Clinical trial NCT02581982
Conditions: Transitional Cell Carcinoma
Keywords: Urothelial cancer Bladder cancer Immunotherapy Paclitaxel
Sponsor: Wake Forest University Health Sciences
Start date: 2016-04-06; Completion date: 2022-12-19
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well paclitaxel and pembrolizumab works in treating patients with urothelial cancer that has not responded to previous treatment and has spread to other places in the body. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving paclitaxel together with pembrolizumab may be an effective treatment for urothelial cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the overall response rate (ORR) of pembrolizumab combined with paclitaxel.

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab combined with paclitaxel.

II. To calculate the progression-free survival (PFS) rate at 6 months.

TERTIARY OBJECTIVES:

I. To determine the immune effects of pembrolizumab combined with paclitaxel. II. To associate immune effects with tumor response. III. To explore changes in immune-regulatory micro ribonucleic acids (RNAs) as biomarkers of response.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and paclitaxel IV over 60 minutes on day 1 and 8. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days and then every 3 months for 1 year.

Arms: arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1 and paclitaxel IV over 60 minutes on day 1 and 8. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Paclitaxel intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
 
 
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 platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 2 of 85 
 
Table of Contents 
SCHEMA ................................................................................................................................... 5 
1.0 
Introduction and Background .......................................................................................... 5 
1.1 
Rationale for current study .......................................................................................... 6 
1.2 
Rationale for Dose Selection/Regimen/Modification ................................................... 7 
2.0 
Hypothesis and Objectives ............................................................................................. 9 
2.1 
Primary Objective ....................................................................................................... 9 
2.2 
Secondary Objectives ................................................................................................. 9 
2.3 
Correlative Objectives ................................................................................................. 9 
3.0 
Patient Selection ............................................................................................................ 9 
3.1 
Inclusion Criteria ......................................................................................................... 9 
3.2 
Exclusion Criteria .......................................................................................................11 
3.3 
Inclusion of Women and Minorities ............................................................................12 
4.0 
Registration Procedures ................................................................................................13 
5.0 
Study Outcomes and Study Measures...........................................................................13 
5.1 
Primary Outcome .......................................................................................................13 
5.2 
Secondary Outcomes ................................................................................................13 
5.3 
Correlative Outcomes ................................................................................................13 
6.0 
Treatment Plan ..............................................................................................................14 
6.1 
Study schema ............................................................................................................14 
6.2 
Study-Related Activities .............................................................................................14 
6.2.1 
Informed Consent ................................................................................................17 
6.2.2 
Inclusion/Exclusion Criteria ..................................................................................17 
6.2.3 
Medical History ....................................................................................................17 
6.2.4 
Prior and Concomitant Medications Review .........................................................18 
6.2.5 
Disease Details and Treatments ..........................................................................18 
6.2.6 
Adverse Event (AE) Monitoring ............................................................................18 
6.2.7 
Physical Exam .....................................................................................................19 
6.2.8 
Laboratory Procedures/Assessments ..................................................................19 
6.3 
Treatment Administration ...........................................................................................19 
6.4 
General Concomitant Medication and Supportive Care Guidelines ............................21 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 3 of 85 
6.4.1 
Acceptable Concomitant Medications ..................................................................21 
6.4.2 
Prohibited Concomitant Medications ....................................................................21 
6.4.3 
Supportive Care Guidelines .................................................................................22 
6.5 
Other Considerations .................................................................................................33 
6.5.1 
Contraception ......................................................................................................33 
6.5.2 
Use in Pregnancy ................................................................................................34 
6.5.3 
Use in Nursing Women ........................................................................................34 
6.6 
Duration of Therapy ...................................................................................................34 
6.7 
Post-treatment Visits..................................................................................................35 
6.7.1 
Safety Follow-up Visit (End-of-treatment visit)......................................................35 
6.7.2  Follow Up .................................................................................................................36 
7.0 
Dosing Delays/Dose Modifications ................................................................................36 
7.1  Pembrolizumab ...............................................................................................................36 
7.2   Paclitaxel...........................................................................................................................39 
8.0 
Measurement of Effect ..................................................................................................40 
8.1 
Antitumor Effect .........................................................................................................40 
8.1.1 
Definitions ............................................................................................................40 
8.1.2 
Methods for Evaluation of Measurable Disease ...................................................42 
8.1.3 
Response Criteria ................................................................................................42 
8.1.4 
Evaluation of Non-Target Lesions ........................................................................42 
8.1.5 
Evaluation of Best Overall Response ...................................................................43 
8.1.6 
Duration of Response ..........................................................................................44 
8.1.7 
Survival Outcomes ...............................................................................................45 
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 
9.1.3 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ........................................................................................................48 
9.1.4 
Merck Requirements for Evaluating Adverse Events ............................................49 
9.2 
Adverse Event Characteristics ...................................................................................50 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 4 of 85 
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 platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 5 of 85 
SCHEMA 
 
 
This will be a single-arm, open label, phase 2 study with the following schema: 
 
 
 
 
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 T-
cell is inactivated.  Both tumor cells and tumor-associated lymphocytes may express PD-
L1 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.   
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 6 of 85 
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 anti-
PD-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.   
 
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 PD-
1 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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 7 of 85 
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. 
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. 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 8 of 85 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 9 of 85 
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.   
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. 
2.1 
Primary Objective 
 
2.1.1 To estimate the overall response rate (ORR) of pembrolizumab combined 
with paclitaxel  
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 
 
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 
3.0 
Patient Selection 
 
3.1 
Inclusion Criteria  
 
3.1.1 Patients diagnosed with platinum-refractory metastatic urothelial cancer 
that is measureable based on Response Evaluation Criteria in Solid 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 10 of 85 
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. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 11 of 85 
3.1.10 Ability to understand and the willingness to sign an IRB-approved informed 
consent document. 
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.   
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 12 of 85 
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., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
3.3 
Inclusion of Women and Minorities 
 
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. 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 13 of 85 
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. 
 
 
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 
5.0 
Study Outcomes and Study Measures 
5.1 
Primary Outcome 
 
5.1.1 The primary outcome measure will be overall response rate. 
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 
 
5.3 
Correlative Outcomes 
 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 14 of 85 
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 
6.0 
Treatment Plan 
 
6.1 
Study schema  
 
 
 
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.  
 
 
 
 
TRIAL FLOW CHART 
 
 
Procedure 
Screeninga 
 
TREATMENT PHASE 
(UP TO 6 MONTHS) 
 
21 day cycle 
(+/- 3 days) 
 
MAINTENANCE PHASE 
(UP TO 18 MONTHS) 
 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 15 of 85 
Within 14 days of 
dosing 
Day 
1 
Day 
8 
End of 
Treatment 
Visitb 
Treatment  
 21 day cyclec  
(+/- 10 days) 
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 
 
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 
 
 
 
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.   
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 16 of 85 
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.  
    


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 17 of 85 
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. 
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.   


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 18 of 85 
6.2.4 
Prior and Concomitant Medications Review 
 
Prior 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.  
 
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. 
6.2.5 Disease Details and Treatments 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.  
 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments 
including systemic treatments, radiation and surgeries. 
 
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 anti-
cancer therapy has been initiated the subject will move into survival follow-up.  
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.   


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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.   
 
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. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
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.   
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. 
6.3 
Treatment Administration 
 
 
REGIMEN DESCRIPTION 
 
Agent 
 
Premedications 
 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Pembrolizumab 
 
200 mg  
30-minute IV 
infusion 
Day 1 
21 days 
Paclitaxel 
Premedicate with 
ondansetron 8 
mg IV or po , 
dexamethasone 
10 mg IV or po, 
diphenhydramine 
80 mg/m2 
60-minute IV 
infusion 
Days 1 
and 8 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 20 of 85 
25 mg IV or po, 
and ranitidine 
50mg IV or po 
(or equivalent H2 
blocker) 30-60 
minutes pre-
treatment.* 
*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. 
 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 21 of 85 
 
6.4 
General 
Concomitant 
Medication 
and 
Supportive 
Care 
Guidelines 
 
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.  
 
 
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. 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 22 of 85 
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. 
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 anti-
inflammatory 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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 23 of 85 
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 re-
challenge the patient develops a second episode of Grade 2 or higher 
pneumonitis. 
 
o For Grade 3-4 events:  
– Discontinue pembrolizumab. 
– 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. 
. 
 
• 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 24 of 85 
– 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. 
 
o For Grade 2 events: 
– Hold pembrolizumab. 
– 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 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.   
 
 
 
• 
Endocrine:  


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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 
 
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: 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 26 of 85 
– 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. 
 
o Type 1 diabetes mellitus (new onset) and ≥ Grade 3 Hyperglycemia 
 
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. 
 
T1DM should be immediately treated with insulin. 
T1DM or Grade 3-4 Hyperglycemia events: 
- Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-
4 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, IA-
2, ZnT8, and insulin may be obtained. 
 
 
• 
Hepatic:  
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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o Grade 4 events: 
– Permanently discontinue pembrolizumab 
– Manage patient as per Grade 3 above 
 
• 
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. 
 
• 
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, 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 29 of 85 
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 
 
 
• 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 30 of 85 
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. 
 
• 
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. 
 
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. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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– 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 
signs as medically indicated 
None 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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 (MK-
3475) 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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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. 
 
 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 34 of 85 
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. 
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. 
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 breast-
feeding are not eligible for enrollment. 
6.6 
Duration of Therapy 
 
TREATMENT PHASE: 
 
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, 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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• 
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.   
 
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. 
 
 
6.7 
Post-treatment Visits 
 
 
6.7.1 Safety Follow-up Visit (End-of-treatment visit) 
 
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.    


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 36 of 85 
 
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 anti-
neoplastic 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.  . 
7.0 
Dosing Delays/Dose Modifications 
 
 
7.1  Pembrolizumab 
 
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. 
 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 37 of 85 
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. 
 
Immune-related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
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 
Increased bilirubin 
Grade 2 
Withhold 
• 
Administer 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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Immune-related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
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 β-
cell failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
• Administer anti-
hyperglycemic 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 
and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-
selective beta-
blockers (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 
dysfunction 
Grade 2 
Withhold  
• 
Administer 
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 
AEs 
Intolerable/ 
persistent Grade 
2 
Withhold 
• 
Based on type 
and severity of AE 
administer 
corticosteroids  
• 
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, 
encephalitis 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
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Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
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).   
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 
peripheral neuropathy)  
Hold paclitaxel until resolution to Grade 1 or below.  If recurs, or not resolved to 
< Grade 2 after having dose held for two weeks, then continue with 
pembrolizumab alone.   
Other Possibly-Related 
Grade 3 AEs 
If probably or possibly related to paclitaxel, hold paclitaxel until resolution to 
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. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
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Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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8.0 
Measurement of Effect 
8.1 
Antitumor Effect 
 
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. 
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 non-
measurable). 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
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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 loco-
regional 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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
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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’. 
8.1.2 Methods for Evaluation of Measurable Disease 
 
 
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. 
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. 
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 non-
pathological 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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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. 
8.1.5 Evaluation of Best Overall Response 
 
Table 1 provides a summary of the overall response status calculation at each time 
point for patients who have measurable disease at baseline. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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 
increasingly used as an endpoint for assessment of efficacy in some trials. To assign this 
category when no lesions can be measured is not advised. 
 
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.  


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
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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. 
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.  
9.0 
Adverse Events List and Reporting Requirements 
9.1 
Assessing and Recording Adverse Events 
 
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. 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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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. 
 
Adverse reactions considered expected for pembrolizumab include: 
 
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 
site conditions 
Asthenia, fatigue, peripheral edema, 
pyrexia 
Hepatobiliary disorders 
Hepatitis 
Injury, poisoning and procedural 
complications 
Infusion related reaction 
Metabolism and nutrition 
complications 
Decreased appetite, diabetic 
ketoacidosis, hyponatremia, Type 1 
diabetes mellitus 
Musculoskeletal and connective 
tissue disorders 
Arthralgia, back pain, myositis 
Renal and urinary disorders 
Nephritis 
Respiratory, thoracic and mediastinal 
disorders 
Cough, dyspnea, pneumonitis 
Skin and subcutaneous tissue 
disorders 
Pruritus, rash, severe skin reactions 
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; 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
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Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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• 
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. 
 
 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
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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). 
 
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. 
 
9.1.3 Definition of an Overdose for This Protocol and Reporting 
of Overdose to the Sponsor and to Merck 
 
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 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
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Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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(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) 
9.1.4 Merck Requirements for Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events 
according to the NCI Common Terminology for Adverse Events (CTCAE), 
version 4.0. Any adverse event which changes CTCAE grade over the 
course of a given episode will have each change of grade recorded on the 
adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness. 
 
An investigator who is a qualified physician, will evaluate all adverse events 
as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event 
as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have 
caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not 
worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a 
serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of 
clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and 
units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused 
the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing 
the likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to 
Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug 
trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or 
(2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS 
SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF 
REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE 
BY THE U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL. 
 
Consistency 
with 
Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the 
Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician 
according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of 
a Merck product relationship). 
Yes, there is a reasonable 
possibility 
of 
Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative 
to the administration of the Merck product is reasonable.  The AE is more likely explained by the 
Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the AE.  
(Also entered for a subject with overdose without an associated AE.) 
 
9.2 
Adverse Event Characteristics 
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. A 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.   
 
• 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
9.3 
STRC SAE Reporting Requirements 
 
The Safety and Toxicity Reporting Committee (STRC) is responsible for reviewing SAEs 
for CCCWFU Institutional studies as outlined in Appendix B. STRC currently requires that 
all unexpected 4 and all grade 5 SAEs on these trials be reported to them for review. All 
CCCWFU Clinical Research Management (CRM) staff members assisting a Principal 
Investigator in investigating, documenting and reporting an SAE qualifying for STRC 
reporting are responsible for informing a clinical member of the STRC as well as the entire 
committee via the email notification procedure of the occurrence of an SAE.  
9.4  
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse events shall 
be promptly reported to the IRB, according to institutional policy. Reporting to the IRB is 
required regardless of the funding source, study sponsor, or whether the event involves 
an investigational or marketed drug, biologic or device. Reportable events are not limited 
to physical injury, but include psychological, economic and social harm. Reportable events 
may arise as a result of drugs, biological agents, devices, procedures or other 
interventions, or as a result of questionnaires, surveys, observations or other interactions 
with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the IRB 
and other applicable parties of unanticipated problems involving risk to subjects or others. 
The Principal Investigator, however, is ultimately responsible for ensuring the prompt 
reporting of unanticipated problems involving risk to subjects or others to the IRB. The 
Principal Investigator is also responsible for ensuring that all reported unanticipated risks 
to subjects and others which they receive are reviewed to determine whether the report 
represents a change in the risks and/or benefits to study participants, and whether any 
changes in the informed consent, protocol or other study-related documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site where 
the study has been approved by the WFUHS IRB (internal events) must be reported to the 
WFUHS IRB within 7 calendar days of the investigator or other members of the study team 
becoming aware of the event. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFUHS IRB (external events) 
must be reported to the WFUHS IRB within 7 calendar days of the investigator or other 
members of the study team becoming aware of the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential benefit of 
the research and as a result warrants a substantive change in the research protocol or 
informed consent process/document in order to insure the safety, rights or welfare of 
research subjects. 
9.5 
Merck Reporting Requirements  
9.5.1 Reporting of Pregnancy and Lactation to the Sponsor and 
to Merck 
 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them), including the pregnancy of 
a male subject's female partner that occurs during the trial or within 120 days of 
completing the trial completing the trial, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier.  All subjects 
and female partners of male subjects who become pregnant must be followed to 
the completion/termination of the pregnancy.  Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, the 
outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
9.5.2 Reporting of SAEs and Events of Clinical Interest 
 
 
 
Any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer 
under study that occurs to any subject from the time the consent is signed 
through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety.  
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global 
Safety and will be handled in the same manner as SAEs.  
 
Additionally, any serious adverse event, considered by an investigator who 
is a qualified physician to be related to Merck product that is brought to the 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
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attention of the investigator at any time outside of the time period specified 
in the previous paragraph also must be reported immediately to the 
Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be 
forwarded to the Merck Global Safety facsimile number:  +1-215-993-
1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA, European Union (EU), Pharmaceutical and Medical 
Devices agency (PMDA) or other local regulators. Investigators will cross 
reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of 
submission.  Additionally investigators will submit a copy of these reports 
to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
at the time of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
10.0 Pharmaceutical Information 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 9.0. 
 
10.1 Pharmaceutical Accountability 
 
Drug accountability logs will be maintained for all investigative agents used under 
this protocol. These logs shall record quantities of study drug received and 
quantities dispensed to patients, including lot number, date dispensed, patient 
identifier number, patient initials, protocol number, dose, quantity returned, 
balance remaining, and the initials of the person dispensing the medication.  
10.2 Pembrolizumab  
 
 
 
Clinical Supplies will be provided by Merck as summarized below. 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 
and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not 
provided. 
 
Marketed Packs: When Study Drug is provided in the marketed package, Merck 
will not supply any Chemistry, Manufacturing, Control (CMC) information. 
Institution’s regulatory submission should reference the Merck Marketing 
Authorization. If any additional labelling of containers is required, e.g. to add 
Study Protocol number, and it has not been agreed for Merck to perform the 
additional labelling, it is Institution’s responsibility to arrange for this action to be 
done in accordance with U.S. regulations. 
 
Storage and Handling Requirements 
The lyophilized drug product after reconstitution with sterile water for injection, and 
the liquid drug product are a clear to opalescent solutions, essentially free of visible 
particles. The reconstituted lyophilized product and the liquid product are intended 
for IV administration. The reconstituted drug product solution or the liquid drug 
product can be further diluted with normal saline or 5% dextrose in the 
concentration range of 1 to 10 mg/mL in intravenous (IV) containers made of 
polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be 
immediately used to prepare the infusion solution in the IV bag and the infusion 
solution should be immediately administered. Diluted pembrolizumab solutions 
may be stored at room temperature for a cumulative time of up to 4 hours. This 
includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion. In addition, IV bags can be stored at 2 to 8°C for up to a 
cumulative time of 20 hours. This recommendation is based on up to 24 hours of 
room temperature and up to 24 hours of refrigerated stability data of diluted MK-
3475 solutions in the IV bags. 
 
Clinical supplies must be stored in a secure, limited-access location. The drug 
product is to be stored as a stable lyophilized powder or liquid solution under 
refrigerated conditions (2 to 8°C). 
 
Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. Clinical supplies may not be used for any purpose other 
than that stated in the protocol. 
 
Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the 
subjects and the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
10.3 Paclitaxel  
 
 
Product description:  Supplied as: 
 
NDC 0015-3475-30 30 mg/5 mL multidose vial individually packaged in a 
carton 
NDC 0015-3476-30 100 mg/16.7 mL multidose vial individually packaged in a 
carton 
NDC 0015-3479-11 300 mg/50 mL multidose vial individually packaged in a 
carton 
 
Solution preparation:  Paclitaxel Injection must be diluted prior to infusion. 
Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose 
Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% 
Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. Upon 
preparation, solutions may show haziness, which is attributed to the formulation 
vehicle. Paclitaxel solutions should be prepared and stored in glass, 
polypropylene, or polyolefin containers. Non-PVC containing administration sets, 
such as those which are polyethylene-lined, should be used. 
 
Storage requirements:  Store the vials in original cartons between 20°–25° C 
(68°–77° F). Retain in the original package to protect from light. 
 
Stability:  Unopened vials of paclitaxel injection are stable until the date indicated 
on the package when stored between 20°–25° C (68°–77° F), in the original 
package. Neither freezing nor refrigeration adversely affects the stability of the 
product. Upon refrigeration, components in the paclitaxel vial may precipitate, but 
will redissolve upon reaching room temperature with little or no agitation. There is 
no impact on product quality under these circumstances. If the solution remains 
cloudy or if an insoluble precipitate is noted, the vial should be discarded. Prepared 
solutions are physically and chemically stable for up to 27 hours at ambient 
temperature (approximately 25° C) and room lighting conditions. 
 
Route of administration:  Paclitaxel should be administered as an intravenous 
infusion through an in-line filter with a microporous membrane not greater than 
0.22 microns. Monitor infusion site for possible infiltration during drug 
administration.  
 
Disposal:  To minimize the risk of dermal exposure, always wear impervious 
gloves when handling vials containing paclitaxel Injection. If paclitaxel solution 
contacts the skin, wash the skin immediately and thoroughly with soap and water. 
Following topical exposure, events have included tingling, burning, and redness. If 
paclitaxel contacts mucous membranes, the membranes should be flushed 


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Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
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thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore 
throat, and nausea have been reported. 
11.0 Correlative/Special Studies 
 
11.1 Laboratory Correlative Studies 
 
 
Peripheral blood will be obtained from each patient prior to initiation of treatment,  
on cycle 4 day 1, cycle 8 day 1, and at the end-of-treatment visit.    A total of six 
(6)  
10mL EDTA tubes will be drawn at each time point.   
 
Changes from baseline and in responding versus nonresponding patients will be 
assessed.   
 
(1) Activated T-cells: The goal is to calculate the number and percentage of 
IFNγ+CD8+ T cells in peripheral blood pre-, on-, and post-treatment. 
i. Sample collection.  Peripheral blood will be obtained from each patient prior 
to initiation of treatment, on cycle 4 day 1, cycle 8 day 1, and at the end-of-
treatment visit.  The lymphocyte fraction will be isolated on a Percoll 
gradient.   
ii. T-cell processing.  Cells will be stimulated overnight with plate-bound anti-
CD3 (1ug/mL) and soluble anti-CD28 (1ug/mL) in the presence of protein 
transport inhibitors Brefeldin A and monensin.  Following stimulation, cells 
will be stained with anti-CD8-FITC antibody, fixed and permeabilized using 
the BD Cytofix/Cytoperm staining kit.  Following permeabilization the cells 
will be stained with anti-IFNg, anti-IL-12, anti-IL2. Stained cells will be run 
on a FACS Canto and analyzed using manufacturer provided software. The 
proportion of IFNg+CD8+ T cells will be quantified, with expression of IL-
12 considered further evidence of activated effector function. 
 
(2) MDSC and Tregs:   The goal is to determine whether combination treatment 
changes the number and proportion of MDSC and Tregs in peripheral blood. 
i. Sample collection.  Peripheral blood will be obtained from each patient prior 
to initiation of treatment, on cycle 4 day 1, cycle 8 day 1, and at the end-of-
treatment visit.  The lymphocyte fraction will be isolated on a Percoll 
gradient.   
ii. MDSC and T-reg processing.  Tregs will be quantified using the human 
Treg staining kit (eBioscience) and established methods. 
 
(3) MicroRNAs:  The goal is to explore changes in circulating and urinary immune-
regulatory microRNAs during treatment, using quantitative real time PCR. 
i. Sample collection. Blood and urine will be collected each patient prior to 
initiation of treatment, on cycle 4 day 1, cycle 8 day 1, and at the end-of-
treatment visit.  10 mL of blood will be drawn into EDTA tubes.  Peripheral 
blood mononuclear cells (PBMC) and plasma will be separated by gradient 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
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Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
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centrifugation.  Urine is centrifuged at 1000 g for 10 minutes to pellet 
cellular debris. All samples are aliquoted and stored at −80°C until further 
use.  
ii. miRs processing. Total RNA will be isolated from plasma and urine using 
the miRNeasy Mini Kit (Qiagen) collected pre-, on-, and post-therapy.    
Pools of plasma samples collected from healthy donors will be tested as 
controls.  Plasma levels of selected miRs will be measured with qRT-PCR, 
normalized to spiked-in synthetic miR, in all patients pre- and post-therapy.  
Reverse transcription reactions are performed using a TaqMan MicroRNA 
Reverse Transcription Kit (Applied Biosystems) according to the 
manufacturer’s instructions. qRT-PCR will be performed using the reverse 
transcription reaction product, TaqMan MicroRNA Assay kits, and TaqMan 
Universal PCR Master Mix (Applied Biosystems. The ΔΔCT method is used 
to determine relative levels (RQ).  Data are normalized to a C. elegans 
synthetic miR sequence, cel-miR-39 (Qiagen), which is spiked in as a 
control during RNA isolation. 
 
11.2 Pathology Correlative Studies 
 
When feasible, a metastatic biopsy will be performed.  Archived tumor TURBT and  
cystectomy specimens will also be accessed.  The goal will be to determine PD-L1  
expression and to analyze cytotoxic T-cell number and function, MDSC, and Treg cells  
in tumor tissue. 
 
(1) Tumor PD-L1 expression:  Biopsy samples will be stored and batched for PD-L1 
immunohistochemistry.  This will be done with QualTek per Merck’s guidelines.  Five 
(5) unstained slides per patient, cut from a formalin-fixed, paraffin-embedded (FFPE) 
tissue block, will be sent to QualTek for PD-L1 staining.   Positively charged ProbeOn 
Plus slides must be used for tissue sections.  Samples may be held as blocks 
indefinitely at the site and then cut in batches. Slides must be shipped to QualTek 
immediately after sectioning to comply with the protocol’s testing requirements.  
Sectioned slides must be shipped cold (2-8°C) and in the dark using the shipping 
materials provided by QualTek.  Sectioned slides provided should contain tumor 
specimen sufficient for pathology review and analysis of tumor sample. If available, 
greater than 50% tumor content is preferred.  Fine-needle aspiration, brushing, cell 
pellet from pleural effusion, bone metastases, lavage specimen, frozen sample, plastic 
embedded sample, or formalin fixed sample that was frozen at any point will not be 
accepted for IHC analysis. Needle core biopsies that are formalin-fixed and paraffin-
embedded are acceptable.  The slides will be evaluated by a Qualtek-associated 
pathologist for review of biomarker staining expression levels. 
 
(2) Tumor immune cells:  Cytotoxic T-cell number and function, MDSC, and Treg cells 
in tumor tissue will be evaluated in both archival tissue and in fresh biopsy specimens. 
Tumor tissue will be digested with DNase and Collagenase using standard protocols, 
and CD8+ T cells will be isolated by flow sorting. Sorted T cells will be stimulated with 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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anti-CD3/anti-CD28, and expression of IFNg and IL-12 will be quantified by flow 
cytometry to determine proportion of functional T-cells.  For detection of Tregs in 
biopsy samples, CD4+CD25+ T cells will be isolated by flow sorting, and post-stained 
for FoxP3.  To detect MDSC, Gr+ and CD11b+ cells will be sorted and confirmed by 
Wright-Giemsa staining of sorted cells.  Concordance of immune cell frequency 
between archival and fresh specimens and the peripheral blood from the same patient 
will be informative.  
12.0 Data Management 
 
 
Informed consent document 
ORIS 
Protocol registration form 
ORIS 
Adverse Events 
ORIS 
Baseline Data Collection Form 
REDCap 
Follow-Up Data Collection Form 
REDCap 
Treatment Evaluation Response Form 
REDCap 
13.0 Statistical Considerations 
 
13.1 Power, Sample Size and Accrual Rate 
 
Simon's minimax two-stage design37 will be used. The null hypothesis that the true 
response rate is 24% will be tested against a one-sided alternative. In the first 
stage, 15 patients will be accrued. If there are 3 or fewer responses in these 15 
patients, the study will be stopped. Otherwise, 12 additional patients will be 
accrued for a total of 27. The null hypothesis will be rejected if 10 or more 
responses are observed in 27 patients. This design yields a type I error rate of .09 
and power of 90% when the true response rate is 48%.   We anticipate an accrual 
rate of 1-2 patients per month or 12-24 patients per year.   
13.2 Analysis of Primary Objective 
 
The primary endpoint will be overall response rate.  The analysis will be 
performed in all patients that are evaluable for efficacy and will have one interim 
analysis.  In this phase 2 trial, we will calculate the overall response rate (primary 
outcome) and 6-month PFS.   For the overall response rate, if 10 or more 
responses are observed in the 27 patients, we will reject the null hypothesis that 
the response rate is 24% or less. 
 
13.3 Analysis of Secondary Objectives 
 
The secondary endpoints include PFS and safety. We will estimate PFS at 6-
months using the Kaplan-Meier method on all evaluable patients. All AEs will be 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 59 of 85 
tabulated and presented by preferred term and/or system organ class and grade.  
All deaths and SAEs will be tabulated. The 6-month PFS will be compared to 
historical rates using a chi-square test. 
 
13.4 Analysis of Correlative Objectives 
 
The correlative endpoints include immune effects.  They will be analyzed in 
exploratory analyses to associate their levels with tumor response. Categorical 
endpoints will be analyzed using chi-square or Fisher’s exact tests, and continuous 
measures will be compared using t-tests to compare response groups. 
References 
 
1. 
Cancer Facts & Figures 2015. Atlanta: American Cancer Society. 
2. 
von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial 
comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in 
patients with bladder cancer. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. Jul 20 2005;23(21):4602-4608. 
3. 
Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection 
by T cell receptor (TCR) transgenic CD8+ T cells. Cancer research. Feb 1 2004;64(3):1140-1145. 
4. 
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting 
programmed death-ligand 1 and programmed death-1. Clinical cancer research : an official 
journal of the American Association for Cancer Research. Dec 15 2012;18(24):6580-6587. 
5. 
Plimack E, Gupta S, Bellmunt J, et al. A phase 1b study of pembrolizumab in patients with 
advanced urothelial tract cancer. ESMO annual meeting. 2014;LBA23. 
6. 
Eruslanov E, Neuberger M, Daurkin I, et al. Circulating and tumor-infiltrating myeloid cell subsets 
in patients with bladder cancer. International journal of cancer. Journal international du cancer. 
Mar 1 2012;130(5):1109-1119. 
7. 
Brandau S, Trellakis S, Bruderek K, et al. Myeloid-derived suppressor cells in the peripheral 
blood of cancer patients contain a subset of immature neutrophils with impaired migratory 
properties. Journal of leukocyte biology. Feb 2011;89(2):311-317. 
8. 
Loskog A, Ninalga C, Paul-Wetterberg G, de la Torre M, Malmstrom PU, Totterman TH. Human 
bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. The Journal of 
urology. Jan 2007;177(1):353-358. 
9. 
Horn T, Grab J, Schusdziarra J, et al. Antitumor T cell responses in bladder cancer are directed 
against a limited set of antigens and are modulated by regulatory T cells and routine treatment 
approaches. International journal of cancer. Journal international du cancer. Nov 
2013;133(9):2145-2156. 
10. 
Chikamatsu K, Sakakura K, Toyoda M, Takahashi K, Yamamoto T, Masuyama K. 
Immunosuppressive activity of CD14+ HLA-DR- cells in squamous cell carcinoma of the head 
and neck. Cancer science. Jun 2012;103(6):976-983. 
11. 
Kim K, Skora AD, Li Z, et al. Eradication of metastatic mouse cancers resistant to immune 
checkpoint blockade by suppression of myeloid-derived cells. Proceedings of the National 
Academy of Sciences of the United States of America. Aug 12 2014;111(32):11774-11779. 
12. 
Mangsbo SM, Sandin LC, Anger K, Korman AJ, Loskog A, Totterman TH. Enhanced tumor 
eradication by combining CTLA-4 or PD-1 blockade with CpG therapy. Journal of immunotherapy. 
Apr 2010;33(3):225-235. 
13. 
Albers P, Park SI, Niegisch G, et al. Randomized phase III trial of 2nd line gemcitabine and 
paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged 
treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Annals of oncology 
: official journal of the European Society for Medical Oncology / ESMO. Feb 2011;22(2):288-294. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 60 of 85 
14. 
Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel 
in patients with previously treated advanced urothelial cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. Feb 15 2002;20(4):937-940. 
15. 
McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced 
or metastatic transitional-cell carcinoma. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. May 1997;15(5):1853-1857. 
16. 
Yuan L, Wu L, Chen J, Wu Q, Hu S. Paclitaxel acts as an adjuvant to promote both Th1 and Th2 
immune responses induced by ovalbumin in mice. Vaccine. Jun 17 2010;28(27):4402-4410. 
17. 
Huang X, Huang G, Song H, Chen L. Preconditioning chemotherapy with paclitaxel and cisplatin 
enhances the antitumor activity of cytokine induced-killer cells in a murine lung carcinoma model. 
International journal of cancer. Journal international du cancer. Aug 1 2011;129(3):648-658. 
18. 
Sevko A, Michels T, Vrohlings M, et al. Antitumor effect of paclitaxel is mediated by inhibition of 
myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. 
Journal of immunology. Mar 1 2013;190(5):2464-2471. 
19. 
Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X. Combined PD-1 blockade and GITR triggering 
induce a potent antitumor immunity in murine cancer models and synergizes with 
chemotherapeutic drugs. Journal of translational medicine. 2014;12:36. 
20. 
Wei H, Zhao L, Li W, et al. Combinatorial PD-1 blockade and CD137 activation has therapeutic 
efficacy in murine cancer models and synergizes with cisplatin. PloS one. 2013;8(12):e84927. 
21. 
Alizadeh D, Larmonier N. Chemotherapeutic targeting of cancer-induced immunosuppressive 
cells. Cancer research. May 15 2014;74(10):2663-2668. 
22. 
Daud AI, Hamid O, Ribas A, et al. Antitumor activity of the anti-PD-1 monoclonal antibody MK-
3475 in melanoma: Correlation of tumor PD-L1 expression with outcome. AACR Annual Meeting. 
2014;Abstract CT104. 
23. 
Gandhi L, Balmanoukian A, Hui R, et al. MK-3475 (anti-PD-1 monoclonal antibody) for non-small 
cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression. AACR 
Annual Meeting. 2014; Abstract CT105. 
24. 
Bellmunt J, Mullane SA, Werner L, et al. Association of PD-L1 expression on tumor-infiltrating 
mononuclear cells and overall survival in patients with urothelial carcinoma. Annals of oncology : 
official journal of the European Society for Medical Oncology / ESMO. Jan 18 2015. 
25. 
Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical results of 
adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. 
Clinical cancer research : an official journal of the American Association for Cancer Research. 
Feb 15 2015;21(4):712-720. 
26. 
Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with 
vaccine in ipilimumab-refractory or -naive melanoma. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. Dec 1 2013;31(34):4311-4318. 
27. 
Miah S, Dudziec E, Drayton RM, et al. An evaluation of urinary microRNA reveals a high 
sensitivity for bladder cancer. British journal of cancer. Jun 26 2012;107(1):123-128. 
28. 
Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine microRNA as tumor 
marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urologic 
oncology. Nov-Dec 2010;28(6):655-661. 
29. 
Adam L, Wszolek MF, Liu CG, et al. Plasma microRNA profiles for bladder cancer detection. 
Urologic oncology. Nov 2013;31(8):1701-1708. 
30. 
Achberger S, Aldrich W, Tubbs R, Crabb JW, Singh AD, Triozzi PL. Circulating immune cell and 
microRNA in patients with uveal melanoma developing metastatic disease. Molecular 
immunology. Apr 2014;58(2):182-186. 
31. 
Triozzi PL, Achberger S, Aldrich W, Elson P, Garcia J, Dreicer R. Differential immunologic and 
microRNA effects of 2 dosing regimens of recombinant human granulocyte/macrophage colony 
stimulating factor. Journal of immunotherapy. Sep 2012;35(7):587-594. 
32. 
Dreicer R, Gustin DM, See WA, Williams RD. Paclitaxel in advanced urothelial carcinoma: its role 
in patients with renal insufficiency and as salvage therapy. The Journal of urology. Nov 
1996;156(5):1606-1608. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
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Page 61 of 85 
33. 
Papamichael D, Gallagher CJ, Oliver RT, Johnson PW, Waxman J. Phase II study of paclitaxel in 
pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. British 
journal of cancer. 1997;75(4):606-607. 
34. 
Seidman AD, Hudis CA, Albanell J, et al. Dose-dense therapy with weekly 1-hour paclitaxel 
infusions in the treatment of metastatic breast cancer. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. Oct 1998;16(10):3353-3361. 
35. 
Friedland DM, Dakhil S, Hollen C, Gregurich MA, Asmar L. A phase II evaluation of weekly 
paclitaxel plus carboplatin in advanced urothelial cancer. Cancer investigation. 2004;22(3):374-
382. 
36. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). European journal of cancer (Oxford, England : 1990). 
Jan 2009;45(2):228-247. 
37. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials. Mar 
1989;10(1):1-10. 
 
 
 
 
 
 
 
 
 
 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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Appendix A – Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE:  ___ ___ ___ ___ ___ 
 
 
SEX:   
  Male      Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
ECOG Performance Status: ___  
 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or e-mailed to 
the registrar at 336-7136772 or registra@wakehealth.edu. 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES  NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory 
urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
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Appendix B – Subject Eligibility Checklist 
 
 
IRB Protocol No.  
CCCWFU Protocol No. 
Study Title: Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory 
urothelial carcinoma  
Principal Investigator: Rhonda Bitting, MD 
 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Patients diagnosed with platinum-refractory 
metastatic urothelial cancer that is measureable 
based on Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria 1.1. Platinum-refractory 
disease is defined as progressive disease on 
cisplatin or carboplatin therapy or within 12 
months of prior platinum treatment (last dose.) 
□ 
□ 
 
At least 1 prior chemotherapy regimen containing 
cisplatin or carboplatin. 
□ 
□ 
 
Be willing to provide tissue from a newly obtained 
core or excisional biopsy of a tumor lesion.  
Newly-obtained is defined as a specimen 
obtained up to 6 months (168 days) prior to 
initiation of treatment on Day 1.  Archived 
specimen can be used for subjects, if available. 
□ 
□ 
 
Age >18 years. 
□ 
□ 
 
Performance status of 0 or 1 on the ECOG 
Performance Scale. 
□ 
□ 
 
Adequate organ function as defined below: 
ANC ≥ 1,500/mcL 
Platelets ≥ 80,000/mcL 
Hemoglobin ≥9 g/dL without transfusion dependency. 
Serum Creatinine  OR  
    Measured or Calculated Creatinine Clearance  
    (GFR can also be used in place of creatinine or CrCl) 
      ≤1.5x upper limit of normal (ULN) OR 
      ≥35 mL/min for subject with creatinine levels >1.5x 
institutional ULN 
Serum Total bilirubin ≤ 1.5x ULN OR 
     Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5x ULN 
AST (SGOT) and ALT (SGPT) ≤ 2.5x ULN  OR ≤ 5x 
ULN for subjects with liver metastases 
Albumin >2.5 mg/dL 
 
□ 
□ 
 
Female subjects of childbearing potential should 
have a negative urine or serum pregnancy within 
72 hours prior to receiving the first dose of study 
medication. If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test 
will be required. 
□ 
□ 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory 
urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 64 of 85 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Female subjects of childbearing potential should 
be willing to use 2 methods of birth control or be 
surgically sterile, or abstain from heterosexual 
activity for the course of the study through 120 
days after the last dose of study medication. 
Subjects of childbearing potential are those who 
have not been surgically sterilized or have not 
been free from menses for >1 year. 
□ 
□ 
 
Male subjects should agree to use an adequate 
method of contraception starting with the first 
dose of study therapy through 120 days after the 
last dose of study therapy. 
□ 
□ 
 
Ability to understand and the willingness to sign 
an IRB-approved informed consent document. 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
Currently receiving or has had treatment with an 
investigational agent or used an investigational 
device within 4 weeks of study Day 1. 
□ 
□ 
 
Anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to agents administered more 
than 4 weeks earlier. 
□ 
□ 
 
Chemotherapy, targeted small molecule therapy, 
or radiation therapy within 2 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 
or at baseline) from adverse events due to a 
previously administered agent. 
 
Note:  Subjects with ≤ Grade 2 neuropathy are an 
exception to this criterion and may qualify for the 
study. 
 
Note:  If subject received major surgery, they 
must have recovered adequately from the toxicity 
and/or complications from the intervention prior to 
starting therapy. 
□ 
□ 
 
Prior therapy with an anti-PD-1, anti-PD-L1, or 
anti-PD-L2 agent. Prior therapy with paclitaxel or 
docitaxel. 
□ 
□ 
 
Hypersensitivity to pembrolizumab, any of its 
excipients, paclitaxel, or any of its excipients. 
□ 
□ 
 
Diagnosis of immunodeficiency or is receiving 
systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to 
the first dose of trial treatment. 
□ 
□ 
 
Known history of active TB   (Bacillus 
Tuberculosis). 
□ 
□ 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory 
urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 65 of 85 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Known additional malignancy that is progressing 
or requires active treatment.  Exceptions include 
basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical 
cancer. 
□ 
□ 
 
Known active central nervous system (CNS) 
metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases 
may participate provided they are stable (without 
evidence of progression by imaging for at least 
four weeks prior to the first dose of trial treatment 
and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at 
least 7 days prior to trial treatment.  This 
exception does not include carcinomatous 
meningitis which is excluded regardless of clinical 
stability. 
□ 
□ 
 
Active autoimmune disease that has required 
systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids 
or immunosuppressive drugs). Replacement 
therapy (eg., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a 
form of systemic treatment. 
□ 
□ 
 
Known history of, or any evidence of active, non-
infectious pneumonitis. 
□ 
□ 
 
Active infection requiring systemic therapy. 
□ 
□ 
 
History or current evidence of any condition, 
therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the 
subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating 
investigator.   
□ 
□ 
 
Known psychiatric or substance abuse disorders 
that would interfere with cooperation with the 
requirements of the trial. 
□ 
□ 
 
Pregnancy or breastfeeding, or expecting to 
conceive or father children within the projected 
duration of the trial, starting with the pre-screening 
or screening visit through 120 days after the last 
dose of trial treatment. 
□ 
□ 
 
Known history of Human Immunodeficiency Virus 
(HIV) (HIV 1/2 antibodies). 
□ 
□ 
 
Known active Hepatitis B (e.g., HBsAg reactive) 
or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
□ 
□ 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory 
urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 66 of 85 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Received a live vaccine within 30 days of planned 
start of study therapy. 
Note:  Seasonal influenza vaccines for injection 
are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines 
(e.g., Flu-Mist®) are live attenuated vaccines, and 
are not allowed. 
□ 
□ 
 
 
This subject is      
 eligible /  ineligible     for participation in this study. 
 
ORIS Assigned PID: __________________  
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility:_______________________ Date: _______________ 
 
Signature of Treating Physician**:  _____________________________________ Date:  _______________ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, 
specifically state which document in the medical record was used to assess eligibility. Also include the date on the 
document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-refractory 
urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 67 of 85 
Appendix C – Race & Ethnicity Verification Form 
 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our information. As 
a brief reminder, the information you provide today will be kept confidential. 
 
1. Are you: 
Hispanic or Latino/a 
Not Hispanic or Latino/a 
 
2. What is your race? One or more categories may be selected. 
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify: ___________________________ 
          
 
 
 
Internal use only: 
 
 
 Name: ____________________ MRN#: ____________________  
 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes        No 
 
Was a discrepancy found?       Yes         No 
         If yes, please provide what is currently indicated in the EMR:  
 
 
Ethnicity: ____________________ 
 
Race: ____________________ 
Additional comments: __________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 68 of 85 
Appendix D – Mandatory STRC SAE Reporting Guidelines 
 
Safety and Toxicity Review Committee 
(STRC)  Serious Adverse Event (SAE) 
Notification SOP 
     Date: 07/10/2019 
 
 
Mandatory STRC SAE Reporting Requirements in WISER  
This document describes reporting requirements of adverse events from WFBCCC Investigator 
Initiated interventional trials to the Safety and Toxicity Review Committee (STRC). A trial is 
considered a WFBCCC Investigator Initiated interventional trial if the following criteria are met:  
  
1. 
The Principal Investigator (PI) of the trial is a member of a department at 
the Wake Forest University Baptist Medical Center.  
2. 
WFBCCC is considered as the primary contributor to the design, 
implementation and/or monitoring of the trial.  
3. 
The trial is designated as “Interventional” using the Clinical Research Categories 
definitions provided by the NCI in the Data Table 
4 documentation. (https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4)  
  
There are two distinct types of WFBCCC Investigator Initiated interventional trials based on where 
patient enrollment occurs.  These include:  
  
1. 
Local WFBCCC Investigator Initiated interventional trials defined as trials 
where all patients are enrolled from one of the WFBCCC sites. These include the 
main outpatient Cancer Center clinics (located in Winston-Salem) as well as WFBCCC 
affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons, Lexington, High 
Point, or Wilkesboro.  
2. 
Multi-Center WFBCCC Investigator Initiated interventional trials defined as 
trials where patients are enrolled from other sites in addition to WFBCCC sites.    
There are three types of trials that are included in this category:  
a. 
Trials sponsored by the NCI Community Oncology Research Program (NCORP) 
that are conducted at multiple sites where the PI is a member of a department at the 
Wake Forest University Baptist Medical Center.  
b. 
Trials sponsored by Industry that are conducted at multiple sites and the PI is a 
member of a department at the Wake Forest University Baptist Medical Center.  
c. 
Trials sponsored by WFBCCC that are conducted at multiple sites and the PI is a 
member of a department at the Wake Forest University Baptist Medical Center.  
  
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients enrolled on 
WFBCCC Investigator Initiated Interventional trials must be entered into the WISER system. The 
only exception to this requirement is for patients enrolled on NCORP trials at non- WFBCCC sites. 


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 69 of 85 
AEs and SAEs for NCORP patients enrolled at WFBCCC sites must be entered into the WISER 
system. Once these AEs and SAEs are entered in WISER, certain actions must be taken regarding 
the reporting of specific Adverse Events to the STRC.  
All Adverse Events that occur during protocol intervention (defined below) and are coded as either 
1) unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours (regardless of 
grade), or grade 5 (death) must be reported to the STRC using the using the SAE console in WISER.  
  
A research nurse or clinical research coordinator when made aware that an adverse event meets one 
of the above criteria has occurred on a WFBCCC Investigator Initiated interventional trial, is 
responsible for informing a clinical member of the STRC by phone (or in-person) about the adverse 
event. The nurse/coordinator should contact the treating physician prior to calling the STRC clinical 
member to obtain all details of the SAE, as well as all associated toxicities to be recorded along with 
the SAE. In addition, this nurse or coordinator is responsible for entering the adverse event 
information into the SAE console in WISER.  Once the adverse event has been entered into the SAE 
console an email informing the entire STRC committee will be generated.  
  
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC 
Institutional Interventional trial. Ultimately, the protocol PI has 
the primary responsibility for AE identification, documentation, grading and assignment of attribution
 to the investigational agent/intervention. However, when an AE event as described 
above is observed, it is the responsibility of the person who observed the event to be sure that 
it is reported to the STRC.  
  
What is considered during protocol intervention?  
During protocol intervention is considered to be the time period while a patient is on study treatment 
or during the time period within 30 days of last study treatment (even if patient begins a new (non-
study) treatment during the 30 days). This window of 30 days should be the standard window to be 
used in all protocols unless a specific scientific rationale is presented to suggest that a shorter 
window can be used to identify events. If it is a trial sponsored by Industry and the sponsor requires a 
longer window for monitoring of SAEs, then the longer window of time specified by the sponsor 
should be followed.  
  
What is considered as an Unexpected Grade 4 event?  
Any grade 4 event that was not specifically listed as an expected adverse event in the protocol should 
be considered as unexpected. A grade 4 adverse event can be considered to be unexpected if it is an 
event that would not be expected based on the treatment being received or if it is unexpected based 
on the health of the patient. In either case, if there is any uncertainty about whether a grade 4 
adverse event is expected or unexpected it should be reported to STRC.  
  


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 70 of 85 
STRC notification responsibilities of the person (e.g., nurse) handling the reporting/documenting of 
the SAE in WISER:  
1. Make a phone call (or speak in person) to the appropriate clinical member of the STRC as listed 
below (page if necessary)  
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in WISER 
WITHIN 24 HOURS of first knowledge of the event. Information can be entered and saved, 
but the STRC members will not be notified until a date is entered into the STRC Notification Date 
Field. This will ensure that all persons that need to be made aware of the event (i.e., study team 
members and STRC members) will be notified; remember to file a copy of the confirmation.  
3. Document that the appropriate person(s) on the STRC has been contacted. Indicate the name of 
the STRC clinician that was contacted in the Event Narrative field in the SAE console of 
the particular subject.  
4. Document whether or not the protocol should be suspended based on the discussion with the 
STRC clinician. This is the major function of the email notification. Enter whether the protocol 
should be suspended in the Event Narrative Field.  
5. Follow up/update the clinical member(s) of STRC regarding any new developments 
or information obtained during the course of the SAE investigation and reporting process.  
  
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 3):  
1. Event Date  
2. Reported Date  
3. Reported by  
4. If Grade 5, enter Death Date  
5. If Grade 5, enter Death occurred: within 30 days  
6. Event Narrative: Brief description (include brief clinical history relevant to this event, including 
therapies believed related to event). Begin narrative with the STRC clinician who was notified and 
Date/Time notified. In addition, state attribution by STRC clinician as either “Unrelated”, “Unlikely”, 
“Possibly”, “Probably”, or “Definitely”.  Always include the following here:  
i. STRC clinician name and comments  
ii.Date of last dose before the event  
iii. Is suspension of the protocol needed? Y/N  
7. Treating Physician comments  
8. PI comments, if available  
9. Protocol Attribution after discussion with STRC clinician  
10. 
Outcome 
(Fatal/Died, 
Intervention 
for 
AE 
Continues, 
Migrated 
AE, 
Not Recovered/Not Resolved, 
Recovered/Resolved 
with 
Sequelae, 
Recovered/Resolved 
without Sequelae, Recovering and Resolving)  
11. 
Consent form Change Required? Y/N  
12. 
SAE Classification *This is required in order for the email notification to be sent*  
13. 
Adverse Event Details – Enter all details for each AE associated with the SAE.  


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 71 of 85 
a. Course start date  
b. Category  
c. AE Detail  
d. Comments  
e. Grade/Severity  
f. Unexpected Y/N  
g. DLT Y/N  
h. Attributions  
i. Action  
j. Therapy  
k. Click ADD to attach the AE Detail to the SAE.  
14. 
Enter Date Notified STRC -- *This is required for the email notification to be sent*  
15. 
Click Submit. The auto-generated notification email will disseminate within 5 minutes. If 
you do not receive an email within 5 minutes, check that you have entered the “Date Notified 
STRC” and the “SAE Classification”. If these have been entered and the email still has not been 
received, take a screen shot of the SAE in WISER and immediately email it out to all of the STRC 
members listed in this SOP. In the subject line, indicate that this is a manual transmission of the SAE 
in lieu of the auto-generated email. It is required that a notification goes to the STRC members 
immediately so that their assessment can be obtained within the 24 hour time frame 
requirement. Contact the Cancer Center Programmer/Analyst to alert that there is an issue with 
the auto-generated email.  
  
The Clinical Members of STRC to Notify by Phone or Page:  
Bayard Powell, MD – Director-at-Large, WFBCCC; Section Head, Hematology/Oncology 6- 
Glenn Lesser, MD – Hematology Oncology 6- 
Stefan Grant, MD, JD-Hematology Oncology 3- 
Jimmy Ruiz, MD-Hematology Oncology 6- 
Mercedes Porosnicu, MD- Hematology Oncology 6- 
         Michael Farris, MD – Radiation Oncology 3- 
  
Definition of Unavailable:  
As a general guideline if the first clinician that is contacted does not respond to the phone call or page 
within 30 minutes, then initiate contact with a different STRC clinician. Allow up to 30 minutes for the 
new STRC clinician to respond to a phone call or page before contacting another member. These 
times (30 minutes) are a general guideline. Best judgment as a clinical research professional should 
be used giving considerations of the time of day, severity of the SAE, and other circumstances as to 
when it is appropriate to contact backup clinicians. If the event occurs near the end of day, then leave 
messages (voice or email) as appropriate and proceed with submitting the STRC notification form. It is 
important to take reasonable steps and to document that some type of contact has been initiated to 
one or more of the clinical members of STRC.  


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 72 of 85 
  
STRC CLINICAN RESPONSIBILITY:  
It is the responsibility of the STRC clinician to review all reported events, evaluate the events as they 
are reported; and communicate a response to the Investigator, event reporter and the members of 
STRC. The review will include but not be limited to the information reported; there may be times 
when additional information is needed in order for an assessment to be made and further 
communication directly with the investigator may be warranted. STRC reserves the right to disagree 
with the Investigator's assessment. If STRC does not agree with the 
Investigator, STRC reserves the right to suspend the trial pending further investigation. If there is any 
immediate danger or harm that could be present for a future patient based on 
the information provided in the STRC report then an immediate suspension of enrollment 
should be considered.  
  
AMENDMENTS TO PREVIOUS REPORTS  
If all pertinent information is unavailable with the initial submission, once the additional information 
is available do not submit a new report. Rather, go to the original email that was sent to the STRC 
and using that email “reply to all”. Entitle this new email “Amendment for (list date of event and 
patient ID)” this will avoid duplications of the same event. List the additional information being 
reported. This information needs to be entered into WISER as well. To do this, go to the Subject 
console and click SAEs on the left column. Click on the 
appropriate SAE number that needs updating. Then click update. This will allow additional informatio
n to be added  
    
Acronyms  
AE – Adverse Event  
STRC-Safety and Toxicity Review Committee  
SAE-Serious Adverse Event  
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center  
NCI-National Cancer Institute  
WISER –Wake Integrated Solution for Enterprise Research  
Screen Shots:  
  
The following screen shots come from the SAE Console within the Subject Console in WISER.  
  
Screen Shot 1:  


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 73 of 85 
  
Screen Shot 2:
  
  
Screen Shot 3:  


Single-arm phase II combination study of low-dose paclitaxel with pembrolizumab in platinum-
refractory urothelial carcinoma  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 74 of 85 
  
  
 Screen Shot 4


   ORIS ID: _______________________ 
 
 
CCCWFU # 
   
Protocol version date 03/10/2020 
 
 
 
 
 
Page 75 of 85 
Appendix E – TUMOR RESPONSE WORKSHEET (RECIST v1.1) 
 
Target Lesions 
TARGET Lesions 
Lesion 
Site 
Nodal/Non-
nodal 
(measure shortest 
diameter for 
nodal) 
Imaging 
(ie,CT, MRI) 
Baseline 
Date: 
Cycle_____ 
Date: 
 
Cycle_____ 
Date: 
 
Cycle_____ 
Date: 
 
Cycle_____ 
Date: 
 
Cycle_____ 
Date: 
 
01 
 
 
 
mm 
mm 
mm 
mm 
mm 
mm 
02 
 
 
 
mm 
mm 
mm 
mm 
mm 
mm 
03 
 
 
 
mm 
mm 
mm 
mm 
mm 
mm 
04 
 
 
 
mm 
mm 
mm 
mm 
mm 
mm 
05 
 
 
 
mm 
mm 
mm 
mm 
mm 
mm 
Sum of Diameters 
mm 
mm 
mm 
mm 
mm 
mm 
% Change (% ∆)  from Baseline or Nadir* & absolute value (AbV) 
 
NA 
        
          NA 
% ∆ 
                        
        AbV 
 
 
 
 
Target Lesion Response 
      N/A 
 
 
 
 
 
 
Non-Target Lesions 
NON-TARGET Lesions 
Lesion 
Site 
Nodal/Non-
nodal 
Imaging 
Baseline 
Cycle_____ 
Cycle_____ 
Cycle_____ 
Cycle_____ 
Cycle_____ 
01 
 
 
 
 
 
 
 
 
 
02 
 
 
 
 
 
 
 
 
 
03 
 
 
 
 
 
 
 
 
 
04 
 
 
 
 
 
 
 
 
 
05 
 
 
 
 
 
 
 
 
 
06 
 
 
 
 
 
 
 
 
 
07 
 
 
 
 
 
 
 
 
 
08 
 
 
 
 
 
 
 
 
 
09 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
Non-Target Lesion Response 
N/A 
 
 
 
 
 
 
New Lesions 
New 
1 
 
 
 
N/A 
 
 
 
 
 
2 
 
 
 
N/A 
 
 
 
 
 
3 
 
 
 
N/A 
 
 
 
 
 
Overall Tumor Response 
 
 
 
 
Cycle___ 
 
Cycle___ 
 
Cycle___ 
 
 
Cycle___ 
 
 
Cycle___ 
     
 
 
 
 
 
Radiologist Signature: 
 
 
 
 
 
 
Treating Physician Signature: 
 
 
 
 
 
 
PI Signature: 
 
 
 
 
 
 
*Terms & Calculations 
 
 
 
 
 
 
 
Baseline: The set of data collected prior to randomization 
 Nadir: The lowest point   


ORIS ID_____________  
Date: __ __/__ __/__ __ 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 76 of 85 
WEEK / CYCLE # 
INVESTIGATOR PRINTED NAME 
INVESTIGATOR SIGNATURE 
DATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TARGET AND NON-TARGET LESIONS 
TARGET LESION 
NON-TARGET LESION 
NEW LESION 
OVERALL RESPONSE 
CR 
CR 
NO 
CR 
CR 
NON-CR/NON-PD 
NO 
PR 
CR 
NOT EVALUATED 
NO 
PR 
PR 
NON-PD OR NOT ALL 
EVALUATED 
NO 
PR 
SD 
NON-PD OR NOT ALL 
EVALUATED 
NO 
SD 
NOT ALL 
EVALUATED 
NON-PD 
NO 
NE 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 


ORIS ID_____________  
Date: __ __/__ __/__ __ 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 77 of 85 
ANY 
ANY 
YES 
PD 
 
Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-Cr/Non-PD 
Not All Evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Any 
PD 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
and NE = not evluated 
 
Target Lesion Timepoint Assessment 
 
Target Lesion Response 
Definition 
Complete Response (CR) 
Disappearance of all target lesions. 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 sum of diameters, taking as reference 
the baseline sum 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 based on all target 
lesions recorded since the treatment started. The sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered 
progression) 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference smallest sum 
diameters while on study 
Not Evaluated (NE)  
Any target lesion present at baseline which was not assessed or 
was unable to be evaluated leading to an inability to determine 
the status of that particular tumor for that time point  
Not Applicable (NA) 
No target lesions were identified at baseline 
 
Non-Target Lesions Timepoint Assessment 
 
Non-Target Lesion Response 
Definition 
 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10 mm short axis)  
Non-Complete Response/Non-
Persistence of one or more non-target lesions not qualifying for 


ORIS ID_____________  
Date: __ __/__ __/__ __ 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 78 of 85 
Progressive Disease 
either CR or PD  
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions.  
• 
 subjects with measurable non-target disease – 
Substantial worsening such that the overall tumor 
burden has increased sufficiently to merit 
discontinuation of therapy.  
• 
 subjects with non-measurable disease – Increase in 
overall tumor burden comparable in magnitude to the 
increase required to declare PD for measurable disease. 
Not Evaluable (NE) 
Any non-target lesion present at baseline which was not 
assessed or was unable to be evaluated leading to an inability to 
determine status 
Not Applicable (NA) 
No non-target lesions identified at baseline 
 


CCCWFU #88215 
v. 6-8-2016 
Page 79 of 85 
Protocol version date 03/10/2020 
Appendix F – Baseline Data Collection Form 
 
Date of visit _ _/_ _/_ _ 
 
1. Oncologic history 
 
a. Most immediate prior cancer therapy (select one):  
 chemotherapy   
 radiation   
 surgery   
 hormone  
 other: ___________________________ 
 
b. Specify most immediate prior cancer therapy: ______________________________________________ 
 
Dates of administration:  Started: __ __ / __ __ / __ __  Stopped: __ __ / __ __ / __ __ 
 
Dose ___________ & total # of treatments ________ 
 
c. Other prior cancer therapies (excluding 1b.) for most recent cancer. Mark all that apply: 
    
 None  
 Chemotherapy  
 Radiation  
 Surgery  
 Hormone therapy  
 Other: _____________ 
 
Regimen Name 
Total # of Treatments 
Date of Last Treatment 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
6. 
 
 
7. 
 
 
8. 
 
 
9. 
 
 
10. 
 
 
 
Site of RT 
Total Dose in Gy 
Date of Last Treatment 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
 
Type of surgery 
Date of surgery 
1. 
 
2. 
 
 
Hormone Therapy Name 
Dose 
Date of Last Treatment 
1. 
 
 
2. 
 
 
 
Other 
Dose 
Date of Last Treatment 
1. 
 
 
2. 
 
 
 
2. Date of baseline imaging: __ __ / __ __ / __ __ 
 
Sites of disease: ___________________________________________________________ 
 
Imaging modality: 
  CT scan   
  PET scan   
MRI scan   
 Bone scan   
Other, specify _________ 
 
 


CCCWFU #88215 
v. 6-8-2016 
Page 80 of 85 
Protocol version date 03/10/2020 
3.   Medical history (check all that apply): 
 Myocardial infarction 
 Congestive heart failure 
 Peripheral vascular disease 
(claudication, arterial bypass, untreated 
aneurysm (≥6cm) 
 Cerebrovascular disease (history of TIA 
or CVA) 
 Dementia 
 Chronic pulmonary disease (with 
symptomatic dyspnea) 
 Connective tissue disease (SLE, 
polymyositis, mixed CTD, polymyalgia 
rueumatic, moterate to severe RA) 
 Peptic ulcer disease (bleeding ulcer) 
 Liver disease (on treatment, cirrhosis without 
portal hypertension, chronic hepatitis); check 
here if mild 
 
    
 Diabetes 
end organ damage? Yes 
 
No 
 
 Hemiplegia 
 Leukemia 
 Lymphoma 
 AIDS 
 Other major medical condition; specify 
___________________________________
 
4.   Concurrent medications and supplements 
a. List all prescription and over-the-counter medications (includes prescription supplements)     
Medication Name 
Is it PRN? 
Medication Name 
Is it PRN? 
1. 
yes          no 
11. 
yes          no 
2. 
yes          no 
12. 
yes          no 
3. 
yes          no 
13. 
yes          no 
4. 
yes          no 
14. 
yes          no 
5. 
yes          no 
15. 
yes          no 
6. 
yes          no 
16. 
yes          no 
7. 
yes          no 
17. 
yes          no 
8. 
yes          no 
18. 
yes          no 
9. 
yes          no 
19. 
yes          no 
10. 
yes          no 
20. 
yes          no 
 
b. List all supplements (excludes prescription supplements) 
Supplement Name 
Is it PRN? 
Supplement Name 
Is it PRN? 
1. 
yes          no 
11. 
yes          no 
2. 
yes          no 
12. 
yes          no 
3. 
yes          no 
13. 
yes          no 
4. 
yes          no 
14. 
yes          no 
5. 
yes          no 
15. 
yes          no 
6. 
yes          no 
16. 
yes          no 
7. 
yes          no 
17. 
yes          no 
8. 
yes          no 
18. 
yes          no 
9. 
yes          no 
19. 
yes          no 
10. 
yes          no 
20. 
yes          no 
 
5.   Physical exam: 
Derm – 
 WNL 
 Abnormal, specify ______________________________ 
HEENT – 
 WNL 
 Abnormal, specify ______________________________ 
CV – 
 WNL 
 Abnormal, specify ______________________________ 
Pulm – 
 WNL 
 Abnormal, specify ______________________________ 
GI – 
 WNL 
 Abnormal, specify ______________________________ 
Other – 
 Abnormal, specify ____________________________ 
 
6.   Vital signs: 
a. HR_________ 
b. BP____ /____ 
c. RR_________ 
d. Temp _______(°F) 


CCCWFU #88215 
v. 6-8-2016 
Page 81 of 85 
Protocol version date 03/10/2020 
e. Weight ______(kg) 
f. Height  ______(cm) 
7.   ECOG Performance Status (check one): 
 
GRADE Description 
   0 
Fully active, able to carry on all pre-disease performance without restriction 
   1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
   2 
Ambulatory and capable of all self care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
   3 
Capable of only limited self care, confined to bed or chair more than 50% of waking hours 
   4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair 
   5 
Dead 
 
8.   Documentation of negative pregnancy test for women of child-bearing potential? 
Yes 
  
 
No 
, reason ____________________  
  
Not applicable 
 
 
9.   Blood Draws: 
 
a.   CBC with Differential, Date drawn __ __ /__ __ / __ __ 
 
b.   Serum Chemistry, Date drawn __ __ /__ __ / __ __ 
 
c.   Urinalysis Date __ __ /__ __ / __ __ 
 
10.   Metastatic tumor biopsy: 
 
a.   Date __ __ /__ __ / __ __ 
 
b.   Site of biopsy:______________________________ 
11.   Archival tumor tissue: 
 
a.   Date __ __ /__ __ / __ __ 
 
b.   Site from which tissue obtained:______________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CCCWFU #88215 
v. 6-8-2016 
Protocol version date 03/10/2020 
 
 
Page 82 of 85 
 
Appendix G – Follow-up Data Collection Forms 
 
Follow-Up Visit:   
Cycle 1    
Cycle 2    
Cycle 3    
Cycle 4    
Cycle 5    
Cycle 6   
Cycle 7  
Cycle 8    
End of Treatment      
Follow-up 
 
Date of Visit: __ __ / __ __ / __ __ 
 
1. Medical History               
Medical Conditions, new from baseline (specify)___________________________ 
 
Hospitalizations since last visit (specify)_________________________________ 
 
 
2.   Concurrent medications and supplements       
a. List all prescription and over-the-counter medications (includes prescription supplements).    
Medication Name 
Is it PRN? 
Medication Name 
Is it PRN? 
1. 
yes          no 
11. 
yes          no 
2. 
yes          no 
12. 
yes          no 
3. 
yes          no 
13. 
yes          no 
4. 
yes          no 
14. 
yes          no 
5. 
yes          no 
15. 
yes          no 
6. 
yes          no 
16. 
yes          no 
7. 
yes          no 
17. 
yes          no 
8. 
yes          no 
18. 
yes          no 
9. 
yes          no 
19. 
yes          no 
10. 
yes          no 
20. 
yes          no 
 
b. List all supplements (excludes prescription supplements). 
Supplement Name 
Is it PRN? 
Supplement Name 
Is it PRN? 
1. 
yes          no 
11. 
yes          no 
2. 
yes          no 
12. 
yes          no 
3. 
yes          no 
13. 
yes          no 
4. 
yes          no 
14. 
yes          no 
5. 
yes          no 
15. 
yes          no 
6. 
yes          no 
16. 
yes          no 
7. 
yes          no 
17. 
yes          no 
8. 
yes          no 
18. 
yes          no 
9. 
yes          no 
19. 
yes          no 
10. 
yes          no 
20. 
yes          no 
 
3.   Physical exam: 
Derm – 
 WNL 
 Abnormal, specify ______________________________ 
HEENT – 
 WNL 
 Abnormal, specify ______________________________ 
CV – 
 WNL 
 Abnormal, specify ______________________________ 
Pulm – 
 WNL 
 Abnormal, specify ______________________________ 
GI – 
 WNL 
 Abnormal, specify ______________________________ 
Other – 
 Abnormal, specify ____________________________ 
4.   Vital signs: 
g. HR_________ 
h. BP____ /____ 
i. 
RR _________ 
j. 
Temp _______(°F) 
k. Weight ______(kg) 
l. 
Height  ______(cm) 


ORIS ID_____________  
Date: __ __/__ __/__ __ 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
Page 83 of 85 
 
 
 
5.  ECOG Performance Status (check one): 
GRADE Description 
   0 
Fully active, able to carry on all pre-disease performance without restriction 
   1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
   2 
Ambulatory and capable of all self care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
   3 
Capable of only limited self care, confined to bed or chair more than 50% of 
waking hours 
   4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or 
chair 
   5 
Dead 
 
6.  Documentation of negative pregnancy test for women of child-bearing potential? 
Yes 
  
 
No 
, reason ____________________  
  
Not applicable 
 
 
7.  Blood Draws 
 
a.   CBC with Differential, Date drawn __ __ /__ __ / __ __ 
 
b.   Serum Chemistry, Date drawn __ __ /__ __ / __ __ 
 
 
c.   Urinalysis Date __ __ /__ __ / __ __ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ORIS ID_____________  
Date: __ __/__ __/__ __ 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
Page 84 of 85 
 
Appendix H – Treatment Response Evaluation 
 
Overall Response Rate is the primary objective for this study.  Patients will be evaluated with 
imaging at baseline, every 9 weeks (+/-7days), and end of treatment. At the end of treatment, if 
no progression, patients will be evaluated with imaging every 3 months (+/-10 days) for 1 year.  
Study Visit: 
 
 Week 9 ( ± 7 days) 
 Week 18 ( ± 7 days) 
 Week 27 ( ± 7 days) 
 Week 36 ( ± 14 days) 
 End of Treatment 
 3 months ( ± 10 days) post Treatment 
 6 months ( ± 10 days) post Treatment 
 9 months ( ± 10 days) post Treatment  
 12 months ( ± 10 days) post Treatment  
 Other visit: (please specify) ________________ 
 
Date of Scan: ___ ___ /___ ___ /___ ___ 
 
Imaging Modality: 
 CT 
 PET/CT 
 MRI  
 Other____________  
 
Evaluation of imaging per clinical review– measurable disease 
 
   Complete Response (CR) 
 
   Partial Response (PR) 
 
   Progressive Disease (PD): Date of progression ___ ___ /___ ___ /___ ___ 
 
   Stable Disease (SD) 
 
   N/A  
 
Evaluation of non-measurable disease (e.g., pleural effusion) 
 
   Complete Response (CR) 
 
   Non-CR/Non-PD 
 
   Progressive Disease (PD): Date of progression ___ ___ /___ ___ /___ ___ 
 
   N/A  
 
 
 
Treating Physician Signature: ______________________ Date: ___ ___ /___ ___ /___ ___ 
 
PI Signature: ___________________________________ Date: ___ ___ /___ ___ /___ ___ 


ORIS ID_____________  
Date: __ __/__ __/__ __ 
CCCWFU # 88215 
 
Protocol version date 03/10/2020 
 
 
 
 
 
Page 85 of 85 
 
Appendix I – Adverse Event Log 
 
 
WFBCCC Adverse Event (AE) Log 
 
 
PI: _________________ 
Subject PID: _________________ 
MRN: ________________ 
Cycle #:  
Cycle Start Date:  
Cycle Start Time: 
Cycle End Date:  
Cycle End Time: 
Adverse Event CTC 
Term 
Lab 
Value 
Grade  
(1-5) per 
CTC 
Start 
Date 
Attribution  
DEF= Definite 
PROB= Probable 
POSS= Possible 
UNLK= Unlikely 
UNRL= Unrelated 
Treating MD 
Initials + 
Date 
End Date 
Expected 
N= No 
Y= Yes 
*Serious Adverse 
Event Detail:    
NO= No 
LT= Life Threatening 
DTH= Death 
DIS= Disability 
HOS= Hospitalization 
CA= Caused 
congenital anomaly 
RI= Required 
intervention to prevent 
impairment 
Dose 
Limiting 
Toxicity 
(DLT)  
N= No 
Y= Yes 
Action Taken 
NO= None 
DR= Dose 
Reduced 
RI= Regimen 
Interrupted 
TD= Therapy 
discontinued 
INTR= Interrupted 
then reduced 
Therapy 
Given 
NO= None 
SYM= 
Symptomatic 
SUP= 
Supportive 
VSUP= 
Vigorous 
Supportive 
Reportable?   
IRB= IRB 
STRC= STRC 
FDA= FDA 
SPON= Sponsor 
(Mark all that 
apply) 
Adverse 
Event 
Report 
(AER) 
filed? 
N= No 
Y= Yes 
Outcome 
R= Recovered 
TX= Still under 
treatment or 
observation 
A= Alive with 
Sequalae 
D= Died 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. 
 
 
CTCAE Version 4 - http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 
STRC = Safety and Toxicity Review Committee 
Version 
10/30/17 

ICF_001.pdf: 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #88215
Page 1 of 11
Adult Consent Form
WFUHS Version: 12/13/2019
Section of Hematology and Oncology
Single-arm phase II combination study of low-dose 
paclitaxel with pembrolizumab in platinum-refractory 
urothelial carcinoma 
Informed Consent Form to Participate in Research
Michael M. Goodman, MD, Principal Investigator
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have a type of cancer called urothelial carcinoma that is either recurrent, 
meaning you have previously received treatment for your cancer, or metastatic, meaning the 
cancer has spread to other parts of your body.  Your participation is voluntary.  Please take your 
time in making your decision as to whether or not you wish to participate. Ask your study doctor 
or the study staff to explain any words or information contained in this informed consent 
document that you do not understand.  You may also discuss the study with your friends and 
family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to compare the effects (good and bad) of pembrolizumab 
given in combination with low-dose paclitaxel.  The drug pembrolizumab is in a class of 
medications called monoclonal antibodies. It works by helping your immune system to slow or 
stop the growth of cancer cells.  Pembrolizumab had been approved for the treatment of 
melanoma and is being studied for the treatment of patients with other cancers including 
urothelial carcinoma.  Paclitaxel is already a standard chemotherapy treatment for urothelial 
carcinoma.  Pembrolizumab has been approved by the US Food and Drug Administration (FDA), 
but it has not been approved for use in this manner, at this dose and for this condition. The goal 
of this study is to determine if paclitaxel and pembrolizumab together can treat urothelial 
carcinoma better than paclitaxel alone, as well as determine how well this combination of drugs 
is tolerated by subjects. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
30 people will take part in this study.
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WHAT IS INVOLVED IN THE STUDY?
Screening
During the first study visit, called a screening visit, you will have medical tests and procedures 
performed to help the study doctor decide if you meet the requirements to be in the study. These 
include an assessment of your medical history, a physical examination, labs, tumor assessments, 
and collection of a tumor tissue sample, unless we already have a sample of your tumor stored at 
the Wake Forest Baptist Health Tumor Bank within the last 6 months. If the results show that 
you meet the requirements, you will be enrolled in the study. 
Intervention
The intervention is:  Pembrolizumab (200mg), given once every three weeks as a 30 minute 
intravenous infusion, followed by standard Paclitaxel (80mg/m2), given weekly for 2 of every 3 
weeks as a 1-hour infusion.  As part of standard therapy, you will also be given several 
medications prior to receiving Paclitaxel for the prevention of symptoms such as nausea, 
inflammation, allergic reactions, and acid reflux.  These “pre-meds” can be given either through 
your IV or by mouth, according to current institutional guidelines.
Study visits

The intervention will be given on a 3 week (21 day) cycle.  Patients will be seen on day 1
of each cycle for a physical exam, labs, and to receive treatment.  Patients will also have
labs and treatment on day 8 of each cycle.

Every 9 weeks, you will have an examination of your tumor(s) by computed tomography
(CT) - an X-ray that uses radiation to produce pictures of your body including tumors, or
magnetic resonance imaging (MRI) - a magnetic field to produce an image of your body
including tumors.  Your study doctor will determine which type of test (either CT or
MRI) is best to assess your cancer.

In addition to the intervention, at the initial visit and every 12 weeks thereafter, blood and
urine samples will be drawn to examine immune response.
Blood drawing
Samples of your blood and urine will be collected throughout the study.  Blood will be taken 
from a vein in your arm using a needle.  For the immune studies, about 2 tablespoons of blood 
will be collected at screening and then every 12 weeks. 
Study participant responsibilities
If you agree to participate in this study, you have certain responsibilities to help ensure your 
safety. These responsibilities are listed below.

Complete all required visits

Take the study medications as prescribed

Report all side effects and medical problems to the study personnel

Inform the study doctor or staff if you decide to discontinue your participation. You will
be asked to complete an end of treatment visit
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HOW LONG WILL I BE IN THE STUDY?
This combination intervention will continue for 6 months (24 weeks) unless your cancer 
progresses, you can no longer tolerate the intervention, your doctor believes it is no longer in 
your best interest to continue the study treatment, or you decide to withdraw from the study.  
After you finish receiving intervention on this study, you will have an End of Treatment study 
visit with a physical exam, labs, and imaging.  At this visit, if your cancer has progressed 
(continued to grow or spread), you will not receive additional treatment as part of this study.  
Your cancer doctor will discuss other treatment options with you.  You will be contacted by a 
member of your study doctor’s research team about every 3 months to see how you are doing 
and ask for an update on other anti-cancer therapies you have taken. This will likely be done 
during a routine clinic visit with your doctor but may be done by telephone.
If your cancer is stable but not gone, and your response to the initial therapy was good, you will 
have the option of remaining on pembrolizumab alone for an additional 18 months or until your 
disease progresses.  If you choose to do this, you will enter a “maintenance phase” where you 
will be seen every 21 days, given the pembrolizumab only, and have routine blood tests done.  
Additionally, you will have imaging and thyroid blood tests done every 3 months (+/- 10 days).  
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first.
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. One risk is that you may get a drug or dose of a drug that does not help treat 
your disease or that makes your condition or disease worse. Another risk is that there may be 
side effects. Risks and side effects related to the drugs we are studying include: fatigue, cough, 
nausea/vomiting, itchy skin, rash, decreased appetite, constipation, muscle aches, diarrhea, 
mouth sores, hair loss, and low blood counts. 
Pembrolizumab treatment may result in auto-immune complications, which is when your 
immune system attacks your normal tissues and organs instead of, or in addition to, the cancer.   
Immune-mediated serious (may cause hospitalization and/or death) side effects seen in 1.0% or 
less of patients treated with pembrolizumab include the following:

Inflammation of the skin so you may have widespread peeling of the skin, itching,
skin redness.  In very rare cases, this can be severe enough to cause
hospitalization and/or lead to death.

Inflammation of the bowels/gut so you may feel stomach pain with loose or
watery stools or stools that are black, tarry, sticky or have blood or mucus

Inflammation of the middle layer of the heart wall (called myocarditis).  This can
lead to hospitalization and/or death.

Inflammation of the lungs so you may feel short of breath and cough.  This can
cause scarring in the lungs or pneumonia and rarely can lead to death.
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
Inflammation of the liver that may cause a poor appetite, feeling tired, mild fever,
muscle or joint aches, upset stomach and vomiting, bleeding and bruising more
easily than normal, stomach pain, yellow eyes and skin, and dark urine

Inflammation of the pituitary gland (a gland in the head), which may cause
headaches, upset stomach, changes in behavior, double vision, few to no
menstrual cycles, weakness, vomiting and dizziness or fainting.  This
inflammation of the pituitary gland may cause the adrenal glands (on top of the
kidneys) to not make enough hormone causing tiredness, weight loss, muscle
weakness, feeling faint, joint, muscle and abdominal aches, nausea, vomiting,
diarrhea, fever, salt craving, rapid heart rate, and sometimes darkening of the skin
like a suntan.

Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak,
tremble, increased sweating, weight loss, hair loss, tired, have diarrhea

Too little thyroid hormone so you may feel tired, gain weight, feel cold, voice
gets deeper, hair loss, have infrequent or hard bowel movements

Inflammation of the kidney so you may pass less urine or have cloudy or bloody
urine, swelling and low back pain

Inflammation of the muscles so you may feel weak or pain in the muscles

Inflammation of the pancreas, (a gland in your abdomen that controls sugar
levels) so you may have severe upper abdominal pain that may move to the back,
sick to your stomach, and vomiting that gets worse when you eat

Inflammation of the eye so you may have redness of the eye, blurred vision,
sensitive to light, have eye pain, see floaters or have headaches

Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of
breath or sick to your stomach at the time of receiving your infusion (IV) or just
after, or pain at the site of infusion

Inflammation of the pancreas (diabetes) so you may have too much sugar in your
blood, may need to urinate more often, lose weight, feel thirsty, and may need
regular insulin shots

Inflammation of the nerves that may cause pain, weakness or tingling in the hands
and feet, and may spread to the legs, arms and upper body leading to severe
muscle weakness

Gastrointestinal Bleeding, also known as gastrointestinal hemorrhage:  a
significant blood loss over a short period of time that can occur from the mouth to
the rectum. Symptoms may include vomiting red blood, vomiting black blood,
bloody stool, or black stool
Paclitaxel treatment may cause neuropathy, or numbness/tingling of hands and feet.  Allergic 
reactions to paclitaxel are possible and steroids are given prior to each treatment to prevent this.  
It is possible that the steroids given to prevent allergic reactions may make the pembrolizumab 
treatment less effective.   Furthermore, the exact dosing schedule of paclitaxel used in this study 
has not been evaluated in patients with urothelial cancer previously.    
There may be other treatment-related side effects or risks that are not known at this time.
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Meeting Date Approved 12/30/2019          
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Possible risks from study procedures
Blood tests: You may experience discomfort, bruising and/or bleeding where the needle is 
inserted. Occasionally some people become dizzy lightheaded or feel faint. Infection may occur 
on rare occasions.  Frequent blood tests can result in low iron in your blood (iron deficient 
anemia).  
CT scans: Participation in this research study will involve exposure to radiation from the CT 
scan. The amount of radiation exposure that you will receive from each CT scan is considered 
minimal. The more radiation received over the course of your life increases the risk of cell 
changes in your body or having cancerous tumors.  The radiation from this study is not expected 
to greatly increase these risks, but the exact increase of such risks is unknown.
Some CT scans require you to take a “contrast solution” either by mouth, enema, or injection 
into a vein. Although rare, the contrast solution may cause an allergic reaction such as nausea, 
vomiting, itching, skin rash, or in very rare instances a swelling of the throat and difficulty in 
breathing. If you feel any of these symptoms of an allergic reaction you must tell the staff 
immediately so that you can be treated without delay.   In addition, because you must lie with 
your head and neck inside the narrow scanner tube, you may become anxious and frightened 
inside the enclosed space (claustrophobic).
MRI: When having an MRI (Magnetic Resonance Imaging) scan, you will lie still on a table that 
slides into a tunnel slightly wider than your body. People who feel uncomfortable in confined 
spaces (claustrophobia) may feel uncomfortable in the narrow cylinder. If you feel 
uncomfortable in confined spaces, please tell your study doctor. Your study doctor may give you 
a medication to make you feel more comfortable in a confined space. MRIs use powerful 
magnets to make images. Therefore, persons with certain metal implants, such as pacemakers, 
should not have an MRI. If you have an implant or any metal in your body, please check with 
your study doctor to see whether you can have an MRI or not. For people without metal 
implants, there are no known health risks associated with exposure to the magnet. As images are 
taken, a loud banging noise will be produced. Earplugs or headphones may be available if 
needed. The MRI can be stopped at any time at your request, but the scan may not be complete.
Fresh Biopsy: If we do not have a sample of tumor tissue stored at the Wake Forest Baptist 
Health Tumor Bank within the last 6 months, will need to perform a fresh biopsy.  A CT scan or 
ultrasound may be used to guide the doctor to the site of the tumor where the biopsy will be 
taken.  Numbing medicine (local anesthetic) will be injected around the site where a needle-like 
instrument will be inserted into your tumor and a small piece of tissue will be removed. The site 
where the needle-like instrument is inserted may need a stitch (or suture) that will later be 
removed by a nurse or a doctor.
Risks associated with tumor biopsy procedures (s) can be:
Likely: Minor local bleeding, pain at the needle insertion site; a swelling under 
the skin that contains blood (hematoma); sleepiness, if you choose to receive a 
‘pain killer’ and/or medicine to make you relax
Unlikely but serious: Infection; shortness of breath that sometimes need you to be 
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Meeting Date Approved 12/30/2019          
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CCCWFU #88215
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admitted to the hospital for observation and a temporary placement of a chest tube  
to allow you to breath, slow heart rate, and low blood pressure. 
Taking part in this research study may involve providing information that you consider 
confidential or private. We will do our best to protect your confidential information. Efforts, 
such as coding research records, keeping research records secure and allowing only authorized 
people to have access to research records, will be made to keep your information safe. There also 
may be other side effects that we cannot predict. You should tell the research staff about all the 
medications, vitamins and supplements you take and any medical conditions you have. This may 
help avoid side effects, interactions and other risks.
Reproductive Risks and other Issues to Participating in Research
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential and men whose female partner can have children must use a reliable 
method of birth control while participating in this study and for 120 days (approximately 4.5 
months) after your last dose of study drug. Reliable methods of birth control are: abstinence (not 
having sex), oral contraceptives, intrauterine device (IUD), DepoProvera, tubal ligation, or 
vasectomy of the partner (with confirmed negative sperm counts) in a monogamous relationship 
(same partner). An acceptable, although less reliable, method involves the careful use of 
condoms and spermicidal foam or gel and/or a cervical cap or sponge. If you suspect that you or 
your partner may have become pregnant during the study, contact the study doctor immediately. 
Your study doctor will want to follow you and the progress of your pregnancy until the baby is 
born. We encourage you to discuss this issue further with your physicians if you have any 
questions.
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required prior to study entry, if you are a 
sexually active woman of childbearing potential.
Contraceptive Measures for Males
Your participation in this research study may damage your sperm, which could cause harm to a 
child that you may father while on this study. Such harm may be currently unforeseeable. If you 
are sexually active, you must agree to use a medically acceptable form of birth control in order to 
be in this study and for 120 days (approximately 4.5 months) afterwards. Medically acceptable 
contraceptives include: (1) surgical sterilization (such as a vasectomy), or (2) a condom used 
with a spermicide. Contraceptive measures such as Plan B (TM), sold for emergency use after 
unprotected sex, are not acceptable methods for routine use. You should inform your partner of 
the potential for harm to an unborn child. She should know that if pregnancy occurs, you will 
need to report it to the study doctor, and she should also promptly notify her doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You may not receive any direct benefit from participating in this study. In some patients, the 
cancer may stop spreading, may shrink in size, or may become undetectable. Even if you do not 
receive any personal benefit from this study, your participation may benefit future patients by 
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helping develop a new therapy for others with similar conditions.
WHAT OTHER CHOICES ARE THERE?
If you do not wish to participate in this study, you may continue to be treated by your doctor and 
your care will not be jeopardized in any way. Your doctor will discuss other treatment options 
available to you. For example, you may receive paclitaxel without participating in this study.  
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes results from 
your blood tests, physical examinations and other tests. It also includes identifying information 
such as your name and date of birth. 
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. We will make every effort to keep your Protected Health Information private. We 
will store records of your Protected Health Information in a cabinet in a locked office or on a 
password protected computer. 
Your Protected Health Information and other information that identifies you may be given to 
others during and after the study. This is for reasons such as to carry out the study, to determine 
the results of the study, to make sure the study is being done correctly, to provide required 
reports, and to get approval for new products. 
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS) and similar agencies in other countries.
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations. Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
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Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished. The results of this study 
may be presented at meetings or in publications; however, your identity will not be disclosed in 
these presentations. Individual results from optional tumor biopsy analysis will not be provided 
to you or your study doctor and will not be placed in your medical chart considering that all this 
data is still investigational and not part of the standard of care procedures.
You can tell Michael Goodman, MD that you want to take away your permission to use and 
share your Protected Health Information at any time by sending a letter to this address:
Michael Goodman, MD
Wake Forest Baptist Health
Section on Hematology and Oncology
Medical Center Blvd.
Winston-Salem, NC  27157
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
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information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
WHAT ARE THE COSTS?
Taking part in this study may lead to added costs to you or your insurance company. We will 
give you an estimate of what the added cost may be based on your particular situation and 
insurance coverage.  You or your insurance company will be charged for any portion of your 
care that is considered standard.  This includes treatment with the standard chemotherapy drug 
Paclitaxel and any other preventative medications given to you during your infusion.
The investigational study drug, Pembrolizumab, will be provided by the study sponsor, Merck, at 
no cost to you.  You will not need to pay for any tests or procedures that are done for the sole 
purpose of this study. You may be responsible for any co-payments and deductibles that are 
standard for your insurance coverage. There will be no additional cost to you to participate in 
this research study. 
Your involvement in this research study is voluntary and you will not be paid for your 
participation. The findings from this research may result in the future development of products 
that are of commercial value. There are no plans to provide you with financial compensation or 
for you to share in any profits if this should occur.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study. Parking 
validation will be provided for all study-related visits.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by Merck & Co., Inc. The sponsor is providing money or other 
support to Wake Forest University Health Sciences to help conduct this study. The researchers 
do not, however, hold a direct financial interest in the sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management.
If you are injured, the sponsor may require information such as your name, social security 
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number, and date of birth in order to pay for your care.  This is because the sponsor is required 
by law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study 
related illness, adverse event, or injury you should call study personnel.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
You may or may not receive any direct benefit from participating in this study. Taking part 
in this study is voluntary. You may choose not to take part or you may leave the study at any 
time. Refusing to participate or leaving the study will not result in any penalty or loss of 
benefits to which you are entitled. If you decide to stop participating in the study we encourage 
you to talk to the investigators or study staff first to learn about any potential health or safety 
consequences. 
Information that identifies you may be removed from the data or specimens that are collected as 
part of this study and could be used for future research or shared with others without additional 
consent.
To ensure your safety, you will be asked to undergo a final evaluation visit. The investigators 
also have the right to stop your participation in the study at any time. This could be because it is 
in your best medical interest, your condition worsened, new information becomes available, you 
had an unexpected reaction, you failed to follow instructions, or because the entire study has 
been stopped. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, or study personnel.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB.
You will be given a copy of this signed consent form. 
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IRB Number: IRB00035397
Meeting Date Approved 12/30/2019          
Version Valid Until: 9/9/2020


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SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00035397
Meeting Date Approved 12/30/2019          
Version Valid Until: 9/9/2020