non-target lesions identified at baseline                                                                                                                                                                              |
appendix f - baseline data
non-target lesions timepoint assessment

Date of visit _ _/_ _/_ _ 1. Oncologic history a. Most immediate prior cancer therapy (select one):
chemotherapy radiation surgery hormone other: ___________________________
b. Specify most immediate prior cancer therapy: ______________________________________________
Dates of administration: Started: __ __ / __ __ / __ __ Stopped: __ __ / __ __ / __ __
Dose ___________ & total \# of treatments ________
c. Other prior cancer therapies (excluding 1b.) for most recent cancer. Mark all that apply:
None Chemotherapy Radiation Surgery Hormone therapy Other: _____________  
| Regimen Name                   | Total # of Treatments   | Date of Last Treatment   |                        |
|--------------------------------|-------------------------|--------------------------|------------------------|
| 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. | Site of RT              | Total Dose in Gy         | Date of Last Treatment |
| 1. 2. 3. 4. 5.                 | Type of surgery         | Date of surgery          |                        |
| 1. 2. Hormone Therapy Name     | Dose                    | Date of Last Treatment   |                        |
| 1. 2.                          | Other                   | Dose                     | Date of Last Treatment |
| 1. 2.                          |                         |                          |                        |  
2. Date of baseline imaging: __ __ / __ __ / __ __
Sites of disease: ___________________________________________________________ Imaging modality: CT scan PET scan MRI scan Bone scan Other, specify _________
3. Medical history (check all that apply):
Myocardial infarction Congestive heart failure Peripheral vascular disease
(claudication, arterial bypass, untreated aneurysm (≥6cm)
Cerebrovascular disease (history of TIA
or CVA)
Dementia Chronic pulmonary disease (with symptomatic dyspnea)
Connective tissue disease (SLE,
polymyositis, mixed CTD, polymyalgia rueumatic, moterate to severe RA)
Peptic ulcer disease (bleeding ulcer) Liver disease (on treatment, cirrhosis without portal hypertension, chronic hepatitis); check here if mild Diabetes end organ damage? Yes No Hemiplegia Leukemia Lymphoma AIDS Other major medical condition; specify
___________________________________  
$$\stackrel{\mathrm{\mathrm{\acute{H}}}\mathsf{R}}{\mathsf{B P}}$$
6. Vital signs:
a. HR_________
b. BP____ /____
c. RR_________ d. Temp _______(°F)  
| a. List all prescription and over-the-counter medications (includes prescription supplements)  Medication Name Is it PRN? Medication Name   | Is it PRN?   |    |     |     |    |
|---------------------------------------------------------------------------------------------------------------------------------------------|--------------|----|-----|-----|----|
| 1.                                                                                                                                          | yes          | no | 11. | yes | no |
| 2.                                                                                                                                          | yes          | no | 12. | yes | no |
| 3.                                                                                                                                          | yes          | no | 13. | yes | no |
| 4.                                                                                                                                          | yes          | no | 14. | yes | no |
| 5.                                                                                                                                          | yes          | no | 15. | yes | no |
| 6.                                                                                                                                          | yes          | no | 16. | yes | no |
| 7.                                                                                                                                          | yes          | no | 17. | yes | no |
| 8.                                                                                                                                          | yes          | no | 18. | yes | no |
| 9.                                                                                                                                          | yes          | no | 19. | yes | no |
| 10.                                                                                                                                         | yes          | no | 20. | yes | no |  
| b. List all supplements (excludes prescription supplements) Supplement Name Is it PRN?   | Supplement Name   | Is it PRN?   |     |     |    |
|------------------------------------------------------------------------------------------|-------------------|--------------|-----|-----|----|
| 1.                                                                                       | yes               | no           | 11. | yes | no |
| 2.                                                                                       | yes               | no           | 12. | yes | no |
| 3.                                                                                       | yes               | no           | 13. | yes | no |
| 4.                                                                                       | yes               | no           | 14. | yes | no |
| 5.                                                                                       | yes               | no           | 15. | yes | no |
| 6.                                                                                       | yes               | no           | 16. | yes | no |
| 7.                                                                                       | yes               | no           | 17. | yes | no |
| 8.                                                                                       | yes               | no           | 18. | yes | no |
| 9.                                                                                       | yes               | no           | 19. | yes | no |
| 10.                                                                                      | yes               | no           | 20. | yes | no |  
| 5.      | Physical exam: Derm -                          | WNL                                              | Abnormal, specify ______________________________   |
|---------|------------------------------------------------|--------------------------------------------------|----------------------------------------------------|
| HEENT - | WNL                                            | Abnormal, specify ______________________________ |                                                    |
| CV -    | WNL                                            | Abnormal, specify ______________________________ |                                                    |
| Pulm -  | WNL                                            | Abnormal, specify ______________________________ |                                                    |
| GI -    | WNL                                            | Abnormal, specify ______________________________ |                                                    |
| Other - | Abnormal, specify ____________________________ |                                                  |                                                    |  
e. Weight ______(kg) f. Height ______(cm) 7. ECOG Performance Status (check one):  
| 0   | Fully active, able to carry on all pre-disease performance without restriction                                                                             |
|-----|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1   | Restricted in physically strenuous activity but ambulatory and able to carry out work of a  light or sedentary nature, e.g., light house work, office work |
| 2   | Ambulatory and capable of all self care, but unable to carry out any work activities. Up and  about more than 50% of waking hours                          |
| 3   | Capable of only limited self care, confined to bed or chair more than 50% of waking hours                                                                  |
| 4   | Completely disabled. Cannot carry on any self care. Totally confined to bed or chair                                                                       |  
8. Documentation of negative pregnancy test for women of child-bearing potential?  
Yes No , reason ____________________ Not applicable 9. Blood Draws:
a. CBC with Differential, Date drawn __ __ /__ __ / __ __ b. Serum Chemistry, Date drawn __ __ /__ __ / __ __ c. Urinalysis Date __ __ /__ __ / __ __
10. Metastatic tumor biopsy:
a. Date __ __ /__ __ / __ __
b. Site of biopsy:______________________________
11. Archival tumor tissue:
a. Date __ __ /__ __ / __ __ b. Site from which tissue obtained:______________________________
appendix g - follow-up data
non-target lesions timepoint assessment

Follow-Up Visit: Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 End of Treatment Follow-up Date of Visit: __ __ / __ __ / __ __
1. Medical History Medical Conditions, new from baseline (specify)___________________________
Hospitalizations since last visit (specify)_________________________________  
2. Concurrent medications and supplements  
a. List all prescription and over-the-counter medications (includes prescription supplements).  
Medication Name Is it PRN? Medication Name Is it PRN?  
1. yes no 11. yes no 2. yes no 12. yes no 3. yes no 13. yes no 4. yes no 14. yes no 5. yes no 15. yes no  
6. yes no 16. yes no 7. yes no 17. yes no  
8. yes no 18. yes no  
9. yes no 19. yes no  
10. yes no 20. yes no  
4. Vital signs:
g. HR_________
h. BP____ /____ i. RR _________
j. Temp _______(°F)
k. Weight ______(kg)  
$$\mathbb{M}$$  
l. Height ______(cm)  
| b. List all supplements (excludes prescription supplements). Supplement Name Is it PRN?   | Supplement Name   | Is it PRN?   |     |     |    |
|-------------------------------------------------------------------------------------------|-------------------|--------------|-----|-----|----|
| 1.                                                                                        | yes               | no           | 11. | yes | no |
| 2.                                                                                        | yes               | no           | 12. | yes | no |
| 3.                                                                                        | yes               | no           | 13. | yes | no |
| 4.                                                                                        | yes               | no           | 14. | yes | no |
| 5.                                                                                        | yes               | no           | 15. | yes | no |
| 6.                                                                                        | yes               | no           | 16. | yes | no |
| 7.                                                                                        | yes               | no           | 17. | yes | no |
| 8.                                                                                        | yes               | no           | 18. | yes | no |
| 9.                                                                                        | yes               | no           | 19. | yes | no |
| 10.                                                                                       | yes               | no           | 20. | yes | no |  
  
| Derm -   | WNL                                            | Abnormal, specify ______________________________   |
|----------|------------------------------------------------|----------------------------------------------------|
| HEENT -  | WNL                                            | Abnormal, specify ______________________________   |
| CV -     | WNL                                            | Abnormal, specify ______________________________   |
| Pulm -   | WNL                                            | Abnormal, specify ______________________________   |
| GI -     | WNL                                            | Abnormal, specify ______________________________   |
| Other -  | Abnormal, specify ____________________________ |                                                    |  
| 5. ECOG Performance Status (check one): GRADE Description  0 Fully active, able to carry on all pre-disease performance without restriction  1 Restricted in physically strenuous activity but ambulatory and able to carry out  work of a light or sedentary nature, e.g., light house work, office work  2 Ambulatory and capable of all self care, but unable to carry out any work  activities. Up and about more than 50% of waking hours  3 Capable of only limited self care, confined to bed or chair more than 50% of  waking hours  4 Completely disabled. Cannot carry on any self care. Totally confined to bed or  chair  5 Dead   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
6. Documentation of negative pregnancy test for women of child-bearing potential?  
Yes No , reason ____________________ Not applicable 7. Blood Draws a. CBC with Differential, Date drawn __ __ /__ __ / __ __ b. Serum Chemistry, Date drawn __ __ /__ __ / __ __ c. Urinalysis Date __ __ /__ __ / __ __
appendix g - follow-up data
appendix h - treatment response

Overall Response Rate is the primary objective for this study. Patients will be evaluated with imaging at baseline, every 9 weeks (+/-7days), and end of treatment. At the end of treatment, if no progression, patients will be evaluated with imaging every 3 months (+/-10 days) for 1 year.  
Study Visit:
Week 9 ( ± 7 days)
Week 18 ( ± 7 days)
Week 27 ( ± 7 days)
Week 36 ( ± 14 days)
End of Treatment 3 months ( ± 10 days) post Treatment 6 months ( ± 10 days) post Treatment 9 months ( ± 10 days) post Treatment 12 months ( ± 10 days) post Treatment Other visit: (please specify) ________________
Date of Scan: ___ ___ /___ ___ /___ ___
Imaging Modality: CT PET/CT MRI Other____________
Evaluation of imaging per clinical review– **measurable disease**
Complete Response (CR)  
Partial Response (PR) Progressive Disease (PD): Date of progression ___ ___ /___ ___ /___ ___ Stable Disease (SD)
N/A
Evaluation of non-measurable disease (e.g., pleural effusion)  
Complete Response (CR)
Non-CR/Non-PD Progressive Disease (PD): Date of progression ___ ___ /___ ___ /___ ___ N/A  
  
Treating Physician Signature: ______________________ Date: ___ ___ /___ ___ /___ ___
PI Signature: ___________________________________ Date: ___ ___ /___ ___ /___ ___
appendix i - adverse event
appendix h - treatment response

WFBCCC Adverse Event (AE) Log PI: _________________ Subject PID: _________________ MRN: ________________
Cycle \#: Cycle Start Date: Cycle Start Time: **Cycle End Date: Cycle End Time:**  
| *Serious Adverse  Event Detail:  NO= No LT= Life Threatening DTH= Death DIS= Disability HOS= Hospitalization CA= Caused  congenital anomaly RI= Required  intervention to prevent  impairment   | Action Taken  NO= None DR= Dose  Reduced RI= Regimen  Interrupted TD= Therapy  discontinued INTR= Interrupted  then reduced Therapy  Given NO= None SYM=  Symptomatic SUP=  Supportive VSUP=  Vigorous  Supportive   | Adverse  Event  Report  (AER)  filed? N= No Y= Yes Outcome R= Recovered TX= Still under  treatment or  observation A= Alive with  Sequalae D= Died   |          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| Attribution DEF= Definite PROB= Probable POSS= Possible UNLK= Unlikely UNRL= Unrelated                                                                                                          | Dose  Limiting  Toxicity  (DLT)  N= No Y= Yes                                                                                                                                                                        | Reportable?  IRB= IRB STRC= STRC FDA= FDA SPON= Sponsor (Mark all that  apply)                                                                       |          |
| Adverse Event CTC  Term Lab                                                                                                                                                                     | Grade                                                                                                                                                                                                                | Start                                                                                                                                                |          |
| Value                                                                                                                                                                                           | (1-5) per  Date CTC                                                                                                                                                                                                  | Treating MD                                                                                                                                          | Expected |
| Initials +                                                                                                                                                                                      | End Date N= No                                                                                                                                                                                                       |                                                                                                                                                      |          |
| Date                                                                                                                                                                                            | Y= Yes                                                                                                                                                                                                               |                                                                                                                                                      |          |  
*Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. CTCAE Version 4 - http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf STRC = Safety and Toxicity Review Committee Version 10/30/17