A Phase II Study of Tadalafil and Pembrolizumab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Head and Neck Cancer, Head and Neck Squamous Cell Carcinoma, Head and Neck Carcinoma, Head and Neck Cancer Stage III, Head and Neck Cancer Stage IV, Head and Neck Cancer Metastatic, Cancer, Cancer of Esophagus, Cancer, Metastatic, Cancer of Head and Neck, Cancer of Mouth, Cancer of Neck
Sponsor: University of California, San Diego

A Phase II Study of Tadalafil and Pembrolizumab in 
Recurrent or Metastatic Head and Neck Squamous 
Cell Carcinoma 
NCT03993353
Document Date: 5/5/2020

UCSD Moores Cancer Center 
Joseph Califano, MD 
HRPP #190098 
Confidential – Califano 
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HRPP #190098 – Version 1.3 (05-May-2020) 
A Phase II Study of Tadalafil and Pembrolizumab in Recurrent or Metastatic Head and Neck 
Squamous Cell Carcinoma  
PRINCIPAL INVESTIGATOR 
Joseph Califano, MD  
UCSD Moores Cancer Center  
3855 Health Sciences Dr #2237 
La Jolla, CA 92093  
Phone: 858-822-7766 (p)  
E-mail: jcalifano@ucsd.edu
Protocol Number:  190098 
Investigational Product: Tadalafil and Pembrolizumab 
Protocol Version:  Version 1.3 (05-May-2020) 
Protocol 
Date 
Original v 1.0 
Protocol v1.1 
Protocol v1.1 
Protocol v1.2 
04-Mar-2019
07-May-2019
19-Jun-2019
30-Dec-2019

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
Confidential – Califano 
 
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LIST OF INVESTIGATORS  
  
PRINCIPAL INVESTIGATOR  
   
Joseph Califano, MD   
UCSD Moores Cancer Center  
3855 Health Sciences Drive, #2237 
La Jolla, CA 92093-0820 Phone: 
(858) 534-7766  
E-mail:  jcalifano@ucsd.edu  
  
  
CO-INVESTIGATOR(S)  
Assuntina G. Sacco, M.D., Hematology-Oncology, agsacco@ucsd.edu  
Gregory Daniels, M.D., Hematology-Oncology, gdaniels@ucsd.edu  
Kevin Brumund, M.D., Head and Neck Surgical Oncology, kbrumund@ucsd.edu  
Charles Coffey, M.D., Head and Neck Surgical Oncology, cscoffey@ucsd.edu  
Ezra Cohen, M.D., Hematology-Oncology, ecohen@ucsd.edu  
Ryan Orosco, MD, Otolaryngology-Head and Neck Surgery, rorosco@ucsd.edu  
Loren Mell, MP, Director, Division of Clinical and Translational Research/ Department of 
Radiation Medicine and Applied Sciences, lmell@ucsd.edu   
Andrew Sharabi, MD, Radiation Medicine, ansharabi@ucsd.edu  
Parag Sanghvi, M.D., Radiation Medicine, psanghvi@ucsd.edu  
Kathryn Gold, M.D., Hematology-Oncology kgold@ucsd.edu  
Scott Lippman, M.D., Hematology-Oncology slippman@ucsd.edu   
  
BIOSTATISTICIAN:  
Karen Messer, Ph.D, Family Medicine and Public Health, kmesser@ucsd.edu  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
Confidential – Califano 
 
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 A Phase II Study of Tadalafil and Pembrolizumab in Recurrent or Metastatic Head and Neck 
Squamous Cell Carcinoma  
 
Signature Page  
  
  
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal regulations and ICH guidelines.  
  
  
  
Principal Investigator (PI) Name: Joseph Califano, M.D.  
  
  
  
PI Signature: _____________________________  
  
  
  
Date: ____________________  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
Confidential – Califano 
 
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SYNOPSIS  
  
Study Title:  
A Phase II Study of Tadalafil and Pembrolizumab in Recurrent or 
Metastatic Head and Neck Squamous Cell Carcinoma  
Protocol Number:  
190098 
Study Phase:  
2  
Study Duration:  
36 months  
Sample Size  
Up to 30 patients will be enrolled  
  
Investigational Product and 
Reference Therapy:  
Tadalafil will be supplied  by Lilly as 10 mg tablets  
Pembrolizumab will be supplied commercially as a clear, colorless liquid 
formulated for intravenous administration.   
Objectives:  
Primary Objective:  
To determine the efficacy (overall survival at 12 months) and safety (rate 
of dose limiting toxicity) for the combination of Tadalafil and 
Pembrolizumab. 
 
Secondary objectives are to assess:  
• 
Response rate by RECIST 1.1  
• 
Progression-free survival  
• 
Safety and toxicity profile   
• 
Duration of response  
Study Design:  
Open-label phase II single arm trial with a Pocock continuous safety 
stopping rule and a Simon 2 stage efficacy design.  All patients will 
receive Tadalafil and Pembrolizumab  
Population:  
This study will enroll patients with head and neck squamous cell 
carcinoma not amenable to curative intent therapy with combined positive 
score (CPS) >1.  
Centers:  
University of California San Diego Moores Cancer Center  
Selected Inclusion Criteria:  
Refer to Section 3.0 for the 
complete and detailed list of 
inclusion/exclusion criteria.  
Disease Related  
• 
Histologically or cytologically proven squamous cell carcinoma of 
the head and neck not amenable to curative intent   
• 
Presence of measurable tumor lesions per RECIST criteria v1.1  
• 
Detectable PD-L1 expression in tumor defined as CPS≥1  
• 
Life expectancy greater than 12 weeks.  
 
Laboratory  
• 
Adequate hematologic, hepatic, and renal function  
• 
Negative serum or urine pregnancy test for women of child bearing 
potential  
 
Demographic  
• 
Men and women ≥ 18 years of age.  

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• 
Eastern Cooperative Oncology Group (ECOG) performance status of 
0-1 
 
Selected Exclusion Criteria:  Disease-Related  
• 
Prior therapy with an PD-1 or PD-L1 inhibitor in the recurrent or 
metastatic setting  
• 
Uncontrolled central nervous system metastases (stable metastases 
permitted)  
• 
Active autoimmune disease  
 
Concurrent Conditions  
• 
Chemotherapy ≤28 days prior to first administration of study  
treatment and/or monoclonal antibody ≤8 weeks prior to first 
administration of study treatment.  
• 
History of other malignancies, except:   
• 
Malignancy treated with curative intent and with no known  
          active disease present for ≥3 years before the first dose of study drug 
          and felt to be at low risk for recurrence by treating physician.  
• 
Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease.  
• 
Adequately treated carcinoma in situ without evidence of disease.   
• 
Medical contraindication to biopsy of target lesion  
• 
Prior daily use of tadalafil or other long-acting PDE5 inhibitors for 
one month or greater within 3 months of trial enrollment  
• 
Current use of all other long-acting PDE5 inhibitors. 
• 
Known severe hypersensitivity to tadalafil or any of the excipients 
of this product  
• 
Current treatment with nitrates  
• 
Current systemic treatment with a potent cytochrome P450 3A4 
(CYP3A4) inhibitor such as ketoconazole or ritonavir.  
• 
Current treatment with guanylate cyclase (GC) stimulators such 
as riociguat.  
• 
History of hypotension and/or blindness and/or sensorineural 
hearing loss during prior treatment with tadalafil or other PDE-5 
inhibitors   
• 
History of known hereditary degenerative retinal disorders, 
including retinitis pigmentosa 
• 
Prior history of  non-arteritic anterior ischemic optic neuropathy 
• 
Pregnant or breastfeeding; a negative pregnancy test is required 
within 14 days of randomization for all women of childbearing 
potential.  
• 
Concurrent malignancy or a history of previous malignancy treated 
with curative therapy within the last 3 months (other than 
squamous/basal cell cancer of the skin or cervical cancer), for which 
the survival prognosis is < 5 years  
• 
Treatment with a non-approved or investigational drug within 30 
days before visit   
• 
Incomplete healing from previous oncologic or other major surgery 

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HRPP #190098 
 
 
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• 
As judged by the investigator, any evidence of severe or 
uncontrolled systemic disease (e.g., unstable or uncompensated 
respiratory, cardiac, hepatic, or renal disease or impairment) 
• 
Evidence of any other significant clinical disorder or laboratory 
finding that makes it undesirable for the subject to participate in the 
trial  
• 
History of significant hypotensive episode requiring hospitalization  
• 
History of stroke within prior 6 months. 
• 
History of acute myocardial infarction within prior 3 months, 
uncontrolled angina, uncontrolled arrhythmia, or uncontrolled 
congestive heart failure  
• 
History of any of the following cardiac conditions:  
• 
Left ventricular outflow obstructions, such as aortic stenosis and 
idiopathic hypertrophic subaortic stenosis 
• 
Angina requiring treatment with long-acting nitrates  
• 
Angina requiring treatment with short-acting nitrates within  
90 days of planned tadalafil administration 
• 
Unstable angina within 90 days of visit 1 (Braunwald 1989)  
• 
Positive cardiac stress test without documented evidence of 
subsequent, effective cardiac intervention  
• 
History of any of the following coronary conditions within 90 days 
of planned tadalafil administration: o Myocardial Infarction  
o Coronary artery bypass graft surgery  
o Percutaneous  coronary  
intervention  
(for 
 
example,  
angioplasty or stent placement)  
o Any evidence of heart disease (NYHA ≥ Class II as 
defined in Protocol Attachment LVHG.3) within 6 
months of planned tadalafil administration  
• 
Concurrent systemic immunosuppressant therapy (e.g., cyclosporine 
A, tacrolimus, etc., or chronic administration of >10 mg/day of 
prednisone or equivalent)   
• 
Prior organ transplantation  
• 
Known history of human immunodeficiency virus (HIV) or active 
infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).   
• 
Any life-threatening illness, medical condition, or organ system 
dysfunction that, in the investigator’s opinion, could compromise 
the subject’s safety or put the study outcomes at undue risk.  
 
 
Study Treatment:  
Treatment will be administered in 21 day cycles with the following dose 
schedule, for up to 24 months:  
 
Drug 
Tadalafil (10mg 
po daily) for up to 
12 months 
Pembrolizumab will 
be administered at 
200 mg IV q3 weeks 
for 24 months (35 
cycles) 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
Confidential – Califano 
 
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                  Dosage  
            10 mg  
                       200 mg 
 
 
Safety Plan:  
  
Data safety and toxicity will be continuously monitored in the study under 
the guidance from the Data Safety Monitoring Committee.   

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
Confidential – Califano 
 
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Statistical Methods and 
Data Analysis:  
This is a phase II study to investigate both safety and efficacy.  
  
The primary safety endpoint is the rate of DLT.  
The primary efficacy endpoint is overall survival (OS) at one year  
  
Secondary endpoints include progression free survival, best overall 
response rate by RECIST 1.1 and tolerability.  
 
Safety will be assessed by computing the DLT rate every 6 months, 
assuming an expected Grade 3 or 4 toxicity rate of 17% for  
Pembrolizumab alone. A Pocock sequential stopping boundary will be 
used, which will stop the trial early with 56% probability, and with < 2 
expected excess events, if the rate of DLT is elevated to 30%.  The trial 
will stop early with 89% probability and < 1 expected excess event if the 
DLT rate is elevated to 40%.    
If safety is satisfied, the primary efficacy analysis will use a Simon 
optimal design, testing one-year OS against a 51% null survival rate   and 
a 74% alternative rate (survival with tadalafil and Pembrolizumab 
combination). 1   
The Simon optimal 2 stage design will examine OS once 14 patients have 
been recruited. An OS rate of 8/14 or greater will result in study 
continuation. If 19 or more subjects experience survival of at least 12 
months among these 30 subjects, the null hypothesis will be rejected and 
the conclusion will be that the survival rate is significantly elevated above 
51%.   
Demographic and clinical characteristics of the patients will be 
summarized by treatment group using frequency counts and percentages, 
means and standard deviations or medians and interquartile ranges, as 
appropriate. Best overall response will be determined by RECIST 1.1 and 
will be summarized as proportion with 95% confidence intervals. Adverse 
events will be summarized by grade, type and patient. Progression-free 
survival, overall survival, and duration of response will be described by 
Kaplan-Meier models to plot these endpoints and estimate median times 
with a 95% confidence interval.   
  
Safety will be evaluated according to the CTCAE v5.0. Safety  
assessments will be based on medical review of adverse event reports and 
the results of vital sign measurements, physical examinations, and clinical 
laboratory tests throughout the conduct of the study. Laboratory test 
abnormalities will be reviewed for clinical significance and only those 
deemed clinically significant will be reported as adverse events. 
Sample Size Determination 
Up to 30 patients will enroll on this trial, depending on initial safety 
assessment. 
 

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HRPP #190098 
 
 
Confidential – Califano 
 
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TABLE OF CONTENTS   
List of investigators..........................................................................................................................2 
SYNOPSIS.......................................................................................................................................4  
1.OBJECTIVES.............................................................................................................................11  
1.1 Primary Objective ...................................................................................................................11  
1.2 Secondary Objectives...............................................................................................................11  
2 BACKGROUND .......................................................................................................................11  
2.1 Head and Neck Squamous Cell Carcinoma ........................................................................... 11  
2.2 Pembrolizumab .......................................................................................................................12  
2.3 Tadalafil ..................................................................................................................................13  
2.4 Antitumor immune effects of tadalafil ....................................................................................13  
2.5 Preclinical data ........................................................................................................................14  
2.6 Current trials with combination tadalafil and nivolumab .......................................................15  
2.7 Rationale .................................................................................................................................15  
3 PATIENT SELECTION ............................................................................................................16  
3.1 Eligibility Criteria ...................................................................................................................16  
3.2 Exclusion Criteria ...................................................................................................................17  
4 TREATMENT PLAN ................................................................................................................19  
4.1 Dosing and Agent Administration ..........................................................................................19  
4.2 Pembrolizumab Administration ..............................................................................................20  
4.3 Tadalafil Administration .........................................................................................................20  
4.4 Definition of Dose-Limiting Toxicity (DLT) .........................................................................21  
4.5 General Concomitant Medication and Supportive Care Guidelines .......................................21  
4.6 Duration of Therapy ................................................................................................................22  
4.7 Duration of Follow Up ............................................................................................................22  
4.8 Criteria for Removal from Study ............................................................................................22  
5 DOSE MODIFICATIONS .........................................................................................................23  
5.1 Dose Modifications for Pembrolizumab .................................................................................23  
5.2 Dose Modifications for Tadalafil ............................................................................................29  
6 ADVERSE EVENTS AND REPORTING ................................................................................31  
6.1 Reporting Requirements for Adverse Events .........................................................................34  
6.2 Safety Reporting to Lilly ........................................................................................................36  
7 PHARMACEUTICAL AGENT SAFETY INFORMATION ...................................................36  
7.1 Tadalafil Safety Information ...................................................................................................41  
7.2 Safety of Combination Tadalafil and PD-1 inhibitor Therapy ...............................................43  
8 STUDY PROCEDURES AND CALENDAR ...........................................................................43  
8.1 Informed Consent.....................................................................................................................44  
8.2 Medical History and Physical Exam .......................................................................................44  
8.3 Clinical Laboratory Tests ........................................................................................................44  
8.4 Tumor Tissue Biopsy….. ........................................................................................................44 
8.5 Research Blood Collection......................................................................................................45 
8.6 Specimen Banking…….. ........................................................................................................46    
8.7 Radiographic Assessment .......................................................................................................46  
8.8 Extended Safety Follow-Up ....................................................................................................46 
8.9 Discontinuation from Study Participation...............................................................................46  
8.10 Study Calendar ......................................................................................................................47  

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9 MEASUREMENT OF EFFECT...............................................................................................48  
9.1 Antitumor Effect ...................................................................................................................48  
10 DATA REPORTING / REGULATORY REQUIREMENTS ...............................................54  
10.1 Conflict of Interest ...............................................................................................................54  
10.2 Institutional Review Board (IRB) Approval and Consent ...................................................54  
10.3 Patient Registration ..............................................................................................................55  
10.4 Subject Data Protection........................................................................................................55  
10.5 Data and Safety Monitoring/Auditing .................................................................................55  
10.6 Adherence to the Protocol ...................................................................................................56  
10.7 Amendments to the Protocol ...............................................................................................57  
10.8 Record Retention .................................................................................................................57  
10.9 Obligations of Investigators .................................................................................................57  
11 STATISTICAL CONSIDERATIONS....................................................................................58  
11.1 Study Design ........................................................................................................................58  
REFERENCES .............................................................................................................................61  
APPENDIX I   PERFORMANCE STATUS CRITERIA .............................................................63  
APPENDIX  II    ECOG PERFORMANCE STATUS.................................................................64  
APPENDIX  III  Management Algorithms For Endocrinopathy, Gastrointestinal, Hepatic,  
Neurological, Pulmonary, Renal, And Skin Adverse Events .......................................................65  
APPENDIX IV Instructions for Reporting Pregnancies on a Clinical Trial ………....................73 
APPENDIX V UCSD Moores Cancer Center Data Monitoring Plan…………………………...75  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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HRPP #190098 
 
 
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1. OBJECTIVES  
  
1.1  
Primary Objective  
  
To determine the efficacy for the combination of tadalafil and pembrolizumab, as assessed by the 
overall survival (OS) at 12 months post-enrollment. 
 
To determine the safety for the combination of tadalafil and pembrolizumab, as assessed by the 
rate of dose limiting toxicity (DLT) at least possibly related to study treatment.  
 
  
1.2  
Secondary Objectives  
  
Secondary objectives are to assess:  
• 
Response rate by RECIST 1.1  
• 
Progression-free survival  
• 
Safety and toxicity profile   
• 
Duration of response  
  
2. BACKGROUND  
  
2.1  
Head and Neck Squamous Cell Carcinoma  
  
Head and neck cancer is the sixth most common cancer worldwide with the predominant 
histology involving squamous cell carcinoma (HNSCC). Within the United States, HNSCC 
accounts for 3% of all cancers diagnosed annually and 2% of cancer-related deaths.2 The 
majority of patients with HNSCC initially present with locally advanced disease.  Despite 
aggressive, combined modality treatment, a significant proportion of patients will develop 
recurrent or metastatic (R/M) disease that is no longer amenable to curative therapy.3 Existing 
treatment options including platinum based doublets, EGFR inhibition, and immunotherapy, but 
outcomes are generally poor, and most patients die within a year of diagnosis of R/M HNSCC.4,5 
Targeted immunotherapy promoting anti-tumor T-cell activity initially demonstrated improved 
survival and durable objective responses in advanced melanoma [12]. As PD-L1 expression is 
observed in close to 68% of HNSCC patients regardless of HPV status [13, 14], targeting 
PD1/PD-L1 in HNSCC was also a rational approach for study. Initially, Pembrolizumab was 
studied in a Phase Ib study in patients with recurrent/metastatic disease [15]. In this study a 
significant clinical benefit with a response rate of close to 18% as well as a prolonged PFS was 
noted in heavily pretreated patients. Furthermore, the benefit was comparable between HPV-
positive and negative groups. Pembrolizumab is now approved for use in recurrent or metastatic 
platinum refractory disease. In addition, the results from Checkmate-141, a phase III trial 
randomizing patients with recurrent or metastatic platinum-refractory HNSCC to Nivolumab 
versus investigator’s choice of chemotherapy, has shown a doubling of the 1-year overall 
survival (36.0% versus 16.6%, p= 0.01); this occurred regardless of p16 status [16]. Based on 

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HRPP #190098 
 
 
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these data Pembrolizumab is approved in patients with recurrent or metastatic platinum 
refractory HNSCC.  
  
Recently, data from Keynote-048 have been released, demonstrating improved overall survival 
for single agent pembrolizumab compared to standard of care cytotoxic chemotherapy in first 
line, recurrent/metastatic head and neck squamous cell carcinoma with PD-L1 expression. 1 
Single agent pembrolizumab demonstrated a 51% 12 month OS vs. 43.6% for EXTREME 
regimen (combination Cetuximab, carboplatin/cisplatin, and 5-fluorouricil), as well as 
superiority of pembrolizumab with a 30.2% vs 18.6% 24 month OS (p=0.0086). In addition, 12 
month progression free survival was superior in the pembrolizumab arm (19.6% and 11.2% at 12 
and 24 months, respectively) compared to the EXTREME arm (11.9 and 5.4% at 12 and 24 
months, respectively), HR 1.16 (1.16 (0.96-1.39, 95% CI)) although not statistically significant.  
In addition, grade 3-5 toxicity in the pemrolizumab arm was 16.7% compared to 69% in the 
EXTREME arm.  
These data define a new standard of care of single agent pembrolizumab as first line therapy in 
PD-L1 expressing recurrent or metastatic head and neck squamous cell carcinoma.  
  
2.2  
Pembrolizumab  
  
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T 
cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors 
and signaling through this pathway can contribute to inhibition of active T-cell immune 
surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor 
and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition 
of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor 
models, blocking PD-1 activity resulted in decreased tumor growth. Other checkpoint inhibitors, 
including PD-1 inhibitors nivolumab and PD-L1 inhibitor durvalumab, have also been studied in 
head and neck cancer.  Pembrolizumab and Nivolumab have shown activity in large trials and 
have been FDA approved for use in recurrent and metastatic HNSCC.  
  
For the most comprehensive nonclinical and clinical information regarding Pembrolizumab 
background, safety, efficacy, and in vitro and in vivo preclinical activity and toxicology refer to 
the latest version of the pembrolizumab Investigator's Brochure.   
2.3  
Tadalafil  
  
Tadalafil is a PDE5 inhibitor marketed in pill form for treating erectile dysfunction (ED) and for 
the treatment of pulmonary arterial hypertension. In October 2011 the U.S. Food and Drug 
Administration (FDA) approved Cialis for treating the signs and symptoms of benign prostatic 
hyperplasia (BPH) as well as a combination of BPH and erectile dysfunction when the conditions 
coincide.  

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For the most comprehensive nonclinical and clinical information regarding tadalafil background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology refer to the latest 
version of the tadalafil Package Insert.  
2.4  
Antitumor immune effects of tadalafil  
  
Efforts to augment anti-tumor 
immunity need to focus on overcoming 
the immunosuppressive mechanisms 
that currently represent the greatest 
barrier to clinically effective 
immunotherapy. Murine as well as 
human data are increasingly shedding 
light on putative targets and potential 
therapeutic interventions aimed at 
reversing NO production or arginase 
activity in MDSC-mediated 
immunosuppression.    In fact, in vitro 
studies employing either L-norvaline or 
L-NMMA –inhibitors of arginase-1 or  
iNOS, respectively, augmented antigen specific responses. 6  However, their use in the clinical 
setting proved excessively toxic resulting in increased mortality. 7  Nitroaspirin derivatives have 
also been shown to reduce arginase-1 expression and to augment T cell function when combined 
with a DNA-based vaccine8. However, the absence of a measurable anti-tumor effect when 
administered as a single agent coupled to its unavailability for clinic studies limits its overall use. 
In attempting to develop a therapeutic strategy that can be quickly tested clinically, we focused 
on phosphodiesterase-5 (PDE5) inhibitors. As shown in Figure 1, PDE5 blockade increases 
intracellular cGMP which, in turn, destabilizes NOS2 mRNA by reducing the ubiquitous mRNA 
binding protein, human antigen-R (HuR) 9.  HuR binds the AU-rich elements in the 
3’untranslated region (UTR) thereby increasing the mRNA half-life 10.  Through this mechanism, 
destabilization of NOS2 mRNA via PDE5 inhibition would abrogate NO-mediated 
immunosuppression more effectively than would the competitive inhibition of NO itself.  
However, considering the role of arginase-1 in MDSC-mediated immunosuppression, we also 
examined the impact of PDE5 inhibitors on Arg1 and found a significant reduction in its 
expression in MDSCs in the presence of sildenafil.  One explanation is that high levels of cGMP 
induced by PDE5 blockade reduces cytosolic Ca2+ concentrations 11 leading to a reduction in the 
calcium-dependent protein kinase C (PKC) activity 12  that in turn prevents upregulation of IL- 
4Rα 13.  
  
Clinical trials at Johns Hopkins and the University of Miami employed phase II, biomarker 
endpoint designs that treated patients for a brief 2-3 week interval prior to institution of standard 
therapy. 14,15 The Johns Hopkins clinical trial was conducted to test the hypothesis that a PDE5 
inhibitor could be used to augment systemic immune function through inhibition of the cancer 
induced MDSCs.  Placebo or tadalafil 20 mg QD was administered for 2 weeks prior to surgery 

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or radiation therapy in patients with head and neck squamous cell carcinoma (HNSCC).  The 
major endpoints of the Johns Hopkins study were laboratory endpoints aimed at demonstrating 
the ability of PDE5 inhibition to modify endogenous immune function in tadalafil vs placebo 
treated patients as measured by peripheral T cell activation and other measures. The University 
of Miami used similar time intervals but the primary endpoint included assessment of tadalafil 
induced augmentation of tumor infiltrating lymphocytes (TILs) in primary tumors treated with 
placebo vs. tadalafil and functionally measuring the response of patients T cells to autologous 
tumor lysate from the patient’s primary tumor. In addition the University of Miami study 
employed two doses of tadalafil, 10 mg QD vs 20 mg QD.  
  
In the Johns Hopkins trial, tadalafil augmented immune response, increasing ex vivo T-cell 
expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), 
reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change 
in control patients (P = 0.001), and increasing general immunity as measured by delayed type 
hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor 
lysate was augmented in tadalafil-treated patients (P = 0.04). These findings demonstrate that 
tadalafil augments general and tumor-specific immunity in patients with HNSCC and has 
therapeutic potential in HNSCC. Of note, the effects of tadalafil on immune parameters were 
independent of tumor site and HPV status.  
  
In the University of Miami trial, MDSCs were characterized in primary HNSCC specimens and 
their intratumoral presence significantly correlated with recurrence. Tadalafil treatment was well 
tolerated and significantly reduced both MDSCs and regulatory T cell concentrations in the 
blood and in the tumor (P < 0.05), and increased CD8+ T-cells in primary tumor. In addition, the 
concentration of peripheral blood CD8+ T-cells reactive to autologous tumor antigens 
significantly increased after treatment (P < 0.05). Taken together, both of these studies indicate 
that tadalafil reduces the inhibitory effect of MDSCs on T-cell function and localization to the 
tumor microenvironment in patients with HNSCC.  In addition, no serious adverse events 
attributable to administration of tadalafil were noted in both of these trials.  
  
Dosing considerations in the University of Miami demonstrated no difference in immune effects 
in the 10 mg vs 20 mg dose, and even noted a potential for dosing advantages with the 10 mg 
QD dose, in that off target effects may be minimized at this dose, without sacrificing the desired 
immune stimulatory effects of tadalafil.  
  
2.5  
Preclinical data   
  
Given the existing clinical trials data demonstrating effectiveness of PD-1 inhibitors in enhancing 
T-cell response in recurrent metastatic HNSCC, and clinical trials demonstrating inhibition of 
MDSC mediated suppression of T-cell response by tadalafil in HNSCC, we hypothesized that 
combination tadalafil and PD-1 inhibition may increase antitumor responses as compared to 
either agent alone. We based this upon the concept that these two therapies address two different 
mechanisms of endogenous suppression of T-Cell directed immune response in HNSCC, and 

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that treatment of MDSC mediated suppression may prevent escape from PD-1 inhibition 
mediated augmentation of antitumor T-cell response. 
  
To test this hypothesis in an animal model, we used two immune competent, syngeneic mouse 
models in a C57BL/6 background, including a locally advanced, HPV negative MOSCC model 
and an HPV16 MEER model.  Both models demonstrate a synergistic effect of combination 
tadalafil and PD-1 inhibition, with complete resolution of tumor in all animals in the MEER 
tadalafil-PD-1 inhibitor combination arm.  This demonstrated in a HNSCC preclinical model 
animal data, the combination of PD-1 inhibition and PDE-5 inhibition is more effective in 
exhibiting objective tumor response in comparison to either therapy alone.   
  
2.6  
Current trials with combination tadalafil and PD1 checkpoint inhibitors  
  
In a window of opportunity trial, investigators at Thomas Jefferson University are currently 
enrolling a two arm open label trial (NCT03238365) in which patients are treated with 
nivolumab alone days 3 and 17 vs nivolumab days 3 and 17 and tadalafil 10 mg po QD on days 
3-31. Patients then undergo surgery on day 31 to determine biomarker endpoints.  As of 
5/22/2108, investigators have accrued 25 patients to the trial, and have only noted one grade 1 
toxicity, headache that stopped once tadalafil administration was halted (Adam Luginbuhl, 
personal communication).  As noted, headache is a known toxicity of tadalafil.   
  
  

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2.7  
Rationale  
  
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide.   
For platinum refractory patients who develop recurrent or metastatic disease, treatment options 
are limited.  Pembrolizumab is an approved treatment options for these patients, but response 
rates are low (<20%) and overall survival is short.  
  
Recent phase II trials with tadalafil in HNSCC showed promising results in previously untreated 
patients in window of opportunity trials, demonstrating immunologic enhancement of T cell 
response to HNSCC via inhibition of myeloid derived suppressor cells (MDSCs).  Immune 
competent animal models of HNSCC demonstrate that combination PDE-5 inhibitor (tadalafil)  
and PD-1 inhibitor therapy is more effective than either therapy alone based on the concept of 
targeting multiple immune repressive abnormalities simultaneously (PD-1 checkpoint and 
myeloid suppressive pathways). This trial will test the hypotheses that combination PD-1 
inhibition and PDE-5 inhibition can be safely co-administered, and that the combination will be 
more effective than PD-1 inhibition alone in platinum refractory, recurrent/metastatic HNSCC.  
  
We have chosen a tadalafil 10 mg daily dosing, as this has been demonstrated to be equivalent, 
and possibly superior to 20 mg daily dose by limiting off target effects in a prior HNSCC clinical 
trial. 14,15  Lower doses, including 5 mg daily dose, do not have data that support immune 
enhancing effects in head and neck cancer. A 40 mg daily dose of tadalafil is approved and safe 
for treatment of pulmonary hypertension. 
   
3. PATIENT SELECTION  
  
3.1  
Eligibility Criteria   
  
3.1.1 Patients must have histologically or cytologically confirmed squamous cell carcinoma of 
the head and neck not amenable to curative intent therapy.  
  
3.1.2 Presence of measurable disease via RECIST 1.1 criteria.  Measurable disease in a 
previously radiated field is acceptable as long as there has been documented progression 
since completion of radiation.  
  
3.1.3 Age ≥18 years.    
  
3.1.4 ECOG performance status 0 or 1.  
  
3.1.5 Life expectancy of greater than 12 weeks  
  
3.1.6 Patients must have normal organ and marrow function as defined below:  
 
absolute neutrophil count 
≥1,500/mcL 

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Platelets 
≥100,000/mcL 
Hemoglobin 
≥9 g/dL 
total bilirubin 
≤1.5 x upper limit of normal (ULN) 
AST(SGOT)/ALT(SGPT) 
≤2.5 × ULN or ≤5 x ULN (for subjects 
with documented metastatic disease to the 
liver)  
creatinine clearance 
≥30 mL/min (according to Cockcroft-Gault 
formula) 
 
3.1.7 Archived tumor specimen available for correlative analysis or biopsy accessible disease  
  
3.1.8 Detectable PD-L1 expression in tumor defined as combined positive score (CPS) >1.  
  
3.1.9 Negative serum or urine pregnancy test for women of childbearing potential  
  
3.1.10  Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of 
study participation, and for at least 60 days after final treatment on study.  Should a woman 
become pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.    
  
3.1.11 Ability to understand and the willingness to sign a written informed consent document.  
  
  
3.2  
Exclusion Criteria  
  
3.2.1 Prior therapy with a PD-1 or PD-L1 inhibitor in the setting of recurrent or metastatic 
squamous cell carcinoma of the head and neck  
  
3.2.2 Chemotherapy within 28 days prior to first administration of study treatment and/or 
monoclonal antibody therapy within 8 weeks prior to the first administration of study 
treatment.  
  
3.2.3 Uncontrolled central nervous system metastases.  Stable, asymptomatic brain metastases 
not requiring escalating steroid doses are permitted.  
  
3.2.4 Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,   
         inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b.               
         Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c.  
         Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). 
 

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3.2.5 Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory 
agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases 
not requiring immunosuppressive treatment are eligible  
  
3.2.6 Prior organ transplantation including allogenic stem-cell transplantation   
  
3.2.7 Active infection requiring systemic therapy  
  
3.2.8 Known history of testing positive for HIV or known acquired immunodeficiency syndrome  
  
3.2.9 Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test positive)  
3.2.10 Vaccination within 4 weeks of the first dose of Pembrolizumab and while on trials is 
prohibited except for administration of inactivated vaccine  
3.2.11 As judged by the investigator, any evidence of severe or uncontrolled systemic disease  
(e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease) 
3.2.12 History of significant hypotensive episode requiring hospitalization  
3.2.13 History of stroke within prior 6 months. 
3.2.14 History of any of the following cardiac conditions:  
• 
Left ventricular outflow obstructions, such as aortic stenosis and idiopathic hypertrophic 
subaortic stenosis 
• 
Angina requiring treatment with long-acting nitrates  
• 
Angina requiring treatment with short-acting nitrates within 90 days of planned tadalafil 
administration  
• 
Unstable angina within 90 days of visit 1 (Braunwald 1989)  
• 
Positive cardiac stress test without documented evidence of subsequent, effective 
cardiac intervention  
• 
History of any of the following coronary conditions within 90 days of planned tadalafil 
administration:  
• 
Myocardial Infarction  
• 
Coronary artery bypass graft surgery  
• 
Percutaneous coronary intervention (for example, angioplasty or stent placement) 
• 
Any evidence of heart disease (NYHA≥Class II as defined in Protocol Attachment 
LVHG.3) within 6 months of planned tadalafil administration 
 
3.2.15 Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or 
chronic administration of >10 mg/day of prednisone or equivalent)   
3.2.16 Prior solid organ transplantation  
3.2.17 Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal antibodies 
(NCI CTCAE v5.0 Grade ≥ 3)  
  
3.2.18 Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 3 months prior 

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to enrollment), unstable angina, congestive heart failure within 6 months of planned 
tadalafil administration (≥ New York Heart Association Classification Class II), or 
serious cardiac arrhythmia requiring medication.  
  
3.2.19 Persisting toxicity related to prior therapy (NCI CTCAE v. 5.0 Grade > 1); however,  
           alopecia, sensory neuropathy Grade  ≤ 2, or other Grade  ≤ 2 not constituting a safety risk   
           based on investigator’s judgment are acceptable. 
 
3.2.20 Other severe acute or chronic medical conditions including immune colitis, inflammatory 
bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions 
including recent (within the past year) or active suicidal ideation or behavior; or 
laboratory abnormalities that may increase the risk associated with study participation or 
study treatment administration or may interfere with the interpretation of study results 
and, in the judgment of the investigator, would make the patient inappropriate for entry 
into this study.  
  
3.2.21 History of other malignancies within the past three years, except:   
• 
Malignancy treated with curative intent and with no known active disease present for ≥3 
years before the first dose of study drug and felt to be at low risk for recurrence by 
treating physician. 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.  
• 
Adequately treated carcinoma in situ without evidence of disease.   
3.2.22 Medical contraindication to biopsy of target lesion  
3.2.23 Prior daily use of tadalafil or other long-acting PDE5 inhibitors for one month or greater 
within 3 months of trial enrollment  
3.2.24. Current use of other long-acting PDE5 inhibitors. 
 
3.2.25 Known severe hypersensitivity to tadalafil or any of the excipients of this product  
3.2.26 Current treatment with nitrates  
3.2.27 Current treatment with guanylate cyclase stimulators such as riociguat.  
3.2.28 Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor such 
as ketoconazole or ritonavir  
3.2.29 History of hypotension and/or blindness and/or sensorineural hearing loss during prior 
treatment with tadalafil or other PDE-5 inhibitors 
3.2.30 History of hereditary degenerative retinal disorders, including retinitis pigmentosa 
3.2.31Use of alpha-blockers or α-adrenoreceptor antagonists  
3.2.32 Daily intake of 5 or more alcoholic drinks  
3.2.33 Prior history of non-arteritic anterior ischemic optic neuropathy 
  
 
 
 

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 4. TREATMENT PLAN  
  
4.1  
Dosing and Agent Administration  
  
Treatment will be administered on an outpatient basis.  No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient's malignancy.    
  
 
Dose Schedule  
 
  
Tadalafil (PO daily, 
days 1-21 of 21 day  
cycle)  
Pembrolizumab (IV 
on days 1 of 21 day  
cycle)  
Dose  
10 mg  
200 mg  
  
Each cycle of therapy will be 21 days.    
4.2  Pembrolizumab Administration  
  
Pembrolizumab will be administered 200 mg IV once every three weeks.  The recommended dose 
of pembrolizumab is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until 
disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression  
Premedication: In order to mitigate infusion-related reactions, a premedication with an 
antihistamine and with acetaminophen 30 to 60 minutes prior to the first four infusions of 
Pembrolizumab is mandatory (25-50 mg diphenhydramine IV or oral and 500-650 mg 
acetaminophen IV or oral). Premedication should be administered for subsequent pembrolizumab 
infusions based upon clinical judgment and presence/severity of prior infusion reactions. This may 
be modified based on local treatment standards and guidelines, as appropriate.    
• 
Setting: Pembrolizumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy 
for anaphylaxis, such as the ability to implement immediate resuscitation measures.  
Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications (IV 
antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access.  
• 
Observation period:  Following pembrolizumab infusions, patients must be observed for 
30 minutes post-infusion for potential infusion-related reactions.    
Pembrolizumab will be supplied as standard of care drug obtained from commercial sources by 
the infusion pharmacy.  
 
 
  

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4.3  
Tadalafil Administration  
  
Tadalafil will be administered in pill form of 10 mg.  Patients will be instructed to take their 
assigned dose once daily. Patients will be encouraged to take their dose at approximately the 
same time each day.   
  
Tadalafil will be supplied by Lilly.  
  
If the patient vomits or misses a dose, an additional dose should not be taken that day.  The next 
prescribed dose should be taken at the usual time.  Tadalafil can be swallowed with water but 
cannot be crushed or dissolved in water.. If the patientis unable to swallow the pills, the 
medication can be provided in the form of oral suspension.  
Patients will be instructed to keep a diary of pill compliance and pill counts will be monitored by 
study personnel.  
   
4.4  
Definition of Dose-Limiting Toxicity (DLT)  
  
Toxicities will be described according to NCI-CTCAE version 5.0.  Dose-limiting toxicity is 
defined as toxicity that is possibly, probably, or definitely attributable to the study regimen in the 
opinion of the principal investigator and that is:  
• 
Grade 3 or higher non-hematologic toxicity excluding nausea and vomiting and skin rash  
• 
Grade 4 neutropenia, febrile neutropenia, or grade 4 thrombocytopenia  
• 
Grade 3 or higher nausea and vomiting that cannot be controlled within two weeks with 
anti-emetics  
• 
Grade 4 skin rash  
As an exception, if the toxicity is regarding as being possibly related to the study regimen but in 
the opinion of the principal investigator is felt to be more likely related to a concurrent 
medication, the underlying malignancy, a co-morbid condition, or some factor other than the 
study regimen, the principal investigator may choose to not regard it as a DLT for the purposes 
of the study.  
  
Any DLT that occurs within the first cycle of therapy (21 days) will be used to make decisions 
about proceeding to the subsequent cohort.  
  
4.5  
General Concomitant Medication and Supportive Care Guidelines  
  
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.    
  
4.5.1 Medication Interactions – CYP3A Inhibitors/Inducers  
  
Tadalafil is primarily metabolized by CYP3A.  Coadministration with a strong CYP3A inhibitor 
(itraconazole) increased the plasma exposure of tadalafil in healthy subjects by 87%.   

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Concomitant use of strong CYP3A inhibitors (including clarithromycin, indinavir, itraconazole, 
ketozonale, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, 
telithromycin, verapamil, and voriconazole) should be avoided during therapy with tadalafil.  
Patients will also be told to avoid grapefruit or grapefruit juice during therapy.  
  
Coadministration of tadalafil with a strong CYP3A inducer can decrease the plasma exposure of 
tadalafil.  Concomitant use of strong CYP3A inducers (phenytoin, rifampin, carbamazepine, and 
St John’s Wort) should be avoided.  Concomitant use of moderate CYP3A inducers (bosentan, 
efavirenz, etravirine, modafinil, and nafcillin) may also decrease the plasma exposure of tadalafil 
and should be avoided.  
  
A comprehensive list of inhibitors, inducers, and substrates may be found at  
http://medicine.iupui.edu/clinpharm/ddis/main-table/.   This website is continually revised and 
should be checked frequently for updates.  
  
4.6  
Duration of Therapy  
  
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies:  
  
• 
Disease progression,  
  
• 
Intercurrent illness that prevents further administration of treatment,  
  
• 
Unacceptable adverse event(s),  
  
• 
Patient decides to withdraw from the study, or  
  
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator.  
  
If a patient discontinues tadalafil of the study drugs for toxicity reasons, the patient may continue 
treatment with pembrolizumab, provided the treating clinician agrees.  
  
Patients may continue treatment following progression if the principal investigator and the 
treating clinician believe the patient continues to benefit from therapy.  
  
4.7  
Duration of Follow Up  
  
Patients will be followed for up to 2 years for survival status after removal from study treatment 
or until death, whichever occurs first.  These follow-ups may occur by phone and will occur 
about every 3 months. Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event.  
  

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4.8  
Criteria for Removal from Study  
  
Patients will be removed from study when any of the criteria listed above applies.  The reason for 
study removal and the date the patient was removed must be documented in the Case Report 
Form.  
  
  
5. DOSE MODIFICATIONS  
  
Dose reductions are permanent once instituted.  If it is unclear what medication is causing 
toxicity, dose modifications will be discussed between the treating clinician and the principal 
investigator.  
  
5.1  
Dose Modifications for Pembrolizumab  
Please refer to the Pembrolizumab Investigator Brochure for toxicity management 
algorithms which include specific treatment guidelines.  These algorithms should be 
followed unless there are specific clinical circumstances for which the treating physician 
decides an alternative treatment approach is clinically appropriate.  Consultation with the 
study chair is recommended.  
In all of the tables for dose modification and holds in this section, the guidelines are for 
adverse events thought at least possibly attributed to study drug. Generally we strongly 
encourage early evaluation while withholding drug, and appropriate treatment as 
indicated in the management tables and event specific guidelines.  
ALL OTHER EVENTS  
Management/Next Dose for Pembrolizumab  
≤ Grade 1  
No change in dose   
Grade 2  
Hold until ≤ Grade 1 OR baseline (exceptions 
as noted below). Resume at same level at 
investigator discretion.  
Grade 3  
Off protocol therapy (exceptions as noted 
below)  
ALL OTHER EVENTS  
Management/Next Dose for Pembrolizumab  
Grade 4  
Off protocol therapy  
Recommended management:  As clinically indicated   
Exceptions:  
• 
Any grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the 
re-treatment period OR requires systemic treatment should go off protocol 
treatment.  
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in  
the judgment of the investigator, presents a substantial clinical risk to the subject with continued 
study drug dosing should go off protocol treatment.  

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• 
Any grade 2-4 drug-related laboratory abnormality or electrolyte abnormality,  
that can be managed independently from underlying organ pathology with electrolyte 
replacement, hormone replacement, transfusion or insulin or that does not require treatment does 
not require hold/discontinuation.  
• 
Tolerable and clinically stable grade 2 toxicities attributed to study drug may 
remain on study with PI approval (e.g. thrombosis that is being 
anticoagulated).  
 
 
Management/Next Dose for Pembrolizumab  
No change in dose *  
Grade 2  
Treatment may continue at investigator discretion. A short course of steroids is 
permitted. If treatment is held, resume at same dose level.  
Grade 3  
Hold* until ≤ Grade 1.  Resume at same level at investigator discretion   
Grade 4  
Off protocol therapy  
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson syndrome, 
TEN, and autoimmune bullous disease including oral lesions of bullous pemphigus/pemphigoid.  Pruritus 
may occur with or without skin rash and should be treated symptomatically if there is no associated liver 
or GI toxicity. Note skin rash typically occurs early and may be followed by additional events particularly 
during steroids tapering.    
Recommended management:  AE management guidelines  
  
Liver Function AST, ALT, Bilirubin  
Management/Next Dose for Pembrolizumab  
≤ Grade 1  
Treatment may be continued at investigator discretion. Dose 
level is maintained.  
Grade 2  
Hold until ULN or baseline.  Resume at same dose level.   
Grade 3  
Off protocol therapy   
Grade 4  
Off protocol therapy  
*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN and T.bili ≤ 5 x ULN  
Continued treatment of active immune mediated hepatitis may exacerbate ongoing inflammation. Holding 
drug to evaluate LFT changes and early treatment are recommended.    
**LFT changes may occur during steroid tapers from other events and may occur together with other GI 
events including cholecystitis/pancreatitis.   
Recommended management:  see Hepatic AE management algorithm  
  
Diarrhea/ Colitis  
Management/Next Dose for Pembrolizumab  
≤ Grade 1  
Symptomatic treatment but continue therapy. No change in dose  
Grade 2  
Hold until baseline. No change in dose  
Grade 3  
Hold until baseline. No change in dose.  

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Grade 4  
Off protocol therapy  
See GI AE Algorithm for management of symptomatic colitis.   
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after resolution.   
Please evaluate pituitary function prior to starting steroids if possible without compromising acute care.   
Evaluation for all patients for additional causes includes C. diff, acute and self-limited infectious and 
foodborne illness, ischemic bowel, diverticulitis, and IBD.   
Recommended management:  see GI AE management Algorithm  
  
 
 
Management/Next Dose for Pembrolizumab  
Continue therapy.  
Grade 2  
Continue therapy.  
Grade 3  
Patients who develop symptomatic pancreatitis or DM should be taken off 
treatment   
Grade 4  
Patients who develop symptomatic pancreatitis or DM should be taken off 
treatment   
Patients with any grade lipase/amylase elevation may continue treatment at investigator discretion if 
asymptomatic.  
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM and DKA.  
Lipase elevation may occur during the period of steroid withdrawal and with other immune mediated 
events or associated with colitis, hepatitis, and patients who have asymptomatic lipase elevation typically 
have self-limited course and may be retreated.   
For treatment management of symptomatic pancreatitis please follow the Hepatic Adverse Event 
Management Algorithm   
  
Pneumonitis  
Management/Next Dose for Pembrolizumab  
≤ Grade 1  
Hold dose pending evaluation and resolution to baseline including baseline pO2.  
Resume no change in dose after pulmonary and/or ID consultation excludes lymphocytic 
pneumonitis.   
Grade 2  
Hold dose pending evaluation. Resume no change in dose after pulmonary and/or ID 
consultation excludes pembrolizumab and associated lymphocytic pneumonitis as the 
cause of the pneumonitis. Off protocol therapy if steroids are required.   
Grade 3  
Hold dose pending evaluation. Refer to Appendix III for diagnostic and treatment 
guidelines.  
Grade 4  
Off protocol therapy  
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do not  
respond to antibiotics and have no causal organism identified including influenza.  Most patients with 
respiratory failure or hypoxia will be treated with steroids.  Bronchoscopy may be required and analysis of 
lavage fluid for lymphocytic predominance may be helpful.  Patients with new lung nodules should be 
evaluated for sarcoid like granuloma.  Please consider recommending seasonal influenza killed vaccine 
for all patients.  
Recommended management:  See Pulmonary Adverse Event Management Algorithm   

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Other GI N-V   
Management/Next Dose for Pembrolizumab  
≤ Grade 1  
No change in dose.   
Grade 2  
Hold pending evaluation for gastritis duodenitis and other immune 
adverse events or other causes. Resume at same dose level after 
resolution to ≤ Grade 1.  
Grade 3  
Hold pending evaluation until ≤ Grade 1. Resume at same dose level. 
For a second occurrence of a grade 3 event, patients should go off 
protocol therapy.  
Grade 4  
Off protocol therapy.  
Patients with grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events.    
  
Fatigue  
Management/Next Dose for Pembrolizumab  
≤ Grade 1  
No change in dose.  
Grade 2  
No change in dose  
Grade 3  
Hold until ≤ Grade 2.  Resume at same dose level.  
Grade 4  
Hold until ≤ Grade 2.  Resume at same dose level.  
Fatigue is the most common adverse event associated with immune checkpoint therapy.  Grade 2 or 
greater fatigue should be evaluated for associated or underlying organ involvement including pituitary, 
thyroid, and hepatic, or muscle (CPK) inflammation   
  
Neurologic events  
Management/Next Dose for Pembrolizumab  
≤ Grade 1  
Hold dose pending evaluation and observation.  Resume with no change in dose 
when resolved to baseline.   
Grade 2  
Hold dose pending evaluation and observation. Hold until ≤ Grade 1. Off protocol 
therapy if treatment with steroids is required.  Resume at same dose level for 
peripheral isolated n. VII (Bell’s palsy)  
Grade 3  
Off protocol therapy   
Grade 4  
Off protocol therapy   
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic hypophysitis, or 
myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other than peripheral n. VII), GB 
syndrome, Myasthenia Gravis should be off study.    
Recommended management:  See Neurologic Adverse Event Management Algorithm   
  

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Management/Next Dose for Pembrolizumab  
≤ Grade 1  
Asymptomatic TSH elevation * May continue therapy pending evaluation, 
consider endocrine consult  
Grade 2  
Hold until patients are on a stable replacement hormone regimen.  If treated 
with steroids patients must be stable off steroids for two weeks. Resume at 
same dose level.   
Grade 3  
See Appendix III for diagnostic and management algorithm.  
Grade 4  
See Appendix III for diagnostic and management algorithm.  
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but including 
severe headache or enlarged pituitary on MRI should be considered grade 3 events.  Isolated thyroid or 
testosterone deficiency may be treated as grade 2 if there are no other associated deficiencies and 
adrenal function is monitored.   
Please evaluate pituitary function before beginning steroid therapy or replacement therapy of any kind.   
*Note patients with thyroiditis may be retreated on replacement therapy.  Patients must be evaluated to 
rule out pituitary disease prior to initiating thyroid replacement.  
Recommended management: See Endocrine Management Algorithm   
  
Renal  
Management/Next Dose for Pembrolizumab combination  
≤ Grade 1  
May continue therapy per investigator discretion.  
Grade 2  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 3  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 4  
Off protocol therapy  
  
Infusion reaction  
Management/Next Dose for Pembrolizumab combination  
≤ Grade 1  
May continue therapy per investigator discretion.  
Grade 2  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 3  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 4  
Off protocol therapy  
Patients with fever should be evaluated as clinically appropriate.  Patients may experience isolated 
fever during infusion reactions or up to several days after infusion.  Evaluation over the course of 1-2 
weeks should be done for other autoimmune events that may present as fever   
See Section 8. Infusion reactions  
  
Fever  
Management/Next Dose for Pembrolizumab combination  
≤ Grade 1  
Evaluate and continue at same dose level  

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Grade 2  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 3  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 4  
Off protocol therapy  
Patients with fever should be evaluated as clinically appropriate.  Patients may experience isolated 
fever during infusion reactions or up to several days after infusion.  Evaluation over the course of 1-2 
weeks should be done for other autoimmune events that may present as fever   
See Section 8. Infusion reactions.    
  
Cardiac*  
Management/Next Dose for Pembrolizumab Cardiac Toxicities  
≤ Grade 1  
Hold dose pending evaluation and observation.** Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia or myositis. Obtain history EKG, 
CK (for concomitant myositis), CK-MB. Repeat troponin, CK and EKG 2-3 
days. If troponin and labs normalize may resume therapy. If labs worsen 
or symptoms develop then treat as below. Hold pending evaluation.   
Grade ≥ 2 with suspected 
myocarditis  
Hold dose.** Admit to hospital. Cardiology consult. Rule out MI and other 
causes of cardiac disease. Cardiac Monitoring. Cardiac Echo. Consider 
cardiac MRI and cardiac biopsy. Initiate high dose methylprednisolone. If 
no improvement within 24 hours, add either infliximab, ATG or tacrolimus. 
Resume therapy if there is a return to baseline and myocarditis is 
excluded or considered unlikely.  
Grade ≥ 2 with confirmed 
myocarditis  
Off protocol therapy. Admit to CCU (consider transfer to nearest Cardiac 
Transplant Unit). Treat as above.  Consider high dose 
methylprednisolone.  
Add ATG or tacrolimus if no improvement.  
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other event”  
Note:  The optimal treatment regimen for immune mediated myocarditis has not been established.  
Since this toxicity has caused patient deaths, an aggressive approach is recommended.  
• 
Drug will be held for grade 2 cardiac dysfunction pending evaluation  
• 
Drug will be permanently discontinued for grade 3 or 4 cardiac dysfunction 
and grade 2 events that do not recover to baseline or that reoccur  
• 
Treatment with steroids as clinically indicated  
If treatment is delayed >6 weeks for an adverse event, the study chair must be consulted for any 
consideration of further therapy.  
Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 events with 
resolution and stable replacement treatment.  
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with 
replacement hormones including thyroid hormone and physiologic doses of corticosteroids.   

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Please note that grading and for hypophysitis with symptoms of headache, visual or neurologic 
changes or radiologic evidence of pituitary enlargement and other CNS events such as aseptic 
meningitis or encephalitis should be considered grade 3 events.   
Any patients who require additional immune suppressive treatment beyond steroids should go off 
study therapy.  
Patients requiring > two dose delays for the same event should go off protocol therapy.  
Prior to starting corticosteroids or hormone replacement for any reason, appropriate endocrine 
testing including cortisol, ACTH, TSH and T4 should be obtained to document baseline. 
However, if urgent steroid use is clinically required, steroid treatment should not be delayed for 
bloodwork.  
Please note that in some cases the treatment algorithms recommend steroids if symptoms do not 
resolve in 7 days. However, this recommendation is not meant to delay steroid treatment at any 
time it is clinically indicated.    
Patients may be dose-delayed for evaluation and restarted depending on results.   
Any patient started on corticosteroids initially who is determined to not require steroid treatment 
for an autoimmune adverse event may resume therapy after a 2 week observation period without 
further symptoms at the discretion of the PI or investigator.  
  
5.2  
Dose Modifications for Tadalafil  
  
Tadalafil has a record of safe administration at study does (10 mg/day).  The most common side 
effects include back pain, dyspepsia, and headache. 
 
In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours 
after dosing and typically resolved within 48 hours. The back pain/myalgia associated with 
tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or 
thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was 
reported as mild or moderate in severity and resolved without medical treatment, but severe back 
pain was reported with a low frequency (<5% of all reports). When medical treatment was 
necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; 
however, in a small percentage of subjects who required treatment, a mild narcotic (e.g.,codeine) 
was used. Please refer to the Tadalafil Package Insert for more information. 
 
  
Any Grade 4 adverse drug reactions (ADRs) require treatment discontinuation with 
Pembrolizumab except for single laboratory values out of normal range that are unlikely related 
to study treatment as assessed by the Investigator, do not have any clinical correlate, and resolve 
within 7 days with adequate medical management  
  
Any Grade 3 ADRs require treatment discontinuation with tadalafil except for any of the 
following:   

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• 
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management  
• 
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, back pain, nausea, 
emesis that resolves to Grade ≤ 1   
• 
Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test 
increase) that are unlikely related to study treatment according to the Investigator, do not 
have any clinical correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical 
management  
• 
Change in ECOG PS to ≥ 3 that does not resolve to ≤ 2 within 14 days (infusions should  
not be given on the following cycle, if the ECOG PS is ≥ 3 on the day of study drug 
administration)  
  
Any Grade 2 ADR should be managed as follows:  
• 
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment 
may continue.  
• 
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, 
administration of tadalafil should not be given on the following cycle.  If at the end of the 
following cycle the event has not resolved to Grade 1, the subject should permanently 
discontinue treatment with tadalafil.  
• 
Upon the second occurrence of the same Grade 2 ADR in the same subject, treatment 
with tadalafil has to be permanently discontinued.  
  
  
 

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6. ADVERSE EVENTS AND REPORTING  
  
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide.   
Definitions  Adverse Events  
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995).  
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions.  
The term “disease progression” should not be reported as an adverse event term.  As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported.  
Adverse events may include, but are not limited to:  
• 
Subjective or objective symptoms provided by the patient and/or observed by the  
Investigator or study staff including laboratory abnormalities of clinical significance.  
• 
Any AEs experienced by the patient through the completion of final study procedures.  
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period   
• 
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies).  
The following are NOT considered AEs:  
• 
Pre-existing condition:  A pre-existing condition (documented on the medical history CRF) 
is not considered an AE unless the severity, frequency, or character of the event worsens 
during the study period.  
• 
Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.   
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  

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Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after enrollment 
in the study for a condition that has not changed from its baseline level.  Elective 
hospitalizations for social reasons, solely for the administration of chemotherapy, or due to 
long travel distances are also not SAEs.  
• 
Diagnostic Testing and Procedures:  Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported.  
• 
Asymptomatic Treatment Related Lymphocytosis: This event should also not be 
considered an AE.  Patients with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures.  
Serious Adverse Events  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes:  
• 
Death  
• 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death.  
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.  
• 
A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32).  
Severity Criteria (Grade 1-5)  
Definitions found in the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 
v5.0) will be used for grading the severity (intensity) of AEs.  The CTCAE v5.0 displays Grades 
1 through 5 with unique clinical descriptions of severity for each referenced AE.  Should a 
patient experience any AE not listed in the CTCAE v5.0, the following grading system should be 
used to assess severity:  

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• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the patient’s daily activities  
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the patient, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures  
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the patient’s usual daily activity, and require systemic drug therapy or other 
treatment  
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in 
imminent danger of death  
• 
Grade 5 (Death related to AE) – experiences which result in patient death  
Causality (Attribution)   
The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions:  
Not Related:  
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration of 
the investigational product; or, a causal relationship is considered 
biologically implausible.  
Unlikely:  
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely.  
Possibly Related:  
There is a clinically plausible time sequence between onset of the 
AE and administration of the investigational product, but the AE 
could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures.  Possibly related should be used 
when the investigational product is one of several biologically 
plausible AE causes.  
Definitely Related:  
The AE is clearly related to use of the investigational product.  
Unexpected Adverse Events  
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's  
Brochure/package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 

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anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation.  
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators Assessment of Adverse Events  
Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation timepoints during the study. All adverse events and serious adverse events 
whether volunteered by the subject, discovered by study personnel during questioning, detected 
through physical examination, clinically significant laboratory test, or other means, will be 
recorded.  Each recorded adverse event or serious adverse event will be described by its duration 
(ie, start and end dates), severity, regulatory seriousness criteria (if applicable), suspected 
relationship to the investigational product, and any actions taken.  
Adverse Event Reporting Period  
All AEs whether serious or non-serious, will be captured from the time signed and dated ICF is 
obtained until 30 days following the last dose of study drug.   
Serious adverse events reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug. Resolution information after 30 days should be 
provided.   
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported.   
All Grade 3 – 5 adverse events, regardless of seriousness, severity, or presumed relationship to 
study drug, must be recorded using medical terminology in the source document. All records will 
need to capture the details of the duration and the severity of each episode, the action taken with 
respect to the study drug, investigator’s evaluation of its relationship to the study drug, and the 
event outcome. Whenever possible, diagnoses should be given when signs and symptoms are due 
to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should 
be reported as "upper respiratory infection").   
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.   
If a death occurs within 30 days after the last dose of study drug, the death must be reported as a 
serious adverse event.   
6.1  
Reporting Requirements for Adverse Events  
  
Expedited Reporting  
  

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A. The Study Chair must be notified within 24 hours of learning of any serious adverse 
events, regardless of attribution, occurring during the study or within 30 days of the last 
administration of the study drug.   
  
B. Please see Section 6.2 for expedited reporting to Lilly.  
  
C. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR).  
The following events meet the definition of UPR:  
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures.  
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk.  
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject.  
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research.  
5. Any breach in confidentiality that may involve risk to the subject or others.  
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator.  
  
D. The FDA must be notified according to the following timelines:  
• 
Within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and   
• 
Within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 3) 
at least possibly related to study participation.  
  
Routine Reporting Requirements  
  
A. The UCSD HRPP must be notified of any serious adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual 
Continuing Review.   
B. The FDA must be notified of all non-serious adverse events annually at the time of the 
annual report.  
  
  

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6.2  
Safety Reporting to Lilly  
  
The investigator’s primary responsibilities in the safety reporting are to identify and follow-up on 
Serious Adverse Events (SAEs) experienced by participants in the study and to forward the 
information to the local regulatory authorities and Lilly, as required by local regulations (for 
regulatory reporting) and IIR agreement (for reporting to Lilly).  
  
The following reportable events must be submitted to Lilly within 24 hours (or immediately 
for death or life-threatening events) using the provided Investigator-Initiated Research 
Serious Adverse Event Form (IIR SAE) with the Lilly Reportable Events Fax Cover Sheet 
with each SAE submission.  
  
• 
Serious Adverse Events  
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event)  
• 
Occupational exposure (even if not associated with an adverse event)  
• 
Potential drug-induced liver injury (Hy’s Law cases):  These events are considered 
important medical events and should be reported as SAEs.  
  
Detailed guidance on the safety reporting is provided in the Safety Reporting Reference Manual.  
  
Contact information for submission of reportable events to Lilly:  
  
Fax:  ARC/Global Patient Safety fax 317-453-3402 or toll free 866-644-16971697 
  
or  
  
E-mail: MAILINDATA_GSMTINDY@LILLY.COM 
• 
PROTOCOL:         
• 
SUBJECT:               
• 
SITE/PI:                  
• 
SAE/ONSET:         
  
7.  
PHARMACEUTICAL AGENT SAFETY INFORMATION  
7.1 Pembrolizumab safety information:  
Pembrolizumab can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis 
occurred in 94 (3.4%) of 2799 patients receiving Pembrolizumab, including grade 1 (0.8%), 2 
(1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients 
with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor 
patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with 
radiographic imaging. Administer corticosteroids for grade 2 or greater pneumonitis. Withhold 
pembrolizumab for grade 2; permanently discontinue Pembrolizumab for grade 3 or 4 or 
recurrent grade 2 pneumonitis.  

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Pembrolizumab can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 
patients receiving Pembrolizumab, including grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 
Monitor patients for signs and symptoms of colitis. Administer corticosteroids for grade 2 or 
greater colitis. Withhold Pembrolizumab for grade 2 or 3; permanently discontinue 
Pembrolizumab for grade 4 colitis.  
Pembrolizumab can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 
patients receiving Pembrolizumab, including grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. 
Monitor patients for changes in liver function. Administer corticosteroids for grade 2 or greater 
hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue 
Pembrolizumab.  
Pembrolizumab can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients 
receiving Pembrolizumab, including grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. 
Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal 
insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. 
Withhold Pembrolizumab for grade 2; withhold or discontinue for grade 3 or 4 hypophysitis.  
Pembrolizumab can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and 
thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving Pembrolizumab, 
including grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) 
of 2799 patients receiving Pembrolizumab, including grade 2 (6.2%) and 3 (0.1%) 
hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with 
hnscc, occurring in 28 (15%) of 192 patients with hnscc, including grade 3 (0.5%) 
hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving pembrolizumab, 
including grade 2 (0.3%) thyroiditis. 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. Administer replacement hormones for 
hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. 
Withhold or discontinue pembrolizumab for grade 3 or 4 hyperthyroidism.  
Pembrolizumab can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have 
been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs 
and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold pembrolizumab 
and administer antihyperglycemics in patients with severe hyperglycemia.  
Pembrolizumab can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 
patients receiving pembrolizumab, including grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. 
Nephritis occurred in 1.7% (7/405) of patients receiving pembrolizumab in combination with 
pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function.  
Administer corticosteroids for grade 2 or greater nephritis. Withhold pembrolizumab for grade 2; 
permanently discontinue pembrolizumab for grade 3 or 4 nephritis.  
Immune-mediated rashes, including stevens-johnson syndrome (sjs), toxic epidermal necrolysis  

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(ten) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. 
Monitor patients for suspected severe skin reactions and based on the severity of the adverse 
reaction, withhold or permanently discontinue pembrolizumab and administer corticosteroids. 
For signs or symptoms of sjs or ten, withhold pembrolizumab and refer the patient for 
specialized care for assessment and treatment. If sjs or ten is confirmed, permanently discontinue 
pembrolizumab.  
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ 
system or tissue in patients receiving pembrolizumab. While immune-mediated adverse reactions 
usually occur during treatment with programmed death receptor-1 (pd-1)/pd-l1 blocking 
antibodies, they may occur after discontinuation of treatment. For suspected immune-mediated 
adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based 
on the severity of the adverse reaction, withhold pembrolizumab and administer corticosteroids. 
Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over at 
least 1 month. Based on limited data from clinical studies in patients whose immune-related 
adverse reactions could not be controlled with corticosteroid use, administration of other 
systemic immunosuppressants can be considered. Resume pembrolizumab when the adverse 
reaction remains at grade 1 or less following corticosteroid taper. Permanently discontinue 
pembrolizumab for any grade 3 immune-mediated adverse reaction that recurs and for any 
lifethreatening immune-mediated adverse reaction.  
The following clinically significant immune-mediated adverse reactions occurred in less than 1% 
(unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, guillain-barré 
syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and 
encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including 
classical hodgkin lymphoma (chl), and postmarketing use.  
Solid organ transplant rejection has been reported in postmarketing use of pembrolizumab. 
Treatment with pembrolizumab may increase the risk of rejection in solid organ transplant 
recipients. Consider the benefit of treatment with pembrolizumab vs the risk of possible organ 
rejection in these patients.  
Pembrolizumab can cause severe or life-threatening infusion-related reactions, including 
hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. 
Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For grade 3 or 4 
reactions, stop infusion and permanently discontinue pembrolizumab.  
Immune-mediated complications, including fatal events, occurred in patients who underwent 
allogeneic hematopoietic stem cell transplantation (hsct) after treatment with pembrolizumab. Of 
23 patients with chl who proceeded to allogeneic hsct after pembrolizumab, 6 developed 
graftversus-host disease (gvhd) (1 fatal case) and 2 developed severe hepatic veno-occlusive 
disease (vod) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute gvhd 
after allogeneic hsct have also been reported in patients with lymphoma who received a pd-1 

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receptor–blocking antibody before transplantation. Follow patients closely for early evidence of 
transplant-related complications such as hyperacute gvhd, grade 3 to 4 acute gvhd, 
steroidrequiring febrile syndrome, hepatic vod, and other immune-mediated adverse reactions, 
and intervene promptly.  
In patients with a history of allogeneic hsct, acute gvhd, including fatal gvhd, has been reported 
after treatment with pembrolizumab. Patients who experienced gvhd after their transplant 
procedure may be at increased risk for gvhd after pembrolizumab. Consider the benefit of 
pembrolizumab vs the risk of gvhd in these patients.  
In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a 
thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these 
patients with a pd-1 or pd-l1 blocking antibody in this combination is not recommended outside 
of controlled clinical trials.  
Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a 
pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, 
apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to 
use highly effective contraception during treatment and for 4 months after the last dose of 
pembrolizumab.  
In keynote-006, pembrolizumab was discontinued due to adverse reactions in 9% of 555 patients 
with advanced melanoma; adverse reactions leading to discontinuation in more than one patient 
were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy 
(0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of pembrolizumab  
occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common 
adverse reactions with pembrolizumab vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% 
with pembrolizumab), rash (24% vs 23%), and nausea (21% with pembrolizumab). 
Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that 
occurred at the same or lower rate than with pembrolizumab.  
In keynote-189, when pembrolizumab was administered with pemetrexed and platinum 
chemotherapy in metastatic nonsquamous nsclc, pembrolizumab was discontinued due to 
adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in 
permanent discontinuation of pembrolizumab were pneumonitis (3%) and acute kidney injury 
(2%). The most common adverse reactions (≥20%) with pembrolizumab were nausea (56%), 
fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), 
vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).  
In keynote-010, pembrolizumab monotherapy was discontinued due to adverse reactions in 8% 
of 682 patients with metastatic nsclc. The most common adverse event resulting in permanent 
discontinuation of pembrolizumab was pneumonitis (1.8%). Adverse reactions leading to 
interruption of pembrolizumab occurred in 23% of patients; the most common (≥1%) were 
diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased 
appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at 

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least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite 
(25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).  
In keynote-012, pembrolizumab was discontinued due to adverse reactions in 17% of 192 
patients with hnscc. Serious adverse reactions occurred in 45% of patients. The most frequent 
serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, 
confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse 
reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. 
Adverse reactions occurring in patients with hnscc were generally similar to those occurring in 
patients with melanoma or nsclc, with the exception of increased incidences of facial edema 
(10% all grades; 2.1% grades 3 or 4) and new or worsening hypothyroidism.  
In keynote-087, pembrolizumab was discontinued due to adverse reactions in 5% of 210 patients 
with chl, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen 
percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. 
Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse 
reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, gvhd, and herpes zoster. 
Two patients died from causes other than disease progression; 1 from gvhd after subsequent 
allogeneic hsct and 1 from septic shock. The most common adverse reactions (occurring in 
≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), 
diarrhea (20%), and rash (20%).  
In keynote-170, pembrolizumab was discontinued due to adverse reactions in 8% of 53 patients 
with pmbcl, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent 
of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse 
reactions occurred in 26% of patients and included: arrhythmia (4%), cardiac tamponade (2%), 
myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients 
died within 30 days of start of treatment. The most common adverse reactions (occurring in > 
20% of patients) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia 
(28% each), cough (26%), fatigue (23%) and dyspnea (21%). 
In keynote-052, pembrolizumab was discontinued due to adverse reactions in 11% of 370 
patients with locally advanced or metastatic urothelial carcinoma. The most common adverse  
reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased 
appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died 
from causes other than disease progression. Five patients (1.4%) who were treated with 
pembrolizumab experienced sepsis which led to death, and 3 patients (0.8%) experienced 
pneumonia which led to death. Adverse reactions leading to interruption of pembrolizumab 
occurred in 22% of patients; the most common (>1%) were liver enzyme increase, diarrhea, 
urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse 
reactions occurred in 42% of patients, the most frequent (>2%) of which were urinary tract 
infection, hematuria, acute kidney injury, pneumonia, and urosepsis. 
 
 

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In keynote-045, pembrolizumab was discontinued due to adverse reactions in 8% of 266 patients 
with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction 
resulting in permanent discontinuation of pembrolizumab was pneumonitis (1.9%). Adverse 
reactions leading to interruption of pembrolizumab occurred in 20% of patients; the most 
common (>1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The 
most common adverse reactions (≥20%) in patients who received pembrolizumab vs those who 
received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus 
(23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). 
Serious adverse reactions occurred in 39% of pembrolizumab-treated patients, the most frequent 
(≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.  
In keynote-158, pembrolizumab was discontinued due to adverse reactions in 8% of 98 patients  
(in cohort e) with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 
39% of patients receiving pembrolizumab. The most frequent serious adverse reactions reported 
included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1%  
each). The most common adverse reactions (occurring in ≥20% of patients) were fatigue (43%), 
musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and 
decreased appetite (21%).  
It is not known whether pembrolizumab is excreted in human milk. Because many drugs are 
excreted in human milk, instruct women to discontinue nursing during treatment with 
pembrolizumab and for 4 months after the final dose.  
There is limited experience in pediatric patients. In a study, 40 pediatric patients (16 children 
aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with 
advanced melanoma, lymphoma, or pd-l1–positive advanced, relapsed, or refractory solid tumors 
were administered pembrolizumab 2 mg/kg every 3 weeks. Patients received pembrolizumab for 
a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The 
safety profile in these pediatric patients was similar to that seen in adults treated with  
pembrolizumab. Toxicities that occurred at a higher rate (≥15% difference) in these patients 
when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal 
pain (28%), hypertransaminasemia (28%), and hyponatremia (18%). Her2/neu = human 
epidermal growth factor receptor 2.  
  
Please see the latest pembrolizumab investigator’s brochure for the latest safety information.  
   
7.1  
Tadalafil Safety Information  
  
Tadalafil has been used by approximately 29,549 subjects participating in ongoing and 
completed clinical trials, and it is estimated that over 72 million patients have been exposed to 
tadalafil worldwide in the post-approval/post-marketing setting for the treatment of ED, BPH, 
and PAH. The most common side effects when using tadalafil are headache, stomach discomfort 
or pain, indigestion, burping, acid reflux, back pain, pain the extremities, muscle aches, flushing, 
and stuffy or runny nose. These side effects reflect the ability of PDE5 inhibition to cause 

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vasodilation (cause blood vessels to widen), and usually go away after a few hours. Back pain 
and muscle aches can occur 12 to 24 hours after taking the drug, and the symptom usually 
disappears after 48 hours.   
In May 2005, the U.S. Food and Drug Administration found that tadalafil (along with other 
PDE5 inhibitors) was associated with vision impairment related to NAION (non-arteritic anterior 
ischemic optic neuropathy) in certain patients taking these drugs in the post-marketing (outside 
of clinical trials) setting. Non-arteritic anterior ischemic optic neuropathy (NAION) is a rare 
condition and a cause of decreased vision, including permanent loss of vision, that has been 
reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Based 
on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males 
aged ≥50. An observational case-crossover study evaluated the risk of NAION when PDE5 
inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), 
compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold 
increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study 
reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors 
for NAION, such as the presence of "crowded" optic disc, may have contributed to the 
occurrence of NAION in these studies.  
 
Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to 
the general population; however, evidence is insufficient to support screening of prospective 
users of PDE5 inhibitors, including CIALIS, for this uncommon condition. 
In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including 
tadalafil, requires a more prominent warning of the potential risk of sudden hearing loss as the 
result of post-marketing reports of deafness associated with use of PDE5 inhibitors.  
Tadalafil has been evaluated extensively for safety. Currently tadalafil is marketed FDA 
approved as 5 mg daily chronic dosing and a 10 mg daily on demand dosage for erectile 
dysfunction, as well as a 40 mg daily dose for pulmonary arterial hypertension. Studies do not 
demonstrate any gender related differences in pharmokinetics or adverse effects.16,17  A recent 
meta-analysis did not demonstrate any higher cardiovascular risk compared to placebo.30 
Hypotension has been noted in patients concurrently taking nitrates, but these patients are 
excluded from the study. Non-arteritic anterior ischemic optic neuropathy has been proposed as a 
rare side effect of PDE5 inhibitors, but definitive data have not been provided due to the rarity of 
this phenomenon in both the population and subject using PDE-5 inhibitors, as well as the 
widespread use of PDE-5 inhibitors.18 Back pain has been noted and our recent trial of tadalafil 
has noted that three of 40 patients discontinued drug due to back pain, but this side effect 
resolves within 24 hours of drug discontinuation. A trial of 581 men with benign prostatic 
hypertrophy with 116 patients assigned to 20 mg daily tadalafil for 12 weeks found that this dose 
was well tolerated.19. Studies that examine 40 mg daily dosing for pulmonary hypertension 
(Reviewed in reference 20) have similarly shown that this dose is well tolerated with treatment 
duration of 4 weeks21, as well as 16 weeks duration 22,23.   
  

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Recent updates on the safety profile of tadalafil demonstrate a small potential increase in risk of 
non-arteritic ischemic neuropathy but no defined clear risk of sensorineural hearing loss or 
evidence for increased rates of other adverse effects, including prostate cancer and melanoma 
risk had been defined, and the FDA has not included prostate cancer and melanoma development 
as risks associated with tadalafil or use of other PDE-5 inhibitors. 24-26  
For the most comprehensive nonclinical and clinical information regarding tadalafil background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology, refer to the latest 
version of the tadalafil Package Insert.  
  
7.2  
Safety of Combination Tadalafil and PD-1 inhibitor Therapy  
In a window of opportunity trial, investigators at Thomas Jefferson University are currently 
enrolling a two arm open label trial in resectable head and neck squamous cell carcinoma, 
(NCT03238365) in which patients are treated with nivolumab alone days 3 and 17  vs nivolumab 
days 3 and 17  and tadalafil po QD on days 3-31. Patients then undergo surgery on day 31 to 
determine biomarker endpoints.  As of 5/22/2108, investigators have accrued 25 patients to the 
trial, and have only noted one grade 1 toxicity, headache that stopped once tadalafil 
administration was halted (Adam Luginbuhl, personal communication).  As noted, headache is a 
known toxicity of tadalafil.  
  
8. STUDY PROCEDURES AND CALENDAR  
  
8.1  
Screening/Baseline Procedures  
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained.  
  
All screening procedures must be performed within 28 days prior to registration unless otherwise 
stated. The screening procedures include:  
• 
Written informed consent (within 28 days).  
• 
Review of inclusion and exclusion criteria.  
• 
Complete medical/oncology history.  
• 
Demographics.  
• 
Documentation of concomitant medications.  
• 
Complete physical examination, including vital signs and height.  
• 
Performance status assessment.  
• 
Laboratory tests (within 28 days; pregnancy test within 7 days).   
• 
Documentation of tumor staging.  
• 
Tumor biopsy tissue collection.   

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8.2  
Informed Consent  
  
Written informed consent will be given by each patient prior to undergoing protocol specific 
evaluations and prior to receiving treatment.    
  
8.3  
Medical History and Physical Exam  
  
A complete medical history and physical exam consistent with standard of care medical history 
and physical exam performed in preparation for standard of care Pembrolizumab therapy is 
performed including vital signs, height, and weight should be obtained within 28 days prior to 
initiation of therapy on study.  ECOG performance status should be recorded at this visit. Of 
note, no additional history and physical exam for enrollment in addition to routine standard of 
care laboratory studies will be performed.  
  
8.4  
Clinical Laboratory Tests  
  
Blood based clinical laboratory tests that are ordinarily performed for standard of care therapy 
with Pembrolizumab will be obtained within 28 days prior to the start of protocol therapy.  Of 
note, no additional testing related to enrollment in addition to routine standard of care laboratory 
studies will be performed. Laboratory studies will be performed on day 1 of each cycle (+/-3 
days), on days 8 and 15 of cycle 1 only (+/- 3 days), and at the end of treatment visit.  These tests 
will include:  
  
Hematology profile:  complete blood count with differential and platelet count 
Chemistry profile:  BUN, creatinine, sodium, potassium, carbon dioxide, total 
bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase  
  
Additional testing:  
Pregnancy test:  Serum or urine pregnancy test will be obtained at baseline within 7 
days prior to treatment in all women of child-bearing potential at baseline and again 
at least monthly and more frequently if clinically indicated.  
T4 and TSH:  within 28 days prior to the start of therapy and every 9weeks (+/- 3 
days).  Also at the end of treatment (if not performed in the previous 8 weeks)  
  
8.5  
Tumor tissue from initial biopsy   
  
Tumor procurement: Patients with accessible tumor of the head and neck that are amenable to 
biopsy in an office setting, either by transcutaneous core biopsy or transoral biopsy will undergo 
biopsy of tumor within 28 days prior to initiating study treatment and during Week 4-6 after 
initiation of therapy.   Coordinator will be present at time of biopsy to collect tissue. See lab 
manual for specific instructions on tissue collection  
  
When possible, 4 core biopsies should be taken for lesions > 1.5 cm, otherwise 2 cores should be 
taken.   

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• 
If 4 cores are obtained, 1 core should be fresh frozen and the rest should be formalin 
fixed paraffin embedded (FFPE).   
  
• 
If < 4 cores are obtained, tissue for research should be FFPE after being divided into the 
research and diagnostic documentation blocks according to the Pathology staff’s 
specifications.  
  
Ten (10) unstained sections (4-5 micron slices) or one (1) 20 micron roll-ups from FFPE tissue 
are desired.  
  
Fresh frozen samples should be stored in liquid nitrogen and FFPE samples at room temperature 
until shipment.  
  
8.6  
Peripheral Blood Mononuclear Cells (PBMCs)    
   
Blood for PBMCs will be collected prior to study treatment at screening (may be collected at the 
same time as blood drawn for routine laboratory tests) and four weeks after treatment initiation.  
  
Blood samples will be collected in five heparin green top tubes (approximately 50 ml). Samples 
should be processed the day of collection according to the PBMC isolation protocol in the 
Laboratory Manual.  
PBMCs should be stored at -80°C.  
  
8.7  
Buffy Coat   
  
Blood samples will be collected in one EDTA purple top tube (approximately 10 ml) prior to study 
treatment at screening (may be collected at the same time as blood drawn for routine laboratory 
tests) and four weeks after treatment initiation.   
  
Samples should be processed the day of collection according to the buffy coat isolation protocol 
in the Laboratory Manual.  
Samples should be stored at -80°C.  
  
8.8  
Specimen Handling  
  
Sample handling and storage may be coordinated by the locations below: 
   
Sharmeela Kaushal  
  
Moores Cancer Center, 3345/3G, GG  
  
3855 Health Sciences Drive  
  
La Jolla, CA 92093-0819  
  
Phone: 858-822-7661  
 

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 Califano Lab 
Moores Cancer Center 
Room 2345, Bay 2L + 2M 
3855 Health Sciences Drive, 
La Jolla, CA 92037 
  
8.9  
Specimen Banking  
  
Patient samples collected for this study will be retained in the UCSD Moores Cancer Center 
laboratories of Dr. Joseph Califano and Dr. Judy Varner for analysis and future cancer research. 
Specimens will be stored indefinitely or until they are used up. Samples will be labeled with the 
protocol number, subject’s de-identified study number and collection date. The link between study 
number and medical record number will be viewed over a password secured encrypted server-
client.  
  
The study research coordinator at each local site will review their subject's medical record for 
demographic and clinical information pertaining to the subject's general medical history, diagnosis, 
and outcomes of any treatments received. This information will be transmitted to and retained by 
UCSD. Samples and data extracted from the subject's medical record will be coded with a de-
identified study number so that the subject's name and identifying information will be removed. A 
log that links the subject's name and identifiers to the study number will be maintained in a secure 
database distinct from the secure database into which the subject's clinical information will be 
entered by study personnel.  
  
Dissemination of specimens for research is at the discretion of the Study Chair, Dr. Califano. 
Potential research collaborators outside of UCSD who approach the Moores Cancer Center for 
clinical specimens will be required to complete an agreement (Material Transfer Agreement or 
recharge agreement) stating that the specimens will only be released for use in disclosed research, 
and any specimen left over from research will either be returned to the Cancer Center or destroyed. 
Any data obtained from the use of clinical specimen will be the property of UCSD for publication 
and any licensing agreement will be strictly adhered to. These outside collaborators may include 
for-profit biotechnology corporations interested in collaborating with UCSD investigators in 
research diagnostic, prognostic assays and drug development.  
  
The specimens, DNA, and their derivatives may have significant therapeutic or commercial value. 
The Informed Consent form contains this information and informs the subject that there is the 
potential for financial gain by UCSD, the investigator or a collaborating researcher or entity.  
  
  
8.10  Radiographic Assessment  
  
Imaging studies will be performed within 28 days (+7 days) prior to the initiation of study 
treatment as per standard of care for patients undergoing therapy with Pembrolizumab. These 
include a CT of the chest and may include other studies, as clinically indicated. Additional 

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imaging studies will be performed per standard of care every three months to assess disease 
status.  
  
8.11  Extended Safety Follow-Up  
  
Given the potential risk for delayed immune-related toxicities, safety follow-up must be 90 days 
(+14 days) after the last dose of Pembrolizumab administration.  
  
This extended safety follow-up beyond 30 days after last study drug administration may be 
performed either via a clinic visit or via a telephone call with subsequent site visit requested in 
case any adverse events of clinical concern (e.g. events possibly related to study drug(s) or 
serious adverse events) are noted during the telephone call. All patients will be assessed for 
adverse events during the clinic visit or telephone call. If there are adverse events of clinical 
concern which require further medical evaluation as determined by a qualified investigator, 
subjects will come in for a clinic visit and standard of care procedures will be completed. These 
may include a physical exam, vitals, labs, or other procedures, as clinically indicated. 
  
8.12  
Discontinuation from Study Participation  
Patients may be removed from study participation for the following reasons (in addition to those 
listed for discontinuation of study treatment):  
• 
The patient or legal representative withdraws consent for follow-up;  
• 
The patient is lost to follow-up;  
• 
The patient dies;  
• 
It is the decision of the investigator.  
• 
Severe allergic or anaphylactic reaction to pembrolizumab or cialis  
• 
Disease progression prior to surgery  
• 
Pregnancy  
• 
Severe or life-threatening toxicity  
  
8.13  Study Calendar  
Required Procedures  
Baseline  
During 
Treatment  
During 
Treatment  
End of 
Treatment  
Long  
Term  
Follow-Up  
Timing  
Within 28 days 
prior to  
treatment  
initiation unless 
otherwise 
specified  
Every 3 
weeks, ± 3  
days, unless 
otherwise 
specified  
Every 3 
months, +/-  
14 days, 
unless  
otherwise 
specified  
Within 30 days 
after the last  
dose of study  
medication 
unless  
otherwise 
specified  
  
Treatment History  
X  
  
  
  
  
Medical History  
X  
  
  
  
  
Demographics  
X  
  
  
  
  
Physical Exam  
X  
X  
  
X  
  

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Vital Signs  
X  
X  
  
X  
  
Height  
X  
  
  
  
  
Weight  
X  
X  
  
X  
  
ECOG PS  
X  
  
  
  
  
Symptoms & Toxicities  
X  
X  
On an ongoing 
basis  
throughout 
study  
  
X  
X  
Concomitant 
Medications  
X  
X  
On an ongoing 
basis  
throughout 
study  
  
X  
  
Hematology Profile  
X  
X*  
  
X  
  
Chemistry Profile  
X  
X*  
  
X  
  
T4/TSH  
X  
X (every 9 
weeks)  
  
X  
  
Pregnancy Test    (serum 
or urine) for all women 
of child bearing 
potential  
X  
  
Within 7 days 
prior to 
treatment  
X  
  
If/when 
clinically 
indicated  
  
Tumor Biopsy and 
blood harvest  
X  
X**  
  
  
  
  
Radiology & Tumor 
Measurements  
X  
 
Within 35 days 
prior to 
treatment 
As indicated to 
assess  
response as per 
standard of 
care  
Radiographic  
studies as 
clinically 
indicated   
  
  
Tadalafil Compliance  
  
X  
At each clinic 
visit  
  
  
  
Extended Safety Follow 
Up  
  
  
  
  
90 days (+ 
14 days) 
after last 
dose of 
study drug+  
Subsequent Anticancer 
Therapy  
  
  
  
  
X  
Survival Status  
  
  
  
  
X  
* Will also be obtained on days 8 and 15 of cycle 1 only (+/- 3 days)  
** Tumor Biopsy and blood collection at Week 4 after first day of treatment (+/- 3 days). A core needle biopsy may 
be obtained at any accessible tumor site (primary or regional metastatic); ultrasound-may be needed to assist 
during the biopsy procedure. Blood will be collected regardless of the ability to biopsy.   
+Extended safety follow up will include an assessment of adverse events, and may include additional standard of 
care procedures, if there are clinical concerns. 

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9. MEASUREMENT OF EFFECT  
  
9.1  
Antitumor Effect   
  
For the purposes of this study, patients should be re-evaluated for response every three months 
plus or minus 14 days.    
  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).27  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.  
  
9.1.1 Study populations  
  
Safety population.  All patients will be evaluable for toxicity from the time of their first 
treatment with any agent on this study.  
  
Modified Intent to treat population (mITT).  Patients who have measurable disease 
present at baseline, and have received at least one cycle of therapy will be considered 
evaluable for response.  These patients will have their response classified according to 
the definitions stated below.  (Note:  Patients who exhibit objective disease progression 
prior to the end of cycle 1 will also be considered evaluable.)  
  
  
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.   
  
9.1.2 Disease Parameters  
  
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).  
  
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 

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conditions under which such lesions should be considered must be defined in the 
protocol.  
  
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 recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.  
  
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable.  
  
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.  
  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions.  
  
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for nonnodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
  
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.   
  

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9.1.3 Methods for Evaluation of Measurable Disease  
  
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
  
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. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
  
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.   
  
  
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).    
  
PET-CT  At present, the low dose or attenuation correction CT portion of a combined  
PET-CT is not always of optimal diagnostic CT quality for use with RECIST  
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.    
  
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.    
  
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 

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assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:   
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDGPET 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.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.  
  
9.1.4 Response Criteria  
  
9.1.4.1  
Evaluation of Target Lesions  
  
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 the diameters of target 
lesions, taking as reference the baseline sum diameters.  
  
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, 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 progressions).  
  
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.  
  
9.1.4.2  
Evaluation of Non-Target Lesions  

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Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).  
  
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
  
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.  
  
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.      
  
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).  
  
9.1.4.3  
Evaluation of Best Overall Response  
  
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.  
  
Target 
Lesions  
Non-Target Lesions  
New Lesions  
Overall Response  
  
CR  
CR  
No  
CR  
  
CR  
Non-CR/Non-PD  
No  
PR  
  
CR  
Not evaluated  
No  
PR  
 
PR  
Non-CR/Non-PD/not 
evaluated  
No  
PR  
SD  
Non-CR/Non-PD/not 
evaluated  
No  
SD  
  
PD  
Any  
Yes or No  
PD  
  
Any  
PD***  
Yes or No  
PD  
Any  
Any  
Yes  
PD  

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∗  
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.  
**        Only for non-randomized trials with response as primary endpoint.  
***      In exceptional circumstances, unequivocal progression in non-target lesions may be         
accepted as disease progression.  
  
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.  
  
  
9.1.5 Duration of Response  
  
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started).  
  
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.  
  
  
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.   
  
9.1.6 Progression-Free Survival  
  
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first.  
  
9.1.7 Overall Survival  
  
Overall survival (OS) is defined as the duration of time from start of treatment to time of 
death.  
  
  
10. DATA REPORTING / REGULATORY REQUIREMENTS  
  
10.1  Conflict of Interest  
  
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed according to UCSD conflict of interest policy.  

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10.2  Institutional Review Board (IRB) Approval and Consent  
  
The IRB should approve the consent form and protocol prior to any study-related activities. It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
  
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki.  
  
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form.  
  
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion.  
  
10.3  Patient Registration  
  
All patients must be registered with the UCSD Moores Cancer Center Clinical Trials Office 
before enrollment to the study. Prior to registration, eligibility criteria must be confirmed with 
the UCSD Study Coordinator. To register a patient, call (858)-246-0357 Monday through Friday, 
8:00am-4:30pm Pacific Time. Patients will be given a unique sequential study number at the 
time of enrollment. UCSD will fax the outside study site for confirmation of patient registration, 
the patient’s study number, and ability to start study treatment.  
  
10.4  Subject Data Protection  
  
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study.  
  
10.5  Data and Safety Monitoring/Auditing  
  
Data and Safety reporting will be supported by the study statisticians according to the attached 
monitoring plan (appendix V).  Briefly, comprehensive safety and data monitoring reports will 

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be generated semi-annually for review by the study team before being sent to the UCSD DSMC, 
described below.  The study will use the VELOS electronic data capture system at UCSD.  
  
In addition to adverse event monitoring and clinical oversight by the Study Chair, site principal 
investigator and co-investigators, quality assurance of the study will be performed by the UCSD 
Moores Cancer Center Clinical Trials Office internal monitor. Monitoring intervals will be 
dependent upon risk-based assessments.  
  
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board 
(DSMB) to provide oversight in the event that this treatment approach leads to unforeseen 
toxicities. Data from this study will be reported annually and will include:  
  
1) the protocol title, IRB protocol number, and the activation date of the study. 2) 
the number of patients enrolled to date.  
3) the date and site of patients’ enrollment.  
4) a summary of all adverse events regardless of grade and attribution.  
5) a response evaluation for evaluable patients when available.  
6) a summary of any recent literature that may affect the ethics of the study.  
  
10.6  Adherence to the Protocol  
  
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, investigators are required to conduct their 
research according to the plans reviewed and approved by the IRB.  
  
10.6.1 Emergency Modifications  
  
Investigators may implement a deviation from, or a change of, the protocol to eliminate apparent 
immediate hazards/risks to trial subjects without prior IRB approval. Any such emergency 
modification implemented must be noted and reported to the IRB along the lines of a protocol 
deviation or violation, depending on the nature of the modification.  
  
10.6.2 Protocol Violations  
  
Any unplanned variance from an IRB approved protocol is considered a violation and must be 
reported to the IRB in a timely fashion. For the UCSD IRB:  
• 
Major violations must be reported to the IRB within 10 working days of awareness of the 
violation.  
• 
Major violations include:  
o Instances that have harmed or increased the risk of harm to one or more research 
participants.  
o Instances that have damaged the scientific integrity of the data collected for the 
study.  

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o Results from willful or knowing misconduct on the part of the investigator(s).  
o Demonstrates serious or continuing noncompliance with federal regulations, State 
laws, or University policies.  
  
• 
Minor violations may be reported to the IRB at the time of the continuing review.  
o Minor violations have no substantive effect on the risks to participants or on the 
scientific integrity of the research plan or the value of the data collected.  
 
10.7  Amendments to the Protocol  
  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Study Chair. It should also be noted that when an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent form 
might be required.  
  
The written amendment, and if required the amended consent form, must be sent to the IRB and 
submitted to the FDA by the Study Chair for approval prior to implementation.  
  
10.8  Record Retention  
  
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms).  
  
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.  
  
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study.  
  
10.9  Obligations of Investigators  
  
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including 
subinvestigators and other study staff members, adhere to the study protocol and all  

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FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion.  
  
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits will be conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. At the completion of the study, all case 
report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data.  
 
  
11. STATISTICAL CONSIDERATIONS  
  
11.1  Study Design   
  
This is an open label, single arm phase II study using a single dose of combination therapy.  
There is a continuous Pocock stopping boundary for safety, and a Simon minimax 2 stage design 
for efficacy.  
  
11.1.1 Primary endpoints  
  
The primary safety endpoint is the rate of dose limiting toxicity (DLT) at least possibly 
attributable to study treatment.  
   
The primary efficacy endpoint is overall survival (OS) at 12 months post-enrollment.  
  
11.1.2 Secondary endpoints  
  
Secondary endpoints include best response within 1 year by RECIST 1.1, progression free 
survival, adverse event rates, and tolerability.  
  
11.1.3 Accrual.  
  
We anticipate accruing 15 patients per year, over a period of 2 years.  
  
11.1.4 Safety stopping rule.  
  
We anticipate the rate of DLT’s with Pembrolizumab alone in this patient population will be 
17%. 1  Given the extensive safety record of Tadalafil, as well as the prior experience of 
combination therapy in 25 patients (section 7.3), in which only 1 grade 1 AE was observe, we do 
not anticipate the baseline rate of DLTs will be increased above 17% with the combination 
therapy.    
  

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We will use a Pocock sequential boundary to monitor the rate of DLTs throughout the study. 28  
If at any time the number of DTL’s at least possibly attributed to study drug is equal to or 
exceeds bn out of n accrued patients in Table 1 below, the study will be halted for safety.  
  
  
 Table 1.  
   
Number of Patients, n  
1  
2  
3 4  
5  
6  7  
8  9  10 11 21 13 14 15 16 17 81 91 20  
Boundary, bn  
-  
-  
3  4  4  
4  5  
5  5  5  6  6  6  7  7  7  7  8  8  8  
Number of Patients, n  
21  22  
23 24 25  
26 27  
28 29 3 
Number of  
1 2 3 4 5 6 7 8 9 10 11 21 13 14 15 16 17 18 91 20  
Patients, n  
Boundar 
y, bn  
-  -  3  4  4  4  5  5  5  5  6  6  6  7  7  7  7  8  8  8  
Number  
of Patients, 21 22 23 24 25 26 72 28 29 30 31 32 33 34 53 63 37 38 
39 04 n  
Boundar 
y, bn  
9  9  9  9  1 
0  
1 
0  
1 
0  
1 
0  
1 
1  11     
  
  
    
  
    
  
  
This stopping rule has 95% probability to continue if the true DLT rate is 17%.  On the other 
hand, if the DLT rate is 30% the study will stop early with 42% probability, and the expected 
number of subjects accrued would be 24 (assuming most DLT’s occur within 30 days).  
  
The stopping rule will be assessed twice per year with a formal safety report, included in the 
annual DSMB report and the semi-annual study report.  Given the anticipated rate of accrual, this 
will result in assessments approximately every 5 patients accrued.  
  
11.1.5 Primary safety analysis  
If the study continues without stopping early, the conclusion will be that there is no evidence of 
an elevated DLT rate due to the combination therapy.  At the end of the study, the DLT rate with 
a 95% confidence interval will be presented, adjusted for the sequential stopping boundary.  The 
safety population will be used for the stopping rule and primary safety analysis.  
  
11.1.6 Primary efficacy analysis and sample size  
  
The efficacy analysis will use a two -stage Simon optimal design. 29  In the KEYNOTE-048 
study, with a similar patient population (CPS >=1), 257 subjects were treated with 
Boundary, bn  
9  
9  
9  9  10  10  10  10  11  1  

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Pembrolizumab alone 200 mg Q3W, and experienced 51% survival at one year 
postrandomization. 1  Hence the null hypothesis will be 50% survival at one year.  With 30 
subjects at the final analysis, if the true OS rate is 74%, we will have 80% power to reject the 
null hypothesis at the 5% significance level.  
  
The analysis will be as follows:  at the first stage, 14 subjects will be recruited.  The interim 
analysis will be assessed when the 14th subject has been on study 12 months or has otherwise 
completed the study. If at this point 8 or fewer subjects have experienced 12 months survival, the 
study will stop. Otherwise, an additional 16 subjects will be recruited, for a total of 30.  If 19 or 
more subjects experience survival of at least 12 months among these 30 subjects, the null 
hypothesis will be rejected and the conclusion will be that the survival rate is significantly 
elevated above 51%.  Kaplan-Meier curves and 95% confidence interval for the final survival 
rate will be given, adjusting for the 2-stage design.   
  
Accrual will not be halted for the interim analysis, but the study stopping rule will be monitored 
bi-annually in the study safety reports.  If at any point it becomes clear that the stopping 
conditions will be met, the study will be halted.  If the null hypothesis is true, the study has 77% 
chance of stopping early.  
  
11.1.7 Secondary analyses  
  
Demographic and clinical characteristics of the patients will be summarized by treatment group 
using frequency counts and percentages, means and standard deviations or medians and 
interquartile ranges, as appropriate. Best overall response will be determined by RECIST 1.1 and 
will be summarized as proportion with 95% confidence intervals. Adverse events will be 
summarized by grade, type and patient. Progression-free survival, overall survival, and duration 
of response will be described by Kaplan-Meier models to plot these endpoints and estimate 
median times with a 95% confidence interval.   
  
Safety will be evaluated according to the CTCAE v5.0. Safety assessments will be based on 
medical review of adverse event reports and the results of vital sign measurements, physical 
examinations, and clinical laboratory tests throughout the conduct of the study. Laboratory test 
abnormalities will be reviewed for clinical significance and only those deemed clinically 
significant will be reported as adverse events.  
  
All adverse events of any grade occurring in the first 48 hours following combinatorial treatment 
administration will also be assessed as potential infusion reactions. The number and percent of 
subjects who develop any adverse event consistent with an infusion reaction will be summarized 
by overall grade.  
  
  
 
 
 
  

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Laryngoscope. 2013;123(6):1527-1530.  
26. 
Yafi FA, Sharlip ID, Becher EF. Update on the Safety of Phosphodiesterase Type 5 
Inhibitors for the Treatment of Erectile Dysfunction. Sex Med Rev. 2018;6(2):242-252.  
27. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.  
28. 
Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics. 2005;61(2):540-545.  
29. 
Simon R. Controlled Clinical Trials. 1989(10):1-10.  
30. 
Kloner RA, Goldstein I, Kirbgy MG, et al. Cardiovascular safety of phosphodiesterase 
type 5 inhibitors after nearly 2 decades on the market. Sex Med Rev. 2018;6(4)583-594. 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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APPENDIX I   
PERFORMANCE STATUS CRITERIA  
  
ECOG Performance Status Scale  
Karnofsky Performance Scale  
Grade  
Descriptions  
Percent  
Description  
0  
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.  
100  
Normal, no complaints, no evidence 
of disease.  
90  
Able to carry on normal activity; 
minor signs or symptoms of disease.  
1  
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).  
80  
Normal activity with effort; some 
signs or symptoms of disease.  
70  
Cares for self, unable to carry on 
normal activity or to do active work.  
2  
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours.  
60  
Requires occasional assistance, but 
is able to care for most of his/her 
needs.  
50  
Requires considerable assistance and 
frequent medical care.  
3  
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.  
40  
Disabled, requires special care and 
assistance.  
30  
Severely disabled, hospitalization 
indicated.  Death not imminent.  
4  
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.  
20  
Very sick, hospitalization indicated. 
Death not imminent.  
10  
Moribund, 
fatal 
processes 
progressing rapidly.  
5  
Dead.  
0  
Dead.  
  
  
  
  
 
 
 
 
  
  
  
   

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APPENDIX  II    ECOG PERFORMANCE STATUS  
  
   
PS 0  
Fully active, able to carry on all pre-disease performance without restriction  
PS 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.  
PS 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.  
PS 3  
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.  
PS 4  
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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APPENDIX III MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL,  
  
HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND SKIN ADVERSE 
EVENTS  

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APPENDIX IV  
INSTRUCTIONS FOR REPORTING PREGNANCIES ON A CLINICAL TRIAL  
What needs to be reported?  
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on pembrolizumab or 
within 28 days of the patient’s last dose of pembrolizumab must be reported in an expeditious 
manner. The outcome of the pregnancy and neonatal status must also be reported.  
How should the pregnancy be reported?  
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be 
reported as an  
Adverse Event  
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported?  
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
What other information do I need in order to complete the  report for a pregnancy?  
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions”  
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.    
• 
The start date of the pregnancy should be reported as the calculated date of conception.    
• 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the Adverse 
Event report.  What else do I need to know when a pregnancy occurs to a patient?  
• 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status in Adverse Events 
reporting mechanism  
• 
The decision on whether an individual female patient can continue protocol treatment will 
be made by the site physician in collaboration with the UCSD DSMB   
  
• 
It is recommended the female subject be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.   
How should the outcome of a pregnancy be reported?  
The outcome of a pregnancy should be reported as an amendment to the initial AE report if 
the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if the 
outcome of the pregnancy occurred on a subsequent cycle, a new AE report should be 
initiated reporting the outcome of the pregnancy.  
What constitutes an abnormal outcome?  

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An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects.    
Reporting a Pregnancy Loss  
A pregnancy loss is defined in CTCAE as “A death in utero.”  
It must be reported as an Adverse Event as a Grade 4 “Pregnancy Loss” under the System 
Organ Class (SOC) “Pregnancy, puerperium and perinatal conditions”.    
A pregnancy loss should NOT be reported as a Grade 5 event as currently the database 
recognizes this event as a patient’s death. Reporting a Neonatal Death  
A neonatal death is defined in CTCAE as “A newborn death occurring during the first 28 
days after birth” that is felt by the investigator to be at least possibly due to the 
investigational  
agent/intervention. However, for this protocol, any neonatal death that occurs within 28 days 
of birth, without regard to causality, must be reported as an AE AND any infant death after 
28 days that is suspected of being related to the in utero exposure to pembrolizumab must 
also be reported as an AE.   It must be reported as Grade 4 “Death neonatal” under the 
System Organ Class (SOC) “General disorder and administration site conditions.”   
A neonatal death should NOT be reported as a Grade 5 event as CTCAE recognizes this 
event as a patient’s death.  
  

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            APPENDIX V - UCSD Moores Cancer Center Data Monitoring Plan  
 
Title: A Phase II Study of Tadalafil and Pembrolizumab in Recurrent or 
Metastatic Head and Neck Squamous Cell Carcinoma 
 
Introduction 
This data reporting plan outlines the routine monitoring reports that are to be 
generated by the study statistician or the study data manager, based on the 
data that have already been entered into the electronic data capture data base 
(VELOS). 
The purposes of these reports are to monitor the progress of trials and the 
safety of participants, to assure data accuracy, data completeness and protocol 
compliance. 
All the study personnel listed on the VELOS Clinical study information and 
personnel contact information page will receive these reports. (see Appendix A). 
For an outline of the report see Appendix B. 
I. Table of Contents  
II. Executive Summary –  
The Executive Summary will be an overarching description of the data analyzed. 
III. Protocol Synopsis -  
The Protocol will be an overarching description of the study.  
             IV. Study Data Report –  
 
The Study Report will include the following Tables: 
 
Table 1: Overall Enrollment  
 
Table 2: Monthly Enrollment 
 
Table 3: Consent and Treatment Dates  
 
Table 4: Screen Failures  
 
Table 5: Off Treatment 
 
Table 6: Gender, Race, Ethnicity 
 
Table 7: Age (years) 
 
Table 8: Subjects Demographics 
 
Table 9: Deaths 
 
Table 10: All Adverse Events 
 
Table 11: Adverse Events Summary 
 
Table 12: Serious Adverse Events 
 
Table 13: 12-month Overall Survival 
 

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Additional tables related to stopping rules will be added dependent on the study 
design.  This protocol will have an efficacy interim report of 12 month Overall 
Survival following subject 14; Table 13 will provide this data, when appropriate. 
This study requires formal semi-annual safety and efficacy reports sent to the 
Principal Investigator.  The UCSD MCC DSMC will be informed of any results 
from these semi-annual reports that require their attention. 
Only, the Principal Investigator will received reports of outcome data and 
appendices that include treatment assessment, response assessment, baseline 
characteristics and data issues, as determined by study statistician.  
Below has details for each of the tables/reports listed above. The frequencies of 
running the reports will be modified according to each study protocol. 
 
1.  Overall Enrollment - Table 1 
 
Purpose 
To monitor enrollment; to ensure that accrual goals are met in a timely manner; 
to notify the team when accrual goal is nearing completion 
 
Components 
Accrual (number of patients and percentages) by site (if more than one) and 
month. 
 Frequency: first two week data analysis, semi-annually, annually 
2. Study Status Report – Tables 2-5 
 
Purpose 
To provide a summary of the status of study subjects. 
 
Components 
1) Total number of accrual as of date; number of subjects who are 
on/off study; number of subjects who are still on study treatment 
(s); number of subjects who are still on study but off study 
treatment (s). 
2) Listings of off study/off treatment with subject ID, date, week and 
reason. 

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 
Frequency: first two week data analysis, semi-annually, annually 
  3. Baseline Characteristics Report –Tables 6-8 and Appendix 
 
Purpose 
To provide a summary of subjects' baseline characteristics  
 
Components 
Baseline variables which are crucial to study design and analysis  
For categorical variables frequency tables will be generated. 
For continuous variables, mean (range) will be reported. 
 
Frequency: first two week data analysis, semi-annually, annually for 
general demographics (Tables 6-8); other baseline characteristics will be 
analyzed in the final report. 
  4. Toxicity/Adverse Event Report – Tables 9-12 
 
Purpose: 
To monitor toxicities; to evaluate unexpected toxicities; to ensure that toxicity 
rates are acceptable. All participants receiving investigational agents will be 
evaluated for safety. This study is under continuous toxicity analysis (Pocock 
rule).     
 Components: adverse events reported to the investigator by participants.   
1) Listing of all deaths. 
2) Frequency tables of all the signs and symptoms or laboratory 
toxicities by grade and across grades 
3) Listing of all adverse events. The list will include patient number, 
toxicity name, severity of reaction (grade), relationship to study drug 
(definitely, possibly, probably, unlikely or not related; or unknown 
relationship).  
 
Frequency: first two week data analysis, semi-annually, annually.   

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5.  Stopping Rules (Table 13) 
 Components: Analysis of DLTs and 12-month OS  
 Frequency: first two week data analysis, semi-annually, annually 
6.  Treatment and Dose Modifications Report (Treatment Form) 
 
Purpose: To monitor treatment and dose adjustment  
 
Components: Listings of study treatment (s) and their corresponding 
dosages, including treatment start date, treatment modification dates and 
off treatment date.  
 
Frequency: first two week data analysis, semi-annually, annually 
7. Issues with Data including Data Completeness Report (various data forms) 
 
Purpose:  
To ensure that clinic visits and other endpoint-related visits are conducted 
according to schedule; that endpoint-related data are collected 
appropriately and in a timely manner; to correct the database; to make sites 
and site principal investigators (PIs) aware of specific problems and to 
ensure that the compliance rate for visits and sample acquisition is high 
enough to satisfy protocol objectives. 
 
Frequency: first two week data analysis, semi-annually, annually 
 

UCSD Moores Cancer Center 
 
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Timeline for Reports 
 
*Accrual and Baseline Characteristics Reports may be discontinued following closing the study 
to accrual 
** The first data reports will be two weeks after the study opens or after the first subject 
 
Date 
Accrual* 
Study 
Status 
Baseline 
Characteristics* 
Study 
Completeness 
Toxicity/Adverse 
Event 
Treatment 
and Dose 
Modifications 
x** 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 

UCSD Moores Cancer Center 
 
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Report Type 
Trial: A Phase II Study of Tadalafil and Pembrolizumab in Recurrent or Metastatic 
Head and Neck Squamous Cell Carcinoma (UCSD IRB #: 190098) 
CONFIDENTIAL DOCUMENT 
 
 
 
Date 
Principal Investigator: Joseph A Califano III, MD  
Statisticians: Karen Messer, PhD and XXX 
 
 
 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
Contents: 
1. Executive Summary 
2. Protocol Synopsis 
3. Report Overview 
4. Quality Management 
5. Methods 
6. Participants Status 
7. Subjects Consent and Treatment Dates 
8. Screen Failures 
9. Off Treatment 
10. Demographics 
11. Stopping Rules 
12. Deaths 
13. Adverse Events 
14. Serious Adverse Events 
15. Outcomes Data 
16. Appendices 
17. Software 
 
 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
1. Executive Summary 
 Report Overview 
This report reviews enrollment and safety data available in the study VELOS 
database as of xxxx (data lock dates will be every six months following enrollment of 
first patient). Tables are provided in the body of the report.  
 Study Site Status 
Report of UCSD activation  
 Enrollment Status 
XXX subjects have been screened for this study. 
XXX subjects have been enrolled. 
 Off Treatment Status 
XXX treated subjects have been discontinued (withdrawn) from the study.  XXX 
treated subjects have completed treatment. 
 Stopping/Halting Rules 
Safety: We will use a Pocock sequential boundary to monitor the rate of DLTs 
throughout the study. Safety will be assessed by computing the DLT rate every 6 
months.  Any DLT that occurs within the first cycle of therapy (28 days) will be used 
to make decisions.  
 
Efficacy: The primary efficacy analysis will use a Simon optimal design, testing one-
year OS. The Simon optimal 2 stage design will examine OS once 14 patients have 
been recruited. An OS rate of 8/14 or greater will result in study continuation. 
 
 Safety Summary 
XXXX adverse events have occurred in XXX subjects.  XXX serious adverse events 
have occurred in XXX subjects. 
Of the XX adverse events: XX were mild (grade 1), XX were moderate (grade 2) and 
XX were severe (Grade 3+). 
 Quality Management 
Quality management reviews are performed semi-annually and were last completed 
on xxxx. 
 
 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
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2. Protocol Synopsis 
Protocol Title: A Phase I/II Study of Tadalafil and Pembrolizumab in Recurrent or 
Metastatic Head and Neck Squamous Cell Carcinoma 
Principal Investigators: Joseph Califano, MD 
Study Sites: Single-center (UCSD)  
Study Activation Date: 
Planned Accrual: N = 30 
Study Design: Open-label phase I, II single arm trial with a Pocock continuous safety 
stopping rule and a Simon 2 stage efficacy design.  All patients will receive Tadalafil 
and Pembrolizumab 
Primary Objective(s): Identify the toxicity for the combination of Tadalafil and 
Pembrolizumab and assess efficacy 
Treatment Description: Treatment will be administered in 21 day cycles with the 
following dose schedule, for up to 12 months: Tadalafil (10mg po daily) and 
Pembrolizumab will be administered at 200 mg IV q3 weeks for 24 months (35 
cycles) 
Tadalafil will be supplied by Lilly as 10 mg tablets  
Pembrolizumab will be supplied as a clear, colorless liquid formulated for 
intravenous administration.  Commercial supply or drug supplied by Merck will be 
used. 
Primary Endpoint:  
The primary safety endpoint is the rate of DLT.  
The primary efficacy endpoint is overall survival (OS) at one year 
 
Definition of Dose-Limiting Toxicity (DLT)  
  
Toxicities will be described according to NCI-CTCAE version 5.0.  Dose-limiting 
toxicity is defined as toxicity that is possibly, probably, or definitely attributable to the 
study regimen in the opinion of the principal investigator and that is:  
• 
Grade 3 or higher non-hematologic toxicity excluding nausea and vomiting 
and skin rash  
• 
Grade 4 neutropenia, febrile neutropenia, or grade 4 thrombocytopenia  
• 
Grade 3 or higher nausea and vomiting that cannot be controlled within two 
weeks with anti-emetics  
• 
Grade 4 skin rash  
As an exception, if the toxicity is regarding as being possibly related to the study 
regimen but in the opinion of the principal investigator is felt to be more likely related 
to a concurrent medication, the underlying malignancy, a co-morbid condition, or 
some factor other than the study regimen, the principal investigator may choose to 
not regard it as a DLT for the purposes of the study.  
  
Any DLT that occurs within the first cycle of therapy (28 days) will be used to make 
decisions about proceeding to the subsequent cohort.  
 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
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Study Stopping Rules: 
Safety: Safety will be assessed by computing the DLT rate every 6 months, assuming 
an expected Grade 3 or 4 toxicity rate of 17% for Pembrolizumab alone. A Pocock 
sequential stopping boundary will be used, which will stop the trial early with 56% 
probability, and with < 2 expected excess events, if the rate of DLT is elevated to 30%.  
The trial will stop early with 89% probability and < 1 expected excess event if the DLT 
rate is elevated to 40%.   If at any time the number of DTL’s at least possibly attributed 
to study drug is equal to or exceeds bn out of n accrued patients in Table below, the 
study will be halted for safety. The stopping boundaries are given below: 
Patient enrollment, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- - 3 4 4 4 5 5 5 5 6 6 6 7 7 7 7 8 8 8 
Patient enrollment, n 21 22 23 24 25 26 27 28 29  
 
 
 
 
 
 
 
 
 
 
Boundary, bn 
9 9 9 9 10 10 10 10 11  
 
 
 
 
 
 
 
 
 
 
 
Efficacy: If safety is satisfied, the primary efficacy analysis will use a Simon optimal 
design, testing one-year OS against a 51% null survival rate   and a 74% alternative 
rate (survival with tadalafil and Pembrolizumab combination). The Simon optimal 2 
stage design will examine OS once 14 patients have been recruited. An OS rate of 
8/14 or greater will result in study continuation. If 19 or more subjects experience 
survival of at least 12 months among these 30 subjects, the null hypothesis will be 
rejected and the conclusion will be that the survival rate is significantly elevated 
above 51%. 
3. Report Overview 
The purpose of this report is to review cumulative enrollment and safety data for 
the subjects enrolled in the Tadalfil + Pembro study. This report reflects data 
from the study database as of xxx. Within the body of the report are summary 
tables of enrollment, demographic characteristics, and adverse events. Readers 
of this report are asked to maintain the confidentiality of the information provided 
in this report. 
 
4. Quality Management 
4.1 Clinical Trials Office Quality Assurance: This study was monitored by the 
UCSD Moores Cancer Center CTO xxxxx 
 
4.2 Protocol deviations/violations: 
 
5. Methods – Data Set 
This report is based on all data downloaded on xxxx from the VELOS portal 
(https://velos.ucsd.edu). 
 
6. Participant Status 
6.1 Overall Enrollment: This section summarizes the participant status and enrollment by study 
month. Enrollment is defined as XXXX 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
 
Table 1: Overall Enrollment 
Consented  
Eligible 
Screen Failures 
 
 
 
 
 
 
 
 Table 2: Monthly Enrollment Status 
Study Month 
Year & Month 
N Subjects Enrolled 
1 
 
 
2 
 
 
3 
 
 
 
XX Subjects have been enrolled in X sites since study initiation.  This trial is accruing at 
a rate of X subjects per month. 
6.2 Consent and Treatment Dates 
Table 3: Consent and Treatment Start Dates 
Subject ID 
Consent Date 
Treatment Start Date 
 
 
 
 
 
 
 
 
6.3 Screen Failures 
 
Table 4: Screen Failures 
Subject ID 
Consent Date 
Screen Failure 
Date 
Reason for Screen 
Failure 
 
 
 
 
 
 
 
 
 
6.4 Off Treatment (Separated by early discontinuation, treatment completion or 
other reasons, if applicable) 
 
Table 5: Off Treatment 
 
Subject ID 
Off Treatment 
Date 
Off Treatment 
Reason 
Duration of 
Treatment  
 
 
 
 
 
 
 
 
 
7. Demographics 
 
7.1 Demographic Summary 
Categorical measures: Categorical variables are summarized using frequency 
tables and percentages by Arm 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
 
Table 6: Gender, Race, Ethnicity 
 
 
Frequency 
Proportion 
Gender 
 
 
Female 
 
 
Male 
 
 
Race 
 
 
White 
 
 
Black, African- American 
 
 
Asian 
 
 
Native America 
 
 
Unknown or Not Reported 
 
 
Ethnicity 
 
 
Non-Hispanic 
 
 
Hispanic 
 
 
 
 
Continuous measures: Continuous variables are summarized with N, mean, 
standard deviation, median. 
 
Table 7: Age (years) 
 
 
N 
Mean 
SD 
Median 
Age 
 
 
 
 
 
 
7.2 Demographic Information for All Treated Subjects 
 
Table 8: Subjects Demographics 
Subject ID 
Stage 
Gender 
Ethnicity 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
8. Safety 
8.1 Deaths  
Table 9: Deaths 
Subject ID 
Date of Death 
Reason for Death 
Within 30 days of 
last treatment? 
 
 
 
 
 
 
 
 
 

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
 
8.2 Adverse Events by Stage 
 
Table 10: List of All Adverse Events 
 
 Adverse Events Summary 
8.3 Adverse Events Summary 
Severity 
N Adverse Events 
Mild (grade 1) 
 
Moderate (grade 
2) 
 
Severe (grade 3) 
 
Life-threatening 
(grade 4) 
 
Fatal (grade 5) 
 
Total 
 
 
Note: These are all AEs; SAEs are also reported in next section. 
 
8.3 Serious Adverse Events 
 
Table 12: Serious Adverse Events 
 
Experimental Treatment Arm 
Patient 
Study ID 
Serious Adverse 
Event Name 
Severity/Grade 
Start 
Date 
Stop 
Date 
Attribution 
  
 
 
  
 
 
 
9 Stopping Rule for safety 
Safety stopping rule will be assessed after each patient has reached 28 days. DLT 
rate will be calculated at every 6 months for the DSMC reviews. 
 
Patient Study 
ID 
Stage 
Treatment 
Start Date 
Did Patient have 
a DLT? 
Please specify the 
DLT 
Patient 
Study ID 
Stag
e 
AE 
week 
Adverse 
Event 
Name 
Severity/Grad
e 
Start 
Date 
Stop 
Date 
Attribution 
  
 
 
 
 
  
 
 
 
 
 
 
  

UCSD Moores Cancer Center 
 
Joseph Califano, MD 
HRPP #190098 
 
 
  
 
 
 
 
 
10 Stopping Rule for efficacy: 12 months overall survival 
 
Patient Study 
ID 
Stage 
Treatment 
Start Date 
Death Date 
Did Patient 
achieve 12 month 
survival? 
  
 
 
 
 
 
11 Appendices 
11.1 Treatment Assessment 
11.2 Response Assessment 
11.3 Issues with data 
BSR data checks include verification of doses, number of appropriate drug and 
response cycles based on treatment start date, redundant and/or missing data, and 
other data elements as needed based on study protocol.