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| Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinumrefractory urothelial carcinoma Comprehensive Cancer Center of Wake Forest University (CCCWFU) CCCWFU # 88215 Principal Investigator: Michael M. Goodman, MD Hem/Onc Staff Physician W.G. (Bill) Hefner VA, Salisbury, NC Wake Forest School of Medicine Medical Center Boulevard Winston-Salem, NC 27157 Co-Investigator(s): Christopher Y. Thomas, MD Section on Hematology and Oncology Wake Forest School of Medicine Pierre Triozzi, MD Section on Hematology and Oncology Wake Forest School of Medicine Rhonda L. Bitting, MD Section on Hematology and Oncology Wake Forest University Health Sciences Biostatistician: Janet Tooze, PhD Comprehensive Cancer Center of Wake Forest University Study Coordinator(s): Jennifer Ward Thomas, MHA, RN, BSN Comprehensive Cancer Center of Wake Forest University Data Manager: Deanna Hissim Comprehensive Cancer Center of Wake Forest University Regulatory Contact: Alexandra Bolick, MBA Comprehensive Cancer Center of Wake Forest University Participating Institution: Comprehensive Cancer Center of Wake Forest University Version Date: 03/10/2020 ClinicalTrials.gov: NCT02581982 12/13/2019 11/18/2019 05/17/2018 Amended: 01/19/2018 04/07/2017 01/17/2017 07/12/2016 06/23/2016 04/06/2016 01/26/2016 Original Version: 10/29/2015 Confidential   |
|---|  
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  
| Table of Contents                                                                                                                                    |                                                                                                                                                            |
|------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA .                                                                                                                                             |                                                                                                                                                            |
| 1.0                                                                                                                                                  | Introduction and Background                                                                                                                                |
| 1.1                                                                                                                                                  | Rationale for current study ................................................................................................................... 6          |
| 1.2                                                                                                                                                  | Rationale for Dose Selection/Regimen/Modification ............................................................ 7                                           |
| 2.0                                                                                                                                                  | Hypothesis and Objectives .................................................................................................................... 9           |
| Primary Objective ................................................................................................................................ 9 |                                                                                                                                                            |
| 2.1                                                                                                                                                  |                                                                                                                                                            |
| 2.2                                                                                                                                                  | Secondary Objectives                                                                                                                                       |
| 2.3                                                                                                                                                  | Correlative Objectives                                                                                                                                     |
| 3.0                                                                                                                                                  | Patient Selection ...................................................................................................................................... 9 |
| 3.1                                                                                                                                                  | Inclusion Criteria ............................................................................................................................... 9       |
| 3.2                                                                                                                                                  | Exclusion Criteria                                                                                                                                         |
| 3.3                                                                                                                                                  | Inclusion of Women and Minorities ..........................................................................................12                             |
| 4.0                                                                                                                                                  | Registration Procedures .................................................................................................................13                |
| 5.0                                                                                                                                                  | Study Outcomes and Study Measures                                                                                                                          |
| Primary Outcome                                                                                                                                      |                                                                                                                                                            |
| 5.1                                                                                                                                                  |                                                                                                                                                            |
| 5.2                                                                                                                                                  | Secondary Outcomes ......................................................................................................................13                |
| 5.3                                                                                                                                                  | Correlative Outcomes .......................................................................................................................13             |
| 6.0                                                                                                                                                  | T Treatment Plan                                                                                                                                           |
| Study schema                                                                                                                                         |                                                                                                                                                            |
| 6.1                                                                                                                                                  |                                                                                                                                                            |
| 6.2                                                                                                                                                  | Study-Related Activities                                                                                                                                   |
| 6.2.1                                                                                                                                                | Informed Consent .......................................................................................................................17                 |
| 6.2.2                                                                                                                                                | Inclusion/Exclusion Criteria ...................................................................................................17                         |
| 6.2.3                                                                                                                                                | Medical History ...........................................................................................................................17              |
| Prior and Concomitant Medications Review ....................................................................18                                      |                                                                                                                                                            |
| 6.2.4                                                                                                                                                |                                                                                                                                                            |
| 6.2.5                                                                                                                                                | Disease Details and Treatments ........................................................................................18                                  |
| 6.2.6                                                                                                                                                | Adverse Event (AE) Monitoring                                                                                                                              |
| 6.2.7                                                                                                                                                | Physical Exam .....................................................................................................................19                      |
| 6.2.8                                                                                                                                                | Laboratory Procedures/Assessments ...............................................................................19                                        |
| Treatment Administration                                                                                                                             |                                                                                                                                                            |
| 6.3                                                                                                                                                  |                                                                                                                                                            |
| 6.4                                                                                                                                                  | General Concomitant Medication and Supportive Care Guidelines ..................................21                                                         |  
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                                                                                                                            |                                                                                                                                          |
|------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|
| 6.4.1                                                                                                                                    | Acceptable Concomitant Medications ..............................................................................21                      |
| Prohibited Concomitant Medications .................................................................................21                   |                                                                                                                                          |
| 6.4.2                                                                                                                                    |                                                                                                                                          |
| 6.4.3                                                                                                                                    | Supportive Care Guidelines ........................................................................................................22    |
| 6.5                                                                                                                                      | O OTHER CONSIDERATIONS                                                                                                                   |
| 6.5.1                                                                                                                                    | Contraception                                                                                                                            |
| Use in Pregnancy ...............................................................................................................34       |                                                                                                                                          |
| 6.5.2                                                                                                                                    | Use in Nursing Women ......................................................................................................34            |
| 6.5.3                                                                                                                                    |                                                                                                                                          |
| 6.6                                                                                                                                      | D Design and the section of the content to the content of the content to the content of the content to the content of the content        |
| 6.7                                                                                                                                      | Post-treatment Visits                                                                                                                    |
| 6.7.1                                                                                                                                    | Safety Follow-up Visit (End-of-treatment visit).............................................................35                           |
| 6.7.2  Follow Up                                                                                                                         |                                                                                                                                          |
| 7.0                                                                                                                                      | Dosing Delays/Dose Modifications ...........................................................................................36           |
| 7.1 Pembrolizumab                                                                                                                        |                                                                                                                                          |
| 7.2 Paclitaxel                                                                                                                           |                                                                                                                                          |
| Measurement of Effect ..........................................................................................................40       |                                                                                                                                          |
| 8.0                                                                                                                                      | Antitumor Effect .................................................................................................................40     |
| 8.1                                                                                                                                      |                                                                                                                                          |
| 8.1.1                                                                                                                                    | DEFINITIONS                                                                                                                              |
| 8.1.2                                                                                                                                    | Methods for Evaluation of Measurable Disease ..........................................................42                                |
| 8.1.3                                                                                                                                    | Response Criteria ...........................................................................................................42          |
| Evaluation of Non-Target Lesions ................................................................................42                      |                                                                                                                                          |
| 8.1.4                                                                                                                                    | Evaluation of Best Overall Response ...............................................................................43                    |
| 8.1.5                                                                                                                                    |                                                                                                                                          |
| 8.1.6                                                                                                                                    | D Duration of Response .........................................................................................................44       |
| 8.1.7                                                                                                                                    | Survival Outcomes                                                                                                                        |
| 8.1.8                                                                                                                                    | Response Review ...............................................................................................................45        |
| 9.0                                                                                                                                      | Adverse Events List and Reporting Requirements ................................................................45                        |
| 9.1                                                                                                                                      | Assessing and Recording Adverse Events .........................................................................45                       |
| 9.1.1                                                                                                                                    | Serious Adverse Events................................................................................................46                 |
| 9.1.2                                                                                                                                    | Events of Clinical Interest .................................................................................................47          |
| Definition of an Overdose for This Protocol and Reporting of Overdose to the                                                             |                                                                                                                                          |
| 9.1.3                                                                                                                                    |                                                                                                                                          |
| Sponsor and to Merck..................................................................................................................48 |                                                                                                                                          |
| Merck Requirements for Evaluating Adverse Events                                                                                         |                                                                                                                                          |
| 9.1.4                                                                                                                                    | Adverse Event Characteristics ........................................................................................................50 |
| 9.2                                                                                                                                      |                                                                                                                                          |  
CCCWFU \# 88215  
| CCCWFU # 88215                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|
| 9.3                                                                                                                                                                                                                                                                                                                                                                                                                                                    | STRC SAE Reporting Requirements 51                                  |
| 9.4                                                                                                                                                                                                                                                                                                                                                                                                                                                    | WFUHS IRB AE Reporting Requirements 51                              |
| 9.5                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Merck Reporting Requirements 52                                     |
| 9.5.1                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Reporting of Pregnancy and Lactation to the Sponsor and to Merck 52 |
| 9.5.2                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Reporting of SAEs and Events of Clinical Interest 52                |
| 10.0                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Pharmaceutical Information 53                                       |
| 10.1                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Pharmaceutical Accountability 53                                    |
| 10.2                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Pembrolizumab 53                                                    |
| 10.3                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Paclitaxel 55                                                       |
| 11.0                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Correlative/Special Studies 56                                      |
| 11.1                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Laboratory Correlative Studies 56                                   |
| 12.0                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Data Management 58                                                  |
| 13.0                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Statistical Considerations 58                                       |
| 13.1                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Power, Sample Size and Accrual Rate 58                              |
| 13.2                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Analysis of Primary Objective 58                                    |
| 13.3                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Analysis of Secondary Objectives 58                                 |
| 13.4                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Analysis of Correlative Objectives 59                               |
| References 59 Appendix A - Protocol Registration Form 62 Appendix B - Subject Eligibility Checklist 63 Appendix C - Race & Ethnicity Verification Form 67 Appendix D - Mandatory STRC SAE Reporting Guidelines 68 Appendix E - TUMOR RESPONSE WORKSHEET (RECIST v1.1) 75 Appendix F - Baseline Data Collection Form 79 Appendix G - Follow-up Data Collection Forms 82 Appendix H - Treatment Response Evaluation 84 Appendix I - Adverse Event Log 85 |                                                                     |  
Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinumrefractory urothelial carcinoma CCCWFU \# 88215
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schema

This will be a single-arm, open label, phase 2 study with the following schema:
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1.0 introduction and background

In the United States, approximately 74,000 new cases of urothelial cancer (UC) and 16,000 deaths from UC are expected in 2015. Patients with distant metastases at the time of diagnosis have only a 6% likelihood of being alive in 5 years; therefore, improvement in the treatment of advanced UC is urgently needed.  
1 The standard-of-care for first-line systemic treatment for patients with metastatic UC is platinum-based combination chemotherapy.  
2 Response rates are about 50%, with durable responses seen in a small fraction of patients. However, many patients are not eligible for cisplatin-based regimens due to renal insufficiency or suboptimal clinical status. For patients who are eligible and are treated, nearly all are destined to progress. Second-line therapy using a variety of cytotoxic agents can be given, but response rates are low and there is no accepted standard.  
Therapies that target the programmed death-1 (PD-1) and the PD-1 ligand (PD-L1) interaction are promising treatments for a variety of solid tumors. The PD-1 receptor is normally expressed on activated T-cells, and when it encounters its ligand, PD-L1, the Tcell is inactivated. Both tumor cells and tumor-associated lymphocytes may express PDL1 and therefore evade host immune surveillance. Disruption of the PD-1/PD-L1 interaction maintains and enhances effector T cell responses, thereby leading to tumor regression.  
3,4 This is now possible due to the development of agents that interact with one of the two molecules. Among these is pembrolizumab, a monoclonal antibody that binds the PD-1 receptor.  
CCCWFU \# 88215 Pembrolizumab treatment can induce tumor regression, including in patients with metastatic urothelial cancer. In KEYNOTE-012, a phase 1b study of pembrolizumab in patients with PD-L1-positive solid tumors, almost 10% of patients with advanced UC had a complete response to therapy and nearly a quarter of patients had no evidence of disease progression at 6 months. The overall response rate in the study for patients with UC was seven of 29 (24%); therefore, while pembrolizumab shows promise as a monotherapy, there is need for improvement.  
5 In general, immunotherapeutic approaches for advanced UC have had limited success due to profound inflammation-associated immune suppression. Myeloid derived suppressor cells (MDSC) with potent T-cell suppressive activities are increased in UC.  
6,7 UC is also dominated by T-regulatory (Treg) cells and immune inhibitory cytokines.  
8 Antitumor T-cell responses in UC are inhibited by MDSC and Treg cells, which increase with cytotoxic chemotherapy.  
9 PD-1 blockade only partially overcomes this MDSC and Treg cell suppression in tumor models, 10 and the effect of treatment with immune checkpoint inhibitors is maximized when MDSCs are fully eradicated.  
11 Preclinical studies in UC models similarly highlight the need to abrogate immune suppression to maximize the antitumor efficacy of PD-1 blockade.  
12 Therefore, the efficacy of pembrolizumab may be enhanced when given in combination with agents that augment antitumor immune responses. Single-agent taxanes are commonly used to treat patients with platinum-refractory UC, however response rates are modest at 5-15%, with no known survival benefit.  
13-15 Although the antitumor effects of taxanes are generally attributed to effects on microtubules and cell division, there is increasing evidence that taxanes are also immunomodulatory. Several studies have shown that treatment with low-dose taxanes reduces MDSC and Treg cells and modifies the tumor microenvironment to promote immunogenic tumor death.  
16,17 Paclitaxel can inhibit MDSC and restore CD8 T-cell effector function, and low-dose cytotoxic therapy enhances the antitumor activity of antiPD-1 antibody in mouse model systems.  
18-20 Overall, the role of chemotherapy to target immunosuppressive cells and improve treatment of advanced cancer is increasingly recognized.  
21 The use of taxanes **at non-cytotoxic doses to block the**
immunosuppressive potential of MDSC and Treg cells is a new therapeutic strategy for enhancing the efficacy of anti-PD-1 immunotherapy with pembrolizumab.
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1.1 rationale for current study

The effects of pembrolizumab with chemotherapy on immune regulatory mechanisms in cancer patients, in general, and in patients with the highly inflammatory UC, specifically, are not known. Furthermore, biomarkers predictive of pembrolizumab response are needed. Assessment of tumor expression of PD1 ligands, which can be technically challenging, has not been consistently informative.  
22,23 Of note, PD-L1 is widely expressed by UC tumor cells but is not prognostic; PD-L1 expression in UC tumor infiltrating mononuclear cells, in contrast, is associated with longer survival.  
24 Antigen-specific T cells, T cell effector and suppressor cells, and MDSC populations have also been assessed to predict PD-1 blockade response, but results have been inconclusive.  
25,26 microRNAs (miRs), small non-coding RNAs that regulate multiple processes at the  
CCCWFU \# 88215 post-transcriptional level, are emerging as important biomarkers. miRs are easily measureable by polymerase chain reaction (PCR) techniques in most biofluids, and the diagnostic and prognostic utility of measuring blood and urine miRs in patients with UC are under investigation.  
27-29 Epigenetic mechanisms of immune response are increasingly being recognized, and several miRs with immune regulatory activities have been identified. For example, in melanoma and in prostate cancer, changes in specific plasma miRs are associated with changes in circulating natural killer, dendritic, and T, MDSC, and Treg cells.  
30,31 To evaluate the potential synergy of paclitaxel and pembrolizumab, we propose a single-arm combination study of pembrolizumab and paclitaxel in patients with platinum-refractory metastatic UC. We hypothesize that combination therapy will double the overall response rate as compared to single-agent pembrolizumab alone. We also incorporate multiple novel biomarker studies. This trial may lead to improved therapy for advanced UC and may also suggest specific interventions to improve antitumor immunologic activity.
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1.2 rationale for dose selection/regimen/modification

The first in human study of pembrolizumab (MK-3475) showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). Recent data from other clinical studies within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target engagement and clinical activity.  
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited volume of distribution, and a long half-life. Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule. A population pharmacokinetic analysis was performed using serum concentration time data from 476 patients. Within the resulting population PK model, clearance and volume parameters of MK-3475 were found to be dependent on body weight. The relationship between clearance and body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and would support both body weight normalized dosing or a fixed dose across all body weights. MK-3475 has been found to have a wide therapeutic range based on the melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established exposure margins of 0.5 - 5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was no significant impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between different indication settings.  
CCCWFU \# 88215 The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range established in melanoma as associated with maximal efficacy response and 3) will maintain individual patients exposure in the exposure range established in melanoma that are well tolerated and safe.  
The rationale for combination therapy is supported by Merck's preclinical work, in which a murine immunocompetent cancer model was treated with the anti-mouse PD-1 antibody in combination with 4 different chemotherapy regimens, including dexamethasone premedication at dose levels 0.5, 1, or 5 mg/kg. The results revealed that none of the combinations had a negative impact on the efficacy of anti–PD-1 treatment. Several treatment regimens, including those in combination with paclitaxel, resulted in a greater antitumor effect, including some complete responses, than treatment with either chemotherapy or PD-1 inhibition alone.  
There are multiple ongoing clinical studies of pembrolizumab in combination with chemotherapy. For example, Merck 021 is U.S.-based a phase I/II study of pembrolizumab in combination with multiple chemotherapy regimens, including paclitaxel, for patients with NSCLC. The chemotherapy in this and other studies is given in cytotoxic doses, and thus far there have been no significant safety issues reported. Paclitaxel is commonly used to treat patients with platinum-refractory UC. Multiple dosing regimens have been studied. One small study gave paclitaxel 175 to 250 mg/m2 by 24-hour infusion every 3 weeks32 and another gave paclitaxel 200 mg/m2 by 3-hour infusion33 to pretreated patients with advanced urothelial cancer.  
Both reported some efficacy with manageable toxicity. Weekly administration of paclitaxel at doses ranging from 80-100 mg/m2 in patients with breast cancer and other solid tumors has shown better tolerance and minimal immunosuppression.  
34 As such, weekly paclitaxel at 80 mg/m2 given over 1 hour was studied in advanced urothelial carcinoma. 30 patients were treated, and a partial response was seen in 10% of patients. Time to progression was 2.2 months and overall survival 7.2 months. Treatment was well-tolerated, with anemia, neuropathy, and asthenia the most common toxicities reported.14 Weekly paclitaxel (135mg/m2) and carboplatin
(AUC 2) has also been studied in advanced UC, but significant treatment-related toxicity was noted. 35 CCCWFU \# 88215 Here we are giving pembrolizumab in combination with weekly paclitaxel at 80 mg/m2, 2 out of every 3 weeks. This dosing regimen of paclitaxel was chosen based on clinical studies showing this dose to be safe and preclinical studies suggesting that taxanes are immunomodulatory, as described above. Paclitaxel will be given 2 out of every 3 weeks in order to limit myelosuppression and steroid exposure. The use of paclitaxel at non-cytotoxic doses, to block the immunosuppressive potential of MDSC and Treg cells, is a new therapeutic strategy for enhancing the efficacy of anti-PD-1 immunotherapy with pembrolizumab.
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2.0 hypothesis and objectives

This study hypothesizes that: 1) Combination therapy with low-dose paclitaxel and pembrolizumab will improve the ORR and PFS compared to single-agent pembrolizumab; 2) Combination of low-dose paclitaxel with pembrolizumab will be safe and adequately tolerated; 3) Combination therapy will result in: a) Increased number and proportion of circulating functional CD8+ T-cells, and b) Decreased number and proportion of circulating MDSC and Treg cells; and 4) Response will be associated with increased CD8+ T-cells and/or decreased MDSC and Treg cells.
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2.1 primary objective

2.1.1 To estimate the overall response rate (ORR) of pembrolizumab combined with paclitaxel
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2.2 secondary objectives

2.2.1 To determine the safety and tolerability of pembrolizumab combined with paclitaxel 2.2.2 To calculate the progression-free survival (PFS) rate at 6 months
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2.3 correlative objectives

2.3.1 To determine the immune effects of pembrolizumab combined with paclitaxel 2.3.2 To associate immune effects with tumor response 2.3.3 To explore changes in immune-regulatory microRNAs as biomarkers of response
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3.0 patient selection 3.1 inclusion

3.1.1 Patients diagnosed with platinum-refractory metastatic urothelial cancer that is measureable based on Response Evaluation Criteria in Solid
CCCWFU \# 88215 Tumors (RECIST) criteria 1.1.36 Platinum-refractory disease is defined as progressive disease on cisplatin or carboplatin therapy or within 12 months of prior platinum treatment (last dose.)  
3.1.2 At least 1 prior chemotherapy regimen containing cisplatin or carboplatin. 3.1.3 Patient must 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.  
3.1.4 Age >18 years. 3.1.5 Performance status of 0 or 1 on the ECOG Performance Scale.
3.1.6 Adequate organ function as defined below:  
| System                                                                                                                        | Laboratory Value                                                                                               |
|-------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| Hematological Absolute neutrophil count (ANC)                                                                                 | ≥1,500 /mcL                                                                                                    |
| Platelets                                                                                                                     | ≥80,000 / mcL                                                                                                  |
| Hemoglobin                                                                                                                    | ≥9 g/dL without transfusion dependency                                                                         |
| Renal Serum creatinine OR Measured or calculated creatinine  clearance (GFR can also be used in place of  creatinine or CrCl) | ≤1.5 X upper limit of normal (ULN) OR ≥35 mL/min for subject with creatinine levels > 1.5 X  institutional ULN |
| Hepatic Serum total bilirubin                                                                                                 | ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels  > 1.5X ULN                     |
| AST (SGOT) and ALT (SGPT)                                                                                                     | ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases                                                    |
| Albumin                                                                                                                       | >2.5 mg/dL                                                                                                     |  
3.1.7 Female subject 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.  
3.1.8 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.  
3.1.9 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.
CCCWFU \# 88215  
3.1.10 Ability to understand and the willingness to sign an IRB-approved informed consent document.
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3.2 exclusion criteria

3.2.1 Currently receiving or has had treatment with an investigational agent or used an investigational device within 4 weeks of study Day 1.  
3.2.2 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.  
3.2.3 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.  
3.2.4 Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Prior therapy with paclitaxel or docetaxel.  
3.2.5 Hypersensitivity to pembrolizumab, any of its excipients, paclitaxel, or any of its excipients.  
3.2.6 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.
3.2.7 Known history of active TB (Bacillus Tuberculosis).  
3.2.8 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.
3.2.9 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.  
CCCWFU \# 88215  
3.2.10 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.  
3.2.11 Known history of, or any evidence of active, non-infectious pneumonitis.  
3.2.12 Active infection requiring systemic therapy. 3.2.13 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.  
3.2.14 Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.  
3.2.15 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.  
3.2.16 Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 3.2.17 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).  
3.2.18 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., FluMist®) are live attenuated vaccines, *and are not allowed.*
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3.3 inclusion of women and

Men and women of all races and ethnicities who meet the above-described eligibility criteria are eligible to participate in this study.  
The study consent form will also be provided in Spanish for Spanish-speaking participants. We do not expect the percentage of Hispanic/Latino or racial minority cancer patients eligible for this study to be higher than the percentage of Hispanic or racial minority new cancer patients seen at CCCWFU (1.7% and 14.4%, respectively); therefore, we plan to enroll at least 1 Hispanic/Latino and at least 4 racial minority patients. Should we not meet or exceed these estimates, the PI will engage the Cancer Center Health Equity Advisory Group to discuss strategies to enhance recruitment in these target populations.  
CCCWFU \# 88215
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4.0 registration procedures

All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control trial, must be registered with the CCCWFU Protocol Registrar or entered into ORIS Screening Log within 24 hours of Informed Consent. Patients **must** be registered prior to the initiation of treatment.  
You must perform the following steps in order to ensure prompt registration of your patient:  
1. Complete the Eligibility Checklist (Appendix B)
2. Complete the Protocol Registration Form (Appendix A)
3. Alert the Cancer Center registrar by phone, *and then* send the signed Informed Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, either by fax or e-mail.
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contact information

Protocol Registrar PHONE (336) 713-6767 Protocol Registrar FAX (336) 713-6772 Protocol Registrar E-MAIL (registra@wakehealth.edu) *Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday.  
4. Fax/e-mail ALL eligibility source documents with registration. Patients **will not** be registered without all required supporting documents.
Note: If labs were performed at an outside institution, provide a printout of the results. Ensure that the most recent lab values are sent.  
To complete the registration process, the Registrar will:  
- assign a patient study number
- register the patient on the study
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5.2 secondary outcomes

5.2.1 Safety, as assessed by adverse events and serious adverse events 5.2.2 Progression-free survival at 6 months
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5.3 correlative outcomes

Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinumrefractory urothelial carcinoma CCCWFU \# 88215  
5.3.1 Immune effects, as assessed by changes in the number and proportion of functional CD8+ T-cells, MDSCs, Tregs, and circulating immune-regulatory microRNAs in peripheral blood 5.3.2 Quantify cytotoxic T-cells, MDSCs, and Tregs and determine the correlation of PD-L1 expression in tumor tissue 5.3.3 Changes in serum and urine immune-regulatory microRNAs
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6.0 treatment plan 6.1 study

6.2 Study-Related Activities  
The Trial Flow Chart below summarizes the trial procedures to be performed at each visit.  
It may be necessary to perform these procedures at unscheduled time points if deemed clinically necessary by the investigator. Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck for reasons related to subject safety.
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trial flow chart

| TREATMENT PHASE           |                  |                                     |
|---------------------------|------------------|-------------------------------------|
| Screeninga                | (UP TO 6 MONTHS) | MAINTENANCE PHASE (UP TO 18 MONTHS) |
| 21 day cycle (+/- 3 days) |                  |                                     |  
CCCWFU \# 88215  
| Follow-up  onlyd (+/- 10 days)                                   |     |     |           |    |    |    |
|------------------------------------------------------------------|-----|-----|-----------|----|----|----|
| Informed consent                                                 | X   |     |           |    |    |    |
| Eligibility criteria                                             | X   |     |           |    |    |    |
| Demographic data                                                 | X   |     |           |    |    |    |
| Concomitant  medicationse                                        | X   | X   | X         |    |    |    |
| Medical history and  physical exam                               | X   | X   | X         | X  | X  |    |
| AE assessmentf                                                   | X   | X   | X         |    |    |    |
| Vital signs, height, and  weightg                                | X   | X   | X         |    |    |    |
| ECOG performance  status                                         | X   | X   | X         |    |    |    |
| Pembrolizumab dosing                                             | X   | X   |           |    |    |    |
| Paclitaxel dosing                                                | X   | X   |           |    |    |    |
| CT chest, abdomen,  pelvish                                      | X   | X   | X         | X  | X  |    |
| Treatment  21 day cyclec (+/- 10 days)                           |     |     |           |    |    |    |
| End of                                                           |     |     |           |    |    |    |
| Within 14 days of                                                | Day | Day | Treatment |    |    |    |
| dosing                                                           | 1   | 8   | Visitb    |    |    |    |
| Standard-of-care laboratory assessmentsi CBC with differential X | X   | X   | X         | X  | X  |    |
| Serum chemistries                                                | X   | X   | X         | X  | X  | X  |
| LDH                                                              | X   | X   |           |    |    |    |
| Complete urinalysis                                              | X   | X   |           |    |    |    |
| Thyroid studies                                                  | X   | X   | X         |    |    |    |
| Urine pregnancy testj                                            | X   |     |           |    |    |    |
| Correlative/research studies Metastatic tumor site  biopsyk      | X   |     |           |    |    |    |
| Archival tumor tissuel                                           | X   |     |           |    |    |    |
| Blood correlatesm                                                | X   | X   |           |    |    |    |
| Urinary correlatesm                                              | X   | X   |           |    |    |    |
| MicroRNA blood &  urine correlatesn                              | X   | X   |           |    |    |    |
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footnotes to study flow chart

a. Screening evaluations must be completed within 14 days of first dose of medication and DO NOT need to be repeated on cycle 1 day 1 of treatment, except for the labs (CBC/CMP) which need to be performed within 72 hours of first dose. CT scan of chest/abdomen/pelvis can be within 30 days of cycle 1 day 1. Contrast scans preferred but noncontrasted studies acceptable if renal insufficiency, contrast allergy, or other medical condition prohibits the use of contrast.  
b. The End of Treatment Visit is to occur no more than 30 days after the last dose of study agent. At the End of Treatment Visit, if progressive disease, patient will be followed for survival status. If stable disease or partial or complete response, patient will have the option of remaining on pembrolizumab alone for an additional 18 months or until disease progression.
CCCWFU \# 88215  
c. Patients who remain on pembrolizumab in the maintenance phase will be seen every 21 days, with imaging every 3 months (+/- 10 days) for up to 18 months.  
d. Patients who do not have progressive disease but who decline maintenance pembrolizumab will be followed every 3 months (+/- 10 days) for up to 18 months after the End of Treatment Visit. These patients will have scans every 3 months (+/- 10 days). All patients will continue to be followed for survival status.  
e. All concomitant medications received within 28 days before the first dose of trial treatment and 30 days after the treatment phase should be recorded, including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  
f. Medical history, physical examination and AE assessments will be performed prior to study agent administration, on day 1 of each cycle. An end-of-study medical history, physical exam, and AE
assessment will be performed at the end of treatment phase.  
g. Vital signs and weight will be recorded at each visit during the treatment phase. Height will be measured at screening only.  
h. Contrast scans preferred but noncontrasted studies acceptable if renal insufficiency, contrast allergy, or other medical condition prohibits the use of contrast. CT scan of chest/abdomen/pelvis can be within 30 days of cycle 1 day 1.  
TREATMENT PHASE: CT scan of chest/abdomen/pelvis to be performed on day 1 of cycle 4, day 1 of cycle 7, and at the end-of-treatment visit (+/-7 days) as part of routine tumor assessment. MAINTENANCE PHASE: CT scan of chest/abdomen/pelvis to be performed every 3 months (+/- 10 days) as part of routine tumor assessment.
These tumor assessments will be performed locally, in accordance with the RECIST 1.1 guidelines.  
i. Standard-of-care laboratory assessments at the times indicated include:
Complete blood count (CBC) with differential: WBC count with differential, platelet count, hemoglobin, and hematocrit. Serum chemistries: Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, carbon dioxide or bicarbonate, calcium, protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and alkaline phosphatase. Note: During maintenance phase, order BMP except on visits where thyroid testing is included (order CMP.)
LDH Urinalysis: Including pH, specific gravity, protein, microscopy, hemoglobin, cell count, crystal evaluation, leukocyte esterase, and nitrite without culture will be collected on day 1 of cycles 1, 4, 8, and at the end of treatment visit. Thyroid studies: TSH, free T4, and T3 will be performed on day 1 of cycles 1, 4, 8, and at the end of treatment visit due to the potential for thyroid abnormalities while on pembrolizumab. Note: In the maintenance phase, thyroid studies will be performed every 3 cycles.  
Note: Day 1 lab tests do not have to be repeated if screening labs are obtained within 3 days prior to the first dose of study drug.  
j. Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  
k. If safely able to be performed, a metastatic (bone, soft tissue, visceral metastasis permitted) or recurrent bladder tumor biopsy under radiologic or cystoscopic guidance will be performed prior to treatment initiation. Biopsies obtained up to 6 months (168 days) prior to treatment initiation are acceptable.  
CCCWFU \# 88215  
l. Previously archived formalin-fixed or frozen tumor blocks will be collected on this study and linked to subject outcomes if available. Frozen primary tumor samples will be collected if available.  
m. Blood and urine correlates will be collected prior to treatment administration on day 1 of cycle 1, day 1 of cycle 4, day 1 of cycle 8, and at the end of treatment visit.  
n. Blood and urine for microRNA analysis will be collected prior to treatment administration on day 1 of cycle 1, day 1 of cycle 4, day 1 of cycle 8, and at the end of treatment visit.
6.2.1 **Informed Consent**
The Investigator must obtain documented consent from each potential subject prior to participating in a clinical trial. Consent must be documented by the subject's dated signature or by the subject's legally acceptable representative's dated signature on a consent form along with the dated signature of the person conducting the consent discussion. A copy of the signed and dated consent form should be given to the subject before participation in the trial.  
The initial informed consent form, any subsequent revised written informed consent form and any written information provided to the subject must receive the IRB/ERC's approval/favorable opinion in advance of use. The subject or his/her legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject's willingness to continue participation in the trial. The communication of this information will be provided and documented via a revised consent form or addendum to the original consent form that captures the subject's dated signature or by the subject's legally acceptable representative's dated signature. Specifics about a trial and the trial population will be added to the consent form template at the protocol level. The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and Sponsor requirements.
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6.2.2 inclusion/exclusion criteria

All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the subject qualifies for the trial.  
6.2.3 **Medical History**
A medical history will be obtained by the investigator or qualified designee. Medical history will include all active conditions, and any condition diagnosed within the prior 10 years that are considered to be clinically significant by the Investigator. Details regarding the disease for which the subject has enrolled in this study will be recorded separately and not listed as medical history.  
CCCWFU \# 88215
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6.2.4 prior and concomitant medications

The investigator or qualified designee will review prior medication use, including any protocol-specified washout requirement, and record prior medication taken by the subject within 28 days before starting the trial. Treatment for the disease for which the subject has enrolled in this study will be recorded separately and not listed as a prior medication.
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concomitant medications

The investigator or qualified designee will record medication, if any, taken by the subject during the trial. All medications related to reportable SAEs and ECIs should be recorded as defined in Section 9.0.
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6.2.5 disease details and treatments

The investigator or qualified designee will obtain prior and current details regarding disease status.
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prior treatment details

The investigator or qualified designee will review all prior cancer treatments including systemic treatments, radiation and surgeries.
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subsequent anti-cancer therapy status

The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy. Once new anticancer therapy has been initiated the subject will move into survival follow-up.
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6.2.6 adverse event (ae) monitoring

The investigator or qualified designee will assess each subject to evaluate for potential new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. Adverse experiences will be graded and recorded throughout the treatment phase of the study according to NCI CTCAE Version 4.0
(see Section 9.0). Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse events, or irAEs); see the separate ECI guidance document regarding the identification, evaluation and management of potential irAEs. Please refer to section 9.0 for detailed information regarding the assessment and recording of AEs.  
CCCWFU \# 88215
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6.2.7 physical exam

The investigator or qualified designee will perform a complete physical exam during the screening period. Clinically significant abnormal findings should be recorded as medical history.  
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified designee will perform a directed physical exam as clinically indicated prior to trial treatment administration.
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vital signs

The investigator or qualified designee will take vital signs at screening, prior to the administration of each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
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eastern cooperative oncology group (ecog)

The investigator or qualified designee will assess ECOG status (see Section 11.1)
at screening, prior to the administration of each dose of trial treatment and discontinuation of trial treatment as specified in the Trial Flow Chart.
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6.2.8 laboratory procedures/assessments

Laboratory tests for screening should be performed within 14 days prior to the first dose of treatment and will need to be repeated if not within 72 hours of first dose. After cycle 1 day 1, all pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of trial treatment. Blood and urine correlates will be collected prior to treatment administration on day 1 of cycles 1, 4, 8, and at the end of treatment visit. A total of six (6) 10 mL EDTA tubes of blood will be collected at each time point. The samples will be kept at room temperature and transported to Dr. Triozzi's lab within 2 hours of collection for further processing.
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6.3 treatment administration

| REGIMEN DESCRIPTION                                            | Cycle                          |              |        |          |        |
|----------------------------------------------------------------|--------------------------------|--------------|--------|----------|--------|
| Agent                                                          | Premedications                 | Dose         | Route  | Schedule | Length |
| Pembrolizumab                                                  | 200 mg                         | 30-minute IV | Day 1  |          |        |
| infusion                                                       |                                |              |        |          |        |
| Paclitaxel                                                     | Premedicate with ondansetron 8 | 21 days      |        |          |        |
| mg IV or po ,  dexamethasone  10 mg IV or po,  diphenhydramine | 80 mg/m2                       | 60-minute IV | Days 1 |          |        |
| infusion                                                       | and 8                          |              |        |          |        |  
CCCWFU \# 88215  
| 25 mg IV or po,  and ranitidine 50mg IV or po  (or equivalent H2  blocker) 30-60  minutes pretreatment.*                                                                           |
|---------------------------------------------------------------------------|
| *Premedications may be substituted according to institutional guidelines. |  
On day 1 of each cycle, pembrolizumab is to be given first, prior to the premedications and then followed by paclitaxel.  
Patients will be observed for 60 minutes after completion of chemotherapy, while in the treatment phase. Patients receiving pembrolizumab alone in the maintenance phase need not have extended monitoring unless clinically indicated.  
Vitals signs (blood pressure, heart rate, respiratory rate, oxygenation, and temperature) will be checked every hour while receiving treatment and prior to discharge from the treatment area. Trial treatment should be administered per the schedule above after all procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.1). Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. All trial treatments will be administered on an outpatient basis.  
CCCWFU \# 88215
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6.4 general concomitant medication and

Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing trial. If there is a clinical indication for one of these or other medications or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be required. The investigator should discuss any questions regarding this with the Merck Clinical team. The final decision on any supportive therapy or vaccination rests with the investigator and/or the subject's primary physician.
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6.4.1 acceptable concomitant medications

All treatments that the investigator considers necessary for a subject's welfare may be administered at the discretion of the investigator in keeping with the community standards of medical care. All concomitant medication will be recorded on the case report form including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, route, and date may also be included on the CRF. All concomitant medications received within 28 days before the first dose of trial treatment and 30 days after the last dose of trial treatment should be recorded. Concomitant medications administered after 30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined in Section 9.0.
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6.4.2 prohibited concomitant medications

Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase (including retreatment for post-complete response relapse)
of this trial:
- Antineoplastic systemic chemotherapy or biological therapy - Immunotherapy not specified in this protocol
- Chemotherapy not specified in this protocol - Investigational agents other than pembrolizumab - Radiation therapy o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator's discretion.  
- Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
- Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology. The use  
CCCWFU \# 88215 of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned treatments for clinical management should be removed from the trial. Subjects may receive other medications that the investigator deems to be medically necessary.  
The Exclusion Criteria describes other medications which are prohibited in this trial. There are no prohibited therapies during the Post-Treatment Follow-up Phase.
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6.4.3 supportive care guidelines

Subjects should receive appropriate supportive care measures as deemed necessary by the treating investigator. Suggested supportive care measures for the management of adverse events with potential immunologic etiology are outlined below and in Section 7.1. Where appropriate, these guidelines include the use of oral or intravenous treatment with corticosteroids as well as additional antiinflammatory agents if symptoms do not improve with administration of corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which might require additional supportive care. The treatment guidelines are intended to be applied when the investigator determines the events to be related to pembrolizumab. Note: if after the evaluation the event is determined not to be related, the investigator is instructed to follow the ECI reporting guidance but does not need to follow the treatment guidance (as outlined in the ECI guidance document). Refer to Section 7.0 for dose modification.  
- **Pneumonitis**:
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Pneumonitis - Interstitial lung disease - Acute interstitial pneumonitis If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a cardiology consultation should be considered. All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral infection. It is **important that patients with a suspected diagnosis of**
pneumonitis be managed as per the guidance below until treatment-related pneumonitis is excluded. Treatment of both a potential infectious etiology and pneumonitis in parallel may be warranted. Management of the treatment of suspected pneumonitis with steroid treatment should not be delayed for  
CCCWFU \# 88215 a therapeutic trial of antibiotics. If an alternative diagnosis is established, the patient does not require management as below; however the AE should be reported regardless of etiology.  
o For **Grade 2 events:**
- Hold pembrolizumab.  
- Consider pulmonary consultation with bronchoscopy and biopsy/BAL.  
- Consider ID consult. - Conduct an in person evaluation approximately twice per week. - Consider frequent Chest X-ray as part of monitoring. - Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Second episode of pneumonitis - discontinue pembrolizumab if upon rechallenge the patient develops a second episode of Grade 2 or higher pneumonitis.
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o for grade 3-4 events

- Hospitalize patient.  
- Bronchoscopy with biopsy and/or BAL is recommended.  
- Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When symptoms improve to Grade 1 or less, a high dose oral steroid
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no less than 4 weeks. - If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional anti-inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional anti-inflammatory measures, as needed - Add prophylactic antibiotics for opportunistic infections.  
.
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- diarrhea/colitis

Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of the event: - Colitis - Colitis microscopic - Enterocolitis
- Enterocolitis hemorrhagic CCCWFU \# 88215
- Gastrointestinal perforation
- Intestinal obstruction - Necrotizing colitis
- Diarrhea All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and endoscopy. However the AE should be reported regardless of etiology.
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o for grade 2 events

- Symptomatic Treatment - For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or mucus, consider GI consultation and endoscopy to confirm or rule out colitis
- Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) - When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- If symptoms worsen or persist > 3 days treat as Grade 3 o For **Grade 3-4 events**:
- Hold pembrolizumab (if grade 3) or discontinue (if grade 4)
- Rule out bowel perforation. Imaging with plain films or CT can be useful. - Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. - Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or bleeding. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. - If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 hours, consider treatment with additional antiinflammatory measures. Discontinue additional anti-inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional anti-inflammatory measures as needed.
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- endocrine

CCCWFU \# 88215 The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require holding/discontinuation/modification of pembrolizumab dosing, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Adrenal insufficiency - Hyperthyroidism
- Hypophysitis
- Hypopituitarism
- Hypothyroidism - Thyroid disorder - Thyroiditis
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o hypophysitis grade 2-4 events

- Hold pembrolizumab - Rule out infection and sepsis with appropriate cultures and imaging. - Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until returned to baseline values.  
- Pituitary gland imaging should be considered. - Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.  
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis. - Consultation with an endocrinologist may be considered.  
o **Hyperthyroidism or Hypothyroidism**:
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.  
Grade 2 hyperthyroidism events (and **Grade 2-4** hypothyroidism):
- Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until returned to baseline values. - Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency.  
- Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is instituted. - In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy. - In hypothyroidism, thyroid hormone replacement therapy is indicated per standard of care.  
- Consultation with an endocrinologist may be considered.  
Grade 3/4 hyperthyroidism events:  
CCCWFU \# 88215
- Hold pembrolizumab (grade 3) or discontinue (grade 4).  
- Rule out infection and sepsis with appropriate cultures and imaging. - Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.  
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.
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o type 1 diabetes mellitus

The following AE terms are considered ECIs and should be reported to the Sponsor within 24 hours of the event: - Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA)
- Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria)
or metabolic acidosis (DKA).  
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening of preexisting diabetes associated with laboratorial evidence of beta cell failure. All attempts should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), T2DM decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or poorly controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above criteria should be reported as ECIs regardless of etiology. The patients may present with hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic acidosis, or low or undetected c-peptide.
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t1dm should be immediately treated

- Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 34 hyperglycemia associated with evidence of beta cell failure, and resume pembrolizumab when patients are clinically and metabolically stable.  
- Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
- Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, and C-peptide. - Consultation with an Endocrinologist is recommended.  
- Consider local testing for islet cell antibodies and antibodies to GAD, IA2, ZnT8, and insulin may be obtained.
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- hepatic

CCCWFU \# 88215 The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification or use of systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Autoimmune hepatitis - Hepatitis
- Transaminase elevations All attempts should be made to rule out other causes such as metastatic disease, infection or other hepatic diseases. However the AE should be reported regardless of etiology. In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient meets the laboratory criteria for potential DILI defined as:
- An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than or equal to three times (3X) the upper limit of normal (ULN) and - An elevated total bilirubin lab value that is greater than or equal to two times
(2X) ULN and
- At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,
- As a result of within-protocol-specific testing or unscheduled testing.  
o **Grade 2** events:
- Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 3.0 times ULN.  
- Monitor liver function tests more frequently until returned to baseline values (consider weekly).  
- Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for opportunistic infections, and resume pembrolizumab per protocol - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Permanently discontinue pembrolizumab for patients with liver metastasis who begin treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% relative to baseline and lasts ≥1 week.  
o **Grade 3** events:
- Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 times ULN.  
- Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if necessary - Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks.  
- If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not recommended due to its potential for hepatotoxicity.  
CCCWFU \# 88215 o **Grade 4** events:
- Permanently discontinue pembrolizumab
- Manage patient as per Grade 3 above
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- renal

The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Nephritis
- Nephritis autoimmune
- Renal failure
- Renal failure acute All attempts should be made to rule out other causes such as obstructive uropathy, progression of disease, or injury due to other chemotherapy agents. A renal consultation is recommended. However the AE should be reported regardless of etiology.  
o **Grade 2** events:
- Hold pembrolizumab - Treatment with prednisone 1-2 mg/kg p.o. daily. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
o **Grade 3-4** events:
- Discontinue pembrolizumab
- Renal consultation with consideration of ultrasound and/or biopsy as appropriate - Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent once per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
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- hematologic

The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of the event: - Autoimmune hemolytic anemia - Aplastic anemia - Disseminated Intravascular Coagulation (DIC) - Haemolytic Uraemic Syndrome (HUS) - Idiopathic (or immune) Thrombocytopenia Purpura (ITP) - Thrombotic Thrombocytopenic Purpura (TTP) - Any Grade 4 anemia regardless of underlying mechanism All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. Relevant diagnostic studies such as peripheral blood smear,  
CCCWFU \# 88215 reticulocyte count, LDH, haptoglobin, bone marrow biopsy or Coomb's test, etc.,
should be considered to confirm the diagnosis. However the AE should be reported regardless of etiology.  
o **Grade 2** events:
- Hold pembrolizumab
- Prednisone 1-2 mg/kg daily may be indicated
- Consider Hematology consultation. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
o **Grade 3** events:
- Hematology consultation - Hold pembrolizumab. Discontinuation should be considered as per specific protocol guidance. - Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
o **Grade 4** events:
- Hematology consultation
- Discontinue pembrolizumab .  
- Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o.  
(or equivalent) as appropriate
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- neurologic

The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 hours of the event: - Autoimmune neuropathy - Demyelinating polyneuropathy - Guillain-Barre syndrome - Myasthenic syndrome All attempts should be made to rule out other causes such as metastatic disease, other medications or infectious causes. However the AE should be reported regardless of etiology.  
o **Grade 2** events:
- Consider withholding pembrolizumab.  
- Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate - Consider Neurology consultation. Consider biopsy for confirmation of diagnosis.  
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
o **Grade 3 and 4** events:
- Discontinue pembrolizumab - Obtain neurology consultation. Consider biopsy for confirmation of diagnosis - Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. If condition worsens consider IVIG or other  
CCCWFU \# 88215 immunosuppressive therapies as per local guidelines. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
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- skin rash and pruritus

The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor within 24 hours of the event:
- Pruritus
- Rash
- In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the physician's judgment, should be treated as an ECI. Clinical significance is left to the physician to determine, and could possibly include rashes such as the following:
- rash with a duration >2 weeks; OR
- rash that is >10% body surface area; OR - rash that causes significant discomfort not relieved by topical medication or temporary cessation of study drug.
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other skin ecis

The following AEs should **always** be reported as ECIs, regardless of grade, and should be reported to the Sponsor within 24 hours of the event: - Dermatitis exfoliative
- Erythema multiforme
- Steven's Johnson syndrome
- Toxic epidermal necrolysis o **Grade 2** events:
- Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in combination with oral anti-pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl). - Treatment with oral steroids is at physician's discretion.  
o **Grade 3** events:
- Hold pembrolizumab. - Consider Dermatology Consultation and biopsy for confirmation of diagnosis.  
- Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent once per day or dexamethasone 4 mg four times orally daily. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
o **Grade 4** events:
- Permanently discontinue pembrolizumab. - Dermatology consultation and consideration of biopsy and clinical dermatology photograph.  
CCCWFU \# 88215
- Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks
- **Ocular**:
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic steroids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of the event: - Uveitis - Iritis All attempts should be made to rule out other causes such as metastatic disease, infection or other ocular disease (e.g. glaucoma or cataracts). However the AE
should be reported regardless of etiology.  
o **Grade 2** events:
- Evaluation by an ophthalmologist is strongly recommended.  
- Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. - Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with topical immunosuppressive therapy.  
o **Grade 3** events:
- Evaluation by an ophthalmologist is strongly recommended - Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance. - Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
o **Grade 4** events:
- Evaluation by an ophthalmologist is strongly recommended
- Permanently discontinue pembrolizumab. - Treat with corticosteroids as per Grade 3 above
- **Management of Infusion Reactions**: Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction associated with administration of pembrolizumab (MK-3475).  
Table 4 Infusion Reaction Treatment Guidelines  
| NCI CTCAE Grade              | Treatment                    | Premedication at subsequent  dosing   |
|------------------------------|------------------------------|---------------------------------------|
| Grade 1                      | Increase monitoring of vital | None                                  |
| signs as medically indicated |                              |                                       |  
CCCWFU \# 88215  
| CCCWFU # 88215                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|
| NCI CTCAE Grade                                                                                                                                                                                                                                            | Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Premedication at subsequent  dosing |
| Mild reaction; infusion  interruption not indicated;  intervention not indicated                                                                                                                                                                           | until the subject is deemed  medically stable in the opinion  of the investigator.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                     |
| Grade 2 Requires infusion  interruption but responds  promptly to symptomatic  treatment (e.g.,  antihistamines, NSAIDS,  narcotics, IV fluids);  prophylactic medications  indicated for < =24 hrs                                                        | Stop Infusion and monitor  symptoms. Additional appropriate medical  therapy may include but is not  limited to: IV fluids Antihistamines NSAIDS Acetaminophen Narcotics Increase monitoring of vital  signs as medically indicated  until the subject is deemed  medically stable in the opinion  of the investigator. If symptoms resolve within one hour of stopping drug  infusion, the infusion may be  restarted at 50% of the  original infusion rate (e.g.,  from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held  until symptoms resolve and  the subject should be  premedicated for the next  scheduled dose. Subjects who develop  Grade 2 toxicity despite  adequate premedication  should be permanently  discontinued from further  trial treatment  administration. | Subject may be premedicated  1.5h (± 30 minutes) prior to  infusion of pembrolizumab (MK3475) with: Diphenhydramine 50 mg po (or  equivalent dose of  antihistamine). Acetaminophen 500-1000 mg  po (or equivalent dose of  antipyretic).                                     |
| Grades 3 or 4 Grade 3: Prolonged (i.e., not rapidly  responsive to symptomatic  medication and/or brief  interruption of infusion);  recurrence of symptoms  following initial improvement;  hospitalization indicated for  other clinical sequelae (e.g., | Stop Infusion. Additional appropriate medical  therapy may include but is not  limited to: IV fluids Antihistamines NSAIDS Acetaminophen Narcotics Oxygen                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | No subsequent dosing                |  
CCCWFU \# 88215  
| NCI CTCAE Grade                                                                                                                                                                                                                                                       | Treatment                            | Premedication at subsequent  dosing   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|---------------------------------------|
| renal impairment, pulmonary  infiltrates) Grade 4: Life-threatening; pressor or  ventilatory support indicated                                                                                                                                                        | Pressors Corticosteroids Epinephrine |                                       |
| Increase monitoring of vital  signs as medically indicated  until the subject is deemed  medically stable in the opinion  of the investigator. Hospitalization may be  indicated. Subject is permanently  discontinued from further  trial treatment  administration. |                                      |                                       |
| Appropriate resuscitation equipment should be available in the room and a physician readily  available during the period of drug administration.                                                                                                                      |                                      |                                       |
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6.5 other considerations 6.5.1 contraception

Pembrolizumab may have adverse effects on a fetus in utero.  
Furthermore, it is not known if pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is
≥45 years of age and has not had menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the duration of the study. The two birth control methods can be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth control from study Visit 1 throughout the study period up to 120 days after the last dose of study therapy. The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during  
CCCWFU \# 88215 the study. In order to participate in the study they must adhere to the contraception requirement (described above) for the duration of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy and Lactation to the Sponsor and to Merck. If there is any question that a subject will not reliably comply with the requirements for contraception, that subject should not be entered into the study.
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6.5.2 use in pregnancy

If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will immediately be removed from the study. The site will contact the subject at least monthly and document the subject's status until the pregnancy has been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male subject impregnates his female partner the study personnel at the site must be informed immediately and the pregnancy reported to the Sponsor and to Merck and followed as described above and in Section 7.2.2.
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6.5.3 use in nursing women

It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects who are breastfeeding are not eligible for enrollment.
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6.6 duration of therapy treatment

In the absence of treatment delays due to adverse events, treatment with the combination of paclitaxel and pembrolizumab may continue for 8 cycles or until one of the following criteria applies:  
- Confirmed radiographic disease progression (a subject may be granted an exception to continue on treatment with confirmed radiographic progression if clinically stable or clinically improved),
- Intercurrent illness that prevents further administration of treatment,
- Unacceptable adverse event(s), - Confirmed positive serum pregnancy test,
- Noncompliance with trial treatment or procedure requirements, - The patient is lost to follow-up,
CCCWFU \# 88215  
- Patient/legal representative withdraws consent, or
- General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the treating physician.
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for the final trial visit should be performed at the time of discontinuation. Any adverse events which are present at the time of discontinuation/withdrawal should be followed in accordance with the safety requirements outlined in Section 9.0.
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maintenance phase

In the absence of treatment delays due to adverse events, treatment with pembrolizumab may continue for 18 months or until one of the following criteria applies:  
- Confirmed radiographic disease progression (a subject may be granted an exception to continue on treatment with confirmed radiographic progression if clinically stable or clinically improved),
- Intercurrent illness that prevents further administration of treatment,
- Unacceptable adverse event(s), - Confirmed positive serum pregnancy test,
- Noncompliance with trial treatment or procedure requirements, - The patient is lost to follow-up, - Patient/legal representative withdraws consent, or
- General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the treating physician.
Patients who remain on pembrolizumab in the maintenance phase will be seen every 21 days, with imaging every 3 months (+/- 10 days) for up to 18 months.
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6.7 post-treatment visits 6.7.1 safety

The mandatory Safety Follow-Up Visit should be conducted within 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should also be followed and recorded.  
If stable disease or partial or complete response noted at this visit, the patient will have the option of remaining on pembrolizumab alone for an additional 18 months, in the maintenance phase as described above.  
CCCWFU \# 88215
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6.7.2 follow up

Patients who do not have progressive disease but who decline maintenance pembrolizumab will be followed every 3 months (+/- 10 days) for up to 18 months after the end of treatment. These patients will have scans every 3 months (+/- 10 days). All patients will be continued to followed for survival status. . Patients who discontinue treatment for reasons other than progressive disease should be assessed every 3 months (± 10 days) by radiologic imaging to monitor disease status. Every effort should be made to collect information regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, end of the study or lost to follow up. Information regarding post-study antineoplastic treatment will be collected if new treatment is initiated.  
All patients will have survival status assessed every 3 months until death or withdrawal of consent. .
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7.0 dosing delays/dose modifications 7.1

Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent an immunologic etiology. These adverse events may occur shortly after the first dose or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening AEs as per the table below. Toxicity must return to Grade 0-1 by day 1 of each cycle. Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be documented in the patient's study record.  
CCCWFU \# 88215  
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab  
General instructions:  
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.  
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to  
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other  
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.  
| resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day  within 12 weeks.   |                                                                                                                                                                                                                         |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
|------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|----|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3.                                                                                                                                       | For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other  immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.   |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| Immune-related AEs                                                                                                                       | Toxicity grade  or conditions  (CTCAEv4.0)                                                                                                                                                                              | Action taken to       | irAE management                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| pembrolizumab                                                                                                                            | with corticosteroid  and/or other  therapies                                                                                                                                                                            | Monitor and follow-up |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| Pneumonitis                                                                                                                              | Grade 2                                                                                                                                                                                                                 | Withhold              | -                                                                                                                                    | Administer  corticosteroids  (initial dose of 1-2  mg/kg prednisone  or equivalent)  followed by taper | -  | Monitor participants for  signs and symptoms of  pneumonitis                                                                                                                                                 |
| -                                                                                                                                        | Evaluate participants with  suspected pneumonitis with  radiographic imaging and  initiate corticosteroid  treatment                                                                                                    |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| -                                                                                                                                        | Add prophylactic antibiotics  for opportunistic infections                                                                                                                                                              |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| Grade 3 or 4, or  recurrent Grade  2                                                                                                     | Permanently  discontinue                                                                                                                                                                                                |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| Diarrhea / Colitis                                                                                                                       | Grade 2 or 3                                                                                                                                                                                                            | Withhold              | -                                                                                                                                    | Administer  corticosteroids  (initial dose of 1-2  mg/kg prednisone  or equivalent)  followed by taper | -  | Monitor participants for  signs and symptoms of  enterocolitis (ie, diarrhea,  abdominal pain, blood or  mucus in stool with or  without fever) and of bowel  perforation (ie, peritoneal  signs and ileus). |
| -                                                                                                                                        | Participants with ≥ Grade 2  diarrhea suspecting colitis  should consider GI  consultation and performing  endoscopy to rule out colitis.                                                                               |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| -                                                                                                                                        | Participants with  diarrhea/colitis should be  advised to drink liberal  quantities of clear fluids. If  sufficient oral fluid intake is  not feasible, fluid and  electrolytes should be  substituted via IV infusion. |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| Grade 4                                                                                                                                  | Permanently  discontinue                                                                                                                                                                                                |                       |                                                                                                                                      |                                                                                                        |    |                                                                                                                                                                                                              |
| AST / ALT elevation or                                                                                                                   | Grade 2                                                                                                                                                                                                                 | Withhold              | -                                                                                                                                    | Administer                                                                                             |    |                                                                                                                                                                                                              |
| Increased bilirubin                                                                                                                      | corticosteroids  (initial dose of 0.5- 1  mg/kg prednisone or  equivalent) followed  by taper                                                                                                                           | -                     | Monitor with liver function tests  (consider weekly or more  frequently until liver enzyme  value returned to baseline or is  stable |                                                                                                        |    |                                                                                                                                                                                                              |
| Grade 3 or 4                                                                                                                             | Permanently discontinue                                                                                                                                                                                                 | -                     | Administer  corticosteroids (initial dose of 1-2  mg/kg prednisone or  equivalent) followed  by taper                                |                                                                                                        |    |                                                                                                                                                                                                              |  
CCCWFU \# 88215  
| CCCWFU # 88215                                     |                                                                                                                                                                          |                            |                                                                                    |                                                                                                      |    |                                                                              |
|----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|----|------------------------------------------------------------------------------|
| Immune-related AEs                                 | Toxicity grade  or conditions  (CTCAEv4.0)                                                                                                                               | Action taken to            | irAE management                                                                    |                                                                                                      |    |                                                                              |
| pembrolizumab                                      | with corticosteroid  and/or other  therapies                                                                                                                             | Monitor and follow-up      |                                                                                    |                                                                                                      |    |                                                                              |
| Type 1 diabetes mellitus  (T1DM) or  Hyperglycemia | Newly onset  T1DM or  Grade 3 or 4  hyperglycemia  associated with  evidence of βcell failure                                                                                                                                                                          | Withhold                   | -                                                                                  | Initiate insulin  replacement  therapy for  participants with  T1DM                                  |    |                                                                              |
| -                                                  | Administer antihyperglycemic in  participants with  hyperglycemia                                                                                                                                                                          | -                          | Monitor participants for  hyperglycemia or other  signs and symptoms of  diabetes. |                                                                                                      |    |                                                                              |
| Hypophysitis                                       | Grade 2                                                                                                                                                                  | Withhold                   | -                                                                                  | Administer  corticosteroids  and initiate  hormonal  replacements as  clinically  indicated.         | -  | Monitor for signs and  symptoms of hypophysitis  (including hypopituitarism  |
| Grade 3 or 4                                       | Withhold or                                                                                                                                                              | and adrenal insufficiency) |                                                                                    |                                                                                                      |    |                                                                              |
| permanently  discontinue1                          |                                                                                                                                                                          |                            |                                                                                    |                                                                                                      |    |                                                                              |
| Hyperthyroidism                                    | Grade 2                                                                                                                                                                  | Continue                   | -                                                                                  | Treat with nonselective betablockers (eg,  propranolol) or  thionamides as  appropriate                                                                                                      | -  | Monitor for signs and  symptoms of thyroid  disorders.                       |
| Grade 3 or 4                                       | Withhold or  permanently  discontinue1                                                                                                                                   |                            |                                                                                    |                                                                                                      |    |                                                                              |
| Hypothyroidism                                     | Grade 2-4                                                                                                                                                                | Continue                   | -                                                                                  | Initiate thyroid  replacement  hormones (eg,  levothyroxine or  liothyroinine) per  standard of care | -  | Monitor for signs and  symptoms of thyroid  disorders.                       |
| Nephritis and Renal                                | Grade 2                                                                                                                                                                  | Withhold                   | -                                                                                  | Administer                                                                                           |    |                                                                              |
| dysfunction                                        | corticosteroids  (prednisone 1-2  mg/kg or  equivalent)  followed by taper.                                                                                              | -                          | Monitor changes of renal  function                                                 |                                                                                                      |    |                                                                              |
| Grade 3 or 4                                       | Permanently  discontinue                                                                                                                                                 |                            |                                                                                    |                                                                                                      |    |                                                                              |
| Myocarditis                                        | Grade 1 or 2                                                                                                                                                             | Withhold                   | -                                                                                  | Based on severity  of AE administer  corticosteroids                                                 | -  | Ensure adequate evaluation  to confirm etiology and/or  exclude other causes |
| Grade 3 or 4                                       | Permanently  discontinue                                                                                                                                                 |                            |                                                                                    |                                                                                                      |    |                                                                              |
| All other immune-related                           | Intolerable/                                                                                                                                                             |                            |                                                                                    |                                                                                                      |    |                                                                              |
| AEs                                                | persistent Grade  2                                                                                                                                                      | -                          | Ensure adequate evaluation  to confirm etiology and/or  exclude other causes       |                                                                                                      |    |                                                                              |
| Grade 3                                            | Withhold or  discontinue based on  the type of event.  Events that require  discontinuation include  and not limited to:  Gullain-Barre  Syndrome,  encephalitisWithhold | -                          | Based on type  and severity of AE  administer  corticosteroids                     |                                                                                                      |    |                                                                              |  
CCCWFU # 88215  
| Comprehensive Cancer Center of Wake Forest University (CCCWFU) CCCWFU # 88215 Grade 4 or  recurrent Grade  3  Permanently  discontinue   |                                                                                                                                                                                                                                                                                                                                                                                                    |
|------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.                                                                                                                                       | Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required,  pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or  achieved metabolic control (in case of T1DM). |
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7.2 paclitaxel

| On day of treatment      | Paclitaxel Modification                                                                                                                                                                                                    |
|--------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ANC < 1000               | Hold paclitaxel for one week. If ANC >1000 the following week, treat at 80  mg/m2. If ANC still <1000, hold for another week and reduce all subsequent  doses to 60 mg/m2.                                                 |
| Platelet < 100,000       | Hold paclitaxel for one week. If platelet > 100K at the following week, reduce  paclitaxel to 60mg/m2 on next and all subsequent doses. If platelets remain  <100K, drop paclitaxel and continue with pembrolizumab alone. |
| Febrile neutropenia      | Hold paclitaxel until episode resolves to grade 1 or below. For next cycle,  reduce paclitaxel to 60 mg/m2. If recurs, drop paclitaxel and continue with  pembrolizumab alone.                                             |
| Neurotoxicity (including | Hold paclitaxel until resolution to Grade 1 or below. If recurs, or not resolved to                                                                                                                                        |
| peripheral neuropathy)   | < Grade 2 after having dose held for two weeks, then continue with  pembrolizumab alone.                                                                                                                                   |
| Other Possibly-Related   | If probably or possibly related to paclitaxel, hold paclitaxel until resolution to                                                                                                                                         |
| Grade 3 AEs              | Grade ≤ 1. If it recurs to Grade 3 or greater, discontinue paclitaxel and continue  with pembrolizumab alone.                                                                                                              |
| All Grade 4 AEs          | All Grade 4 AEs possibly related to paclitaxel should result in discontinuation of  paclitaxel                                                                                                                             |  
Management of acute hypersensitivity will be as per local institutional guidelines.  
Further therapy should be customized depending upon the clinical situation. The clinical tolerance of the patient, the overall tumor response and the medical judgment of the investigator will determine if it is in the patient's best interest to continue or discontinue treatment.  
CCCWFU \# 88215
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8.0 measurement of effect 8.1

Response and progression will be evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.36 While in the treatment phase, the patients will be reevaluated for response prior to cycle 4, prior to cycle 7, and at the end-of-treatment. In addition to a baseline scan, confirmatory scans should also be obtained as per RECIST criteria following initial documentation of objective response.
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8.1.1 definitions

- Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with pembrolizumab
- Inevaluable for objective response: When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at that time point.  
o If only a subset of lesion measurements are made at an assessment, usually the case is also considered NE at that time point, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would not change the assigned time point response. This would most likely happen in the case of PD.  
- Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans have slice thickness >5 mm, the minimum size should be twice the slice thickness);
o 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as nonmeasurable).  
o 20 mm by chest X-ray.  
- Measurable lesions:
o Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness is recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.  
o Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that can be evaluated by crosssectional imaging techniques such as CT or MRI can be considered measurable if the soft tissue component meets the definition of measurability described above.  
o 'Cystic lesions' thought to represent cystic metastases can be considered measurable if they meet the definition of measurability CCCWFU \# 88215 described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions.  
- Non-measurable lesions: Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis), as well as truly non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.  
o Lesions with prior local treatment, such as those situated in a previously irradiated area or in an area subjected to other locoregional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.  
- Target lesions: All measurable lesions up to a maximum of two lesions per organ and five lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline.  
o Target lesions should be selected on the basis of their size (lesions with the longest diameter) and be representative of all involved organs, as well as their suitability for reproducible repeated measurements.  
o All measurements should be recorded in metric notation using calipers if clinically assessed.  
o A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters, which will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. If lymph nodes are to be included in the sum, only the short axis will contribute.  
o Lymph nodes identified as target lesions should always have the actual short axis measurement recorded even if the nodes regress to below 10 mm on study. When lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if complete response criteria are met since a normal lymph node is defined as having a short axis of <10 mm.  
o Target lesions that become 'too small to measure': While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even when very small. However, sometimes lesions or lymph nodes become so faint on a CT scan that the radiologist may not feel comfortable assigning an exact measure and may report them as being 'too small to measure', in which case a default value of 5 mm should be assigned.  
o Lesions that split or coalesce on treatment: When non-nodal lesions
'fragment', the longest diameters of the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter measurements of each  
CCCWFU \# 88215 individual lesion. If the lesions have truly coalesced such that they are no longer separable, the vector of the longest diameter in this instance should be the maximal longest diameter for the 'coalesced lesion'.  
- Non-target lesions: All lesions (or sites of disease) not identified as target lesions, including pathological lymph nodes and all non-measurable lesions, should be identified as non-target lesions and be recorded at baseline. Measurements of these lesions are not required and they should be followed as 'present', 'absent' or in rare cases, 'unequivocal progression'.
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8.1.2 methods for evaluation of

The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. While either CT or MRI may be utilized, as per RECIST 1.1, CT
is the preferred imaging technique in this study.
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8.1.3 response criteria

- Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
- Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters
- Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this may include the baseline sum). The sum must also demonstrate an absolute increase of at least 5 mm.  
- Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
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8.1.4 evaluation of non-target lesions

- Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be nonpathological in size (<10 mm short axis).  
- Non-CR / Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker levels above normal limits.  
- Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
o When patient has measurable disease: To achieve 'unequivocal progression' on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A  
CCCWFU \# 88215 modest 'increase' in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status.  
o When patient has only non-measurable disease: There is no measurable disease assessment to factor into the interpretation of an increase in non-measurable disease burden. Because worsening in non-target disease cannot be easily quantified, a useful test that can be applied is to consider if the increase in overall disease burden based on change in non-measurable disease is comparable in magnitude to the increase that would be required to declare PD for measurable disease. Examples include an increase in a pleural effusion from 'trace' to 'large' or an increase in lymphangitic disease from localized to widespread.  
- New lesions: The appearance of new malignant lesions denotes disease progression.  
o The finding of a new lesion should be unequivocal (i.e., not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor, especially when the patient's baseline lesions show partial or complete response).  
o If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan.  
o A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and disease progression.  
o It is sometimes reasonable to incorporate the use of FDG-PET
scanning to complement CT in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is PD based on a new lesion.  
No FDG-PET at baseline and a positive FDG-PET at follow-up:
- If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  
- If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
- If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
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8.1.5 evaluation of best overall

Table 1 provides a summary of the overall response status calculation at each time point for patients who have measurable disease at baseline.  
CCCWFU \# 88215  
| Table 1. Overall response for patients with target (± non-target) disease Target Lesions Non-Target Lesions New Lesions   | Overall Response            |           |    |
|---------------------------------------------------------------------------------------------------------------------------|-----------------------------|-----------|----|
| CR                                                                                                                        | CR                          | No        | CR |
| CR                                                                                                                        | Non-CR/Non-PD               | No        | PR |
| CR                                                                                                                        | NE                          | No        | PR |
| PR                                                                                                                        | Non-PD or not all evaluated | No        | PR |
| SD                                                                                                                        | Non-PD or not all evaluated | No        | SD |
| Not all evaluate                                                                                                          | Non-PD                      | No        | NE |
| PD                                                                                                                        | Any                         | Yes or No | PD |
| Any                                                                                                                       | PD                          | Yes or No | PD |
| Any                                                                                                                       | Any                         | Yes       | PD |
| CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive  Disease, NE = Inevaluable           |                             |           |    |  
When patients have non-measurable (therefore non-target) disease only, Table 2 should be used.  
| Table 2. Overall response for patients with non-target disease Non-Target Lesions New Lesions                                                              | Overall Response   |                |
|------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|----------------|
| CR                                                                                                                                                         | No                 | CR             |
| Non-CR/Non-PD                                                                                                                                              | No                 | Non-CR/Non-PD1 |
| Not all evaluated                                                                                                                                          | No                 | NE             |
| Unequivocal PD                                                                                                                                             | Yes or No          | PD             |
| Any                                                                                                                                                        | Yes                | PD             |
| CR = Complete Response, PD = Progressive Disease, NE = Inevaluable 1 Non-CR / non-PD is preferred over 'Stable Disease' for non-target disease since SD is |                    |                |
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8.1.6 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded)
until the first date that recurrent or progressive disease is objectively documented
(taking as reference for progressive disease the smallest measurements recorded on study). The duration of overall complete response is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.  
Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.  
CCCWFU \# 88215
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8.1.7 survival outcomes

Progression-Free Survival is defined as the duration of time from the start of treatment to the time of progression, death, or date of last contact.  
Overall Survival is defined as the duration of time from the start of treatment to date of death or date of last contact.
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8.1.8 response review

For trials where the response rate is the primary endpoint, it is strongly recommended that all responses be reviewed by an expert(s) independent of the study at the study's completion. Simultaneous review of the patients' files and radiological images is the best approach.
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9.0 adverse events list and

An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Merck's product, is also an adverse event.  
Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels are not to be considered adverse events. Examples of this may include, but are not limited to, teething, typical crying in infants and children and onset of menses or menopause occurring at a physiologically appropriate time.  
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent or protocol-specified procedure, whether investigational
(including placebo or active comparator medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for human use.  
Adverse events may occur during the course of the use of Merck product in clinical trials or within the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.  
CCCWFU \# 88215 Adverse events may also occur in screened subjects during any pre-allocation baseline period as a result of a protocol-specified intervention, including washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Progression of the cancer under study is not considered an adverse event unless it is considered to be drug related by the investigator.  
All adverse events will be recorded from the time the consent form is signed through 30 days following cessation of treatment and at each examination on the Adverse Event case report forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is described in section 9.5.  
| System Organ Class                           | Adverse Event Term                                                                                                   |
|----------------------------------------------|----------------------------------------------------------------------------------------------------------------------|
| Blood and lymphatic system disorders         | Anemia                                                                                                               |
| Endocrine disorders                          | Hyperthyroidism, hypophysitis,  hypopituitarism, hypothyroidism,  secondary adrenal insufficiency,  thyroid disorder |
| Eye disorders                                | Uveitis                                                                                                              |
| Gastrointestinal disorders                   | Abdominal pain, colitis, constipation,  diarrhea, nausea, pancreatitis,  vomiting                                    |
| General disorders and administration         | Asthenia, fatigue, peripheral edema,                                                                                 |
| site conditions                              | pyrexia                                                                                                              |
| Hepatobiliary disorders                      | Hepatitis                                                                                                            |
| Injury, poisoning and procedural             | Infusion related reaction                                                                                            |
| complications Metabolism and nutrition       | Decreased appetite, diabetic                                                                                         |
| complications                                | ketoacidosis, hyponatremia, Type 1  diabetes mellitus                                                                |
| Musculoskeletal and connective               | Arthralgia, back pain, myositis                                                                                      |
| tissue disorders Renal and urinary disorders | Nephritis                                                                                                            |
| Respiratory, thoracic and mediastinal        | Cough, dyspnea, pneumonitis                                                                                          |
| disorders Skin and subcutaneous tissue       | Pruritus, rash, severe skin reactions                                                                                |
| disorders                                    |                                                                                                                      |  
Adverse reactions considered expected for pembrolizumab include:
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9.1.1 serious adverse events

A serious adverse event is any adverse event occurring at any dose or during any use of Merck's product that:
- Results in death;
- Is life threatening; - Results in persistent or significant disability/incapacity; CCCWFU \# 88215  
- Results in or prolongs an existing inpatient hospitalization; - Is a congenital anomaly/birth defect;
- Is a new cancer (that is not a condition of the study); - Is associated with an overdose;
- Is another important medical event
Refer to the table in section 9.1.4 below for additional details regarding each of the above criteria. In the pembrolizumab monotherapy trials, the most commonly reported DRSAEs (those that occurred in 3 or more subjects overall in at least 1 study) were pneumonitis (range of 0.7% to 1.3% of subjects); colitis (range of 0.3% to 1.1% of subjects), pyrexia (range of 0.3% to 0.5% of subjects);
diarrhea (range of 0.2% to 0.4%); hepatitis (0.7% of subjects); nausea, adrenal insufficiency, hyponatremia, hyperthyroidism, hypophysitis, vomiting, and dyspnea (0.3% of subjects each); and dehydration, generalized edema, hypothyroidism, renal failure acute, and pericardial effusion (0.2% of subjects each). The remaining DRSAEs occurred in 1 or 2 subjects each per study.  
In the combination therapy trials, all DRSAEs were reported in 1 subject each. In P021, 8 subjects experienced DRSAEs; the DRSAEs were as follows: anemia, febrile neutropenia, atrial fibrillation, colitis, pyrexia, hypersensitivity, alanine aminotransferase increased, aspartate aminotransferase increased, drug eruption, rash, and urticaria. In P023, 2 subjects experienced DRSAEs; 1 subject had an event of pneumonia and the other had an event of tumor lysis syndrome.
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9.1.2 events of clinical interest

Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)Events of clinical interest for this trial include:
1. an overdose of Merck product, as defined in Section 9.1.3, that is not associated with clinical symptoms or abnormal laboratory results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to specify a threshold of abnormal  
CCCWFU \# 88215 hepatic tests that may require an additional evaluation for an underlying etiology. The trial site guidance for assessment and follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent).
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additional adverse events

A separate guidance document has been provided entitled "Event of Clinical Interest Guidance Document." This document can be found in the Investigator Trial File Binder (or equivalent) and provides guidance regarding identification, evaluation and management of ECIs.  
ECIs (both non-serious and serious adverse events) identified in this guidance document from the date of first dose through 90 days following cessation of treatment, or 30 days after the initiation of a new anticancer therapy, whichever is earlier, need to 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), regardless of attribution to study treatment, consistent with standard SAE reporting guidelines.  
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be evaluated and subjects should be asked for signs and symptoms suggestive of an immune-related event. Subjects who develop an ECI thought to be immune-related should have additional testing to rule out other etiologic causes. If lab results or symptoms indicate a possible immune-related ECI, then additional testing should be performed to rule out other etiologic causes. If no other cause is found, then it is assumed to be immune-related.
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9.1.3 definition of an overdose

For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times the indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. If an adverse event(s) is associated with ("results from") the overdose of a Merck product, the adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met.  
If a dose of Merck's product meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest  
CCCWFU \# 88215
(ECI), using the terminology "accidental or intentional overdose without adverse effect."
All reports of overdose with and without an adverse event must be reported within 24 hours to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)