A Phase 1 Trial of Intratumoral Cisplatin for Early Stage, Resectable, Non-Small Cell Lung Cancer
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer
Sponsor: University of Vermont

 
NCT04809103 
 
03 February 2022 
 
A PHASE I TRIAL OF INTRATUMORAL CISPLATIN FOR EARLY STAGE, 
RESECTABLE, NON-SMALL CELL LUNG CANCER 
 
 

 
A PHASE I TRIAL OF INTRATUMORAL CISPLATIN FOR EARLY STAGE, 
RESECTABLE, NON-SMALL CELL LUNG CANCER 
 
 
Principal Investigator: 
C. Matthew Kinsey MD, MPH 
Director, Interventional Pulmonology, University of Vermont Medical Center 
Given D Suite 208, 89 Beaumont Avenue 
Burlington, VT 05405 
Telephone: 802.656.3521 
Fax: 802.656.3526 
Email: Matt.Kinsey@med.uvm.edu 
 
Co-Investigators: 
Hannah Kooperkamp MD 
Assistant Professor of Cardiothoracic Surgery 
Department of Surgery, University of Vermont Medical Center 
 
Garth Garrison 
Director, Lung Cancer Transdisciplinary Team 
Division of Pulmonary and Critical Care, University of Vermont Medical 
 
Bernard Cole Ph.D. 
Professor, Department of Mathematics and Statistics, University of Vermont 
Director, Cancer Control and Population Health Sciences Section, Vermont Cancer Center  
 
Farrah B. Khan MD 
Lung Clinical Trials Lead 
Hematology and Oncology Division, University of Vermont Medical Center 
 
Kelly Butnor MD 
Lung and Thoracic Pathology 
Department of Pathology, University of Vermont Medical Center 
 
Mitch Norotsky MD 
Chief of Surgery  
Department of Surgery, University of Vermont Medical Center 
 
Pamela C. Gibson MD 
Vice Chair, Staff and Faculty Affairs 
Department of Pathology, University of Vermont Medical Center 
 
Scott Anderson MD 
Director, Cytopathology 
Department of Pathology, University of Vermont Medical Center 
 
 

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ABBREVIATIONS: 
NSCLC: Non-small cell lung cancer 
EBUS: endobronchial ultrasound 
ROSE: Rapid on-site cytopathologic 
examination  
CT: computed tomography 
DLT: dose limiting toxicity 
MTD: maximum tolerated dose 
 
MTV: maximum tolerated volume 
 
CTCAE: Common Terminology Criteria for Adverse Events 
 

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STUDY PROTOCOL TABLE OF CONTENTS: 
1. SYNOPSIS.................................................................................................................................5  
2. BACKGROUND.......................................................................................................................6 
2.1. Study Disease.....................................................................................................................6 
2.2. Rationale............................................................................................................................6 
2.3. Investigational Agent……….............................................................................................7 
3. PATIENT SELECTION............................................................................................................9  
3.1. Inclusion Criteria...............................................................................................................9 
3.2. Exclusion Criteria.............................................................................................................10 
4. TREATMENT PLAN..............................................................................................................10 
4.1. Agent Administration.......................................................................................................10 
4.2. Study Duration.................................................................................................................13 
4.3. Treatments and Evaluations by Visit...............................................................................14 
5. PHARMACEUTICAL INFORMATION................................................................................17 
6. STATISTICAL CONSIDERATIONS.....................................................................................18 
6.1. Study Design....................................................................................................................18 
6.2. Criteria for endpoint evaluation.......................................................................................18 
6.3. Samples Size.....................................................................................................................21 
6.4. Power................................................................................................................................21 
6.5. Statistical Analysis Plan...................................................................................................21 
7. DATA SAFETY AND MONITORING..................................................................................21 
8. ADVERSE EVENT REPORTING..........................................................................................23 
9. DATA COLLECTION AND METHODS..............................................................................26 
10. TABLE OF STUDY VISITS AND PROCEDURES..............................................................28 
11. REFERENCES........................................................................................................................32 
 
 
 

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APPENDICES:  
 
APPENDIX A: DSM REPORTING TABLE FOR ADVERSE EVENTS..............................29 
 
APPENDIX B: NCI COMMON ADVERSE EVENTS FOR COMMONLY USED  
ONCOLOGY DRUGS (CAEPR) .............................................................................................30 
 
APPENDIX C: SCRIPT FOR IDENTIFICATION OF ADVERSE EVENTS BASED ON  
NCI CAEPR...............................................................................................................................31 
 
 
 
 
 
 
 
 
 
 
 

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1. SYNOPSIS: 
 
TITLE:  A PHASE I TRIAL OF INTRATUMORAL CISPLATIN FOR EARLY 
STAGE, RESECTABLE, NON-SMALL CELL LUNG CANCER 
 
RATIONALE:  
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the 
United States.  Even for early stage disease, the rate of recurrence following surgical 
resection is as high as 50%.  Although neoadjuvant therapy, administered before surgery, for 
early stage lung cancer is associated with a survival benefit, it is rarely used due to the 
systemic toxicity of intravenous (IV) cytotoxic chemotherapy.  IV immunotherapies are also 
being evaluated in combination with systemic therapies in the neoadjuvant setting.  However, 
only a minority of patients respond to immunotherapy. One of the most common reasons for 
failure of immunotherapy is lack of presentation of tumor antigens to the immune system, a 
problem that may be potentially addressed with cytotoxic agents. 
   
Over the last several years, case series have demonstrated the feasibility and safety of 
delivering cisplatin directly into lung tumors. For patients that have recurrent lung cancer in 
a previous radiation field, our prior work demonstrated that a series of four injections results 
in a 71% complete or partial response rate based on RECIST criteria of the treated volume.  
The only toxicity seen in this series was nausea and/or vomiting.  Further, there are in vitro 
data that support the idea that cisplatin may modulate the immune system.   
    
Given the current knowledge of safety and tolerability of intratumoral cisplatin, coupled with 
the potential to achieve immune priming that may help address systemic micrometastases, 
have led us to postulate that intratumoral cisplatin is a well-tolerated, and potentially 
effective, neoadjuvant therapy for patients with early stage, resectable, non-small cell lung 
cancer.  
 
PRIMARY OBJECTIVE:  
To identify the maximum tolerated dose (MTD) of intratumoral cisplatin, delivered during a 
single bronchoscopy with cone-beam CT confirmation, in a dose escalation protocol  
 
DESIGN: 3+3 dose escalation. The amount of delivered cisplatin is based on the volume of 
the tumor being treated, beginning at a volume of cisplatin of 1/4th the volume of the tumor.  
 
 
 
 
 
 
 
 
 
 
 
 

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2. BACKGROUND: 
2.1. Study Disease: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related 
death in the United States.1 Even for tumors that are identified at an early stage and 
resected, the rate of recurrence may be as high as 50%.2  Direct intratumoral (IT) delivery 
of cisplatin into early stage lung cancers at the time of diagnosis has several clear potential 
benefits.  First, it reduces time to treatment from time of diagnosis, potentially improving 
outcomes through this mechanism alone.  Second, intratumoral delivery of cisplatin may 
provide the benefits of intravenous (IV) neoadjuvant chemotherapy while minimizing the 
systemic, off-target toxicities that have limited the adoption of this approach. Finally, there 
is increasing evidence that chemotherapy induced tumor cell death may “prime” the 
immune system by allowing immune effector cells to recognize tumor epitopes and kill 
undetected micrometastatic tumor cells beyond the resection specimen.3 
 
2.2. Rationale:  
NSCLC Commonly Results in a Prolonged Diagnosis to Treatment Time: Lung cancer 
remains one of the most challenging diseases to diagnose, stage, and treat.  Patients 
generally undergo CT scans, PET-CT scans, and MRIs to determine the stage and extent 
of a potential or confirmed NSCLC. This can result in prolonged times to surgical 
resection. In fact, diagnosis to surgical resection times greater than 8 weeks appear to 
occur in approximately 30% of patients, and are independently associated with stage 
progression and a decreased median survival.4 In a highly homogenous group of patients 
with Stage 1 squamous cell carcinoma, delayed surgery (>38 days) was associated with a 
worse overall survival.5 Initiating therapy earlier has the potential to improve outcomes 
for patients with early stage NSCLC. 
 
Neoadjuvant Therapy for Resectable Lung Cancer is Effective but Rarely Performed: In 
early-stage, resectable, lung cancer, neoadjuvant chemotherapy improves survival, with a 
13% reduction in the relative risk of death.6  The majority of neoadjuvant chemotherapy 
trials have utilized IV cisplatin, or a closely related drug, carboplatin. However, 
neoadjuvant IV chemotherapy results in significant rates of adverse effects. For instance, 
neoadjuvant cisplatin plus gemcitabine results in a 32% rate of systemic hematologic 
toxicity.7  Intratumoral therapy, delivered at the time of diagnosis, has the potential to 
immediately initiate therapy and capture the benefits of neoadjuvant chemotherapy while 
minimizing systemic toxicity.   
 
“Priming” the Immune System May Facilitate Immune Mediated Tumor Destruction: In 
2015, the first immunotherapy drug for lung cancer was approved for the treatment of 
NSCLC.8 Nivolumab is a humanized antibody that binds the programmed death ligand  1 
(PD-L1), one of several immune checkpoint inhibitors (ICIs), that prevent tumor-
mediated downregulation of cytotoxic T lymphocytes (CTLs). Nivolumab demonstrated 
a significant increase in median overall survival compared to docetaxel for patients with 
advanced squamous NSCLC.  This median difference was driven by a significantly 
prolonged survival in the 20% of patients who responded. Similarly, the ICIs 
pembrolizumab and durvalumab result in response rates of 45% in treatment-naive 
advanced NSCLC and 28% in locally advanced non-resectable NSCLC, respectively.9,10 
Within each of these studies, there are groups of patients that experienced durable and 

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prolonged NSCLC remissions.   
 
The impressive results achieved for a minority of patients with NSCLC have led to 
considerable interest in additional mechanisms of immune modulation. Some of the most 
notable ICI responses in fact have occurred in melanoma and lung cancer.11,12 These are 
considered carcinogen-driven cancers with high rates of human tumor-specific peptides 
that arise from somatic mutations in the cancer genome.13 One reason for failure of ICI 
therapy is lack of presentation of these antigens to the immune system.  This may lead to 
a relative absence of CTLs in the tumor microenvironment and is associated with failure 
of ICI therapy.14 One mechanism for recruiting immune effector cells is tumor cell death 
which can be induced by cytotoxic agents or radiation.15  
 
2.3. Investigational Agent:  
Cisplatin Delivered IV is Highly Toxic: One of the most commonly used IV cytotoxic 
medications for the treatment of lung cancer is cisplatin. Cisplatin binds to DNA, cross-
linking strands and thereby inhibiting mitosis, which in turn leads to apoptosis of the tumor 
cell.16 However, it has more recently been recognized that cisplatin may have 
immunomodulatory effects that extend beyond those related merely to cell death.17 In vitro 
studies implicate cisplatin in upregulation of the major histocompatibility complex (MHC 
class 1), recruitment and proliferation of effector cells, upregulation of the activity of 
cytotoxic effector cells, and downregulation of the immunosuppressive environment.  
Specifically, cisplatin appears to increase recruitment of CTLs and to upregulate Fas 
receptor, a death signal.18 Importantly, there is also evidence that cisplatin may work 
synergistically with PD-1 inhibitors.19,20 Although many standard regimens for the 
treatment of NSCLC include an IV platinum agent, this delivery approach is complicated 
by significant toxicity. Systemic IV cisplatin is associated with greater than 40 untoward 
effects; the most common is nephrotoxicity, but may commonly include gastrointestinal, 
hematologic, cardiac, and hepatic events.16 These off-target effects greatly impair patient 
quality of life and tolerance of the drug, which in turn limits the dose and frequency at 
which the medication can be given. In fact, for Stage IV NSCLC there is evidence that 
platinum-based chemotherapy may hasten death compared to palliative care.21  The FDA 
guidance document for cisplatin highlights a feature of this drug that is atypical for 
chemotherapeutics, namely that it is more highly absorbed in normal tissues versus 
tumor tissue. Direct intratumoral (IT) delivery thus has the potential to maximize the 
therapeutic effect of cisplatin while minimizing off-target adverse effects. 
 
Safety of IT Cisplatin in Prior Clinical Studies: There is accumulating evidence that 
cisplatin may be safely delivered directly into a lung tumor with minimal side effects. In 
general, intratumoral injection for lung cancer dates back to at least 1978.22 The first Phase 
III trial of a bronchoscopically delivered agent, the Bacillus Calmette-Guerin vaccine, was 
completed in 1986.23 This study established the safety of IT delivery via a needle into early 
stage lung cancers but did not demonstrate significant clinical effect. The development of 
modern technologies such as endobronchial ultrasound, navigational bronchoscopy, 
robotic bronchoscopy, and intraoperative cone-beam CT scan has resulted in the ability to 
precisely deliver an agent into a tumor, and the opportunity to synergistically augment the 
effect of modern therapies.    

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In 2006, Celikuoglu et al used intratumoral injection of a maximum dose of 40mg of 
cisplatin through a flexible bronchoscope for patients with obstructive, inoperable 
NSCLC.24 This same group also performed bronchoscopic injection of cisplatin into 
centrally located, early-stage lung cancers. They demonstrated endobronchial regression 
of tumor which enabled subsequent surgical resection.25 Intratumoral cisplatin has  
subsequently been used in multiple other studies at doses of 30-40mg.26 In a Phase III 
clinical trial, 4 patients with limited-stage small cell lung cancer (SCLC) received 
intratumoral cisplatin at a dose of 40mg (ClinicalTrials.gov Identifier: NCT01487499). 
There were insufficient numbers of patients to assess for the primary outcome of 
progression-free survival, but no reported adverse effects. Our group has utilized 
intratumoral cisplatin for treatment of late stage disease at a maximum injected dose of 
40mg, with only nausea and vomiting identified as adverse effects. At these doses, there 
appears to be significant efficacy with a 71% complete or partial response rate based on 
data from two centers (manuscript accepted to the Journal of Thoracic Oncology). We 
have preliminary data using flow cytometric analyses of lesions sampled 1 week after 
intratumoral cisplatin administration of cisplatin at these doses that demonstrate up to 90% 
cell death in the treated volume. Intratumoral cisplatin in the range of 40mg can result in 
detectable platinum blood levels following administration.  Nausea and vomiting were 
also the most common adverse events documented in a larger series of 36 patients.27 
Serious adverse events have been reported when IT cisplatin is combined with other 
therapies. Bronchomediastinal fistula has occurred when IT cisplatin was delivered 
concomitantly with re-irradiation.27 Similarly, organizing pneumonia occurred in a patient 
who was simultaneously receiving intravenous cisplatin.28  Full details of prior studies 
have been included in the Summary of Prior Human Studies.   
 
Delivery of IT Cisplatin: Despite series demonstrating the overall safety of intratumoral 
cisplatin, there has been little systematic investigation of the optimal dose or delivery 
location.  For instance, in many studies an identical dose of 40mg of cisplatin has been 
delivered, regardless of morphology or other tumor characteristics.  Further, intraoperative 
imaging has not been evaluated to guide or assess IT delivery. It is therefore critical to 
establish a safe dose for intratumoral cisplatin in a prospective study in patients with 
early stage resectable NSCLC with appropriate assessment for dose limiting toxicity 
(DLT).  
 
Rationale for Dosing: Prior studies have generally treated large tumors (>3cm diameter) 
and focused on using a fixed dose of cisplatin. However, for smaller tumors the delivery 
volume of the agent (1mg/ml concentration) may result in reaching the maximum tolerated 
volume before reaching the MTD. For instance, a 2 cm diameter tumor would have a 
volume of approximately 4 mL (assuming a spherical morphology). It is clear that 
delivering a 40mg dose (40mL) is not feasible in this setting.  The additional variance of 
tumor size in this study motivated further analysis to determine feasibility of alternative 
dosing strategies for smaller tumor volumes.  We evaluated 28 cases of patients with 
recurrent lung cancer in a previously radiated field treated with intratumoral cisplatin at 
the University of Vermont and the University of Florida.  We applied our published 
computational model of intratumoral cisplatin pharmacokinetics29 to evaluate a volumetric 

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dosing strategy. This series include 
tumors less than 3 cm in diameter, 
many of which empirically received 
a lower dose of cisplatin. Each case 
was evaluated for response using 
RECIST criteria, v1.1.30  This model 
was used to simulate the percentage 
of tumor cells that reach the  
threshold intracellular concentration 
of cisplatin required for cell death 
(Fig 1). These results demonstrate 
robust distribution of the agent, and 
associated cytotoxicity, across a 
broad range of smaller tumors. For 
instance, a 4 cm diameter tumor is 
approximately 30 cm3 in volume. 
Delivering one-half of the tumor 
volume in total drug volume, with a 
1/mg/ml concentration, results in a 
15mg dose of delivered cisplatin, 
which would be predicted to lead to 
cytotoxicity to over 90% of the 
tumor.  
 
The second consideration for dosing in the current study is the maximum administered 
dose.  The majority of prior series have not used doses above 40mg.  In our open Phase 
1A study of intratumoral cisplatin for metastatic NSCLC, the 20mg dose cohort did not 
result in any dose limiting toxicity and we are moving to the 40mg dose cohort.  Thus, for 
this protocol we consider 40mg to be the maximum dose.  We have outlined three dosing 
cohorts in the protocol: an Initial cohort at 1/4th tumor volume, a De-escalation cohort at 
1/8th tumor volume, and an Escalation cohort at 1/2 tumor volume. If we reached the 
Escalation cohort (1/2 volume) the maximum dose delivered would be 32.8mg.  Tables 
detailing example doses for each cohort have been included in Section 4.  
 
 
3. PATIENT SELECTION 
3.1. Inclusion criteria 
3.1.1. Age ≥18 years.   
 
3.1.2. ECOG performance status 0 or 1 
 
3.1.3. Patients must have adequate organ and marrow function as defined below: 
3.1.3.1. 
Leukocytes ≥3,000/mcL 
3.1.3.2. 
Platelets ≥100,000/mcL 
3.1.3.3. 
Total bilirubin ≤ institutional upper limit of normal (ULN) 
3.1.3.4. 
AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN 
Tumor Volume (cm3)
Cisplatin Dose (mg)
Percentage of Tumor Reaching Cytotoxic Threshold 
Figure 1: Dosing of Cisplatin Based on Tumor 
Volume. Isodose lines demonstrate  robust coverage 
of small tumors with low doses of intratumoral 
cisplatin (1mg/ml). For reference, a 10 cm³ volume
corresponds to a 2.7 cm diameter tumor (assuming a
spherical morphology). 

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3.1.3.5. 
Creatinine ≤ institutional ULN 
 
3.1.4. Patients with a prior or concurrent malignancy whose natural history or treatment 
does not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial 
 
3.1.5. Have known or suspected clinical stage I-IIb NSCLC after CT and/or PET_CT at 
time of enrollment 
 
3.1.6. Presence of a target lesion with a minimum volume of 1.0 cm3, (approximately1.2 
cm in diameter) and  ≤ 5.0 cm in diameter 
 
3.1.7. Agreement from a cardiothoracic surgeon, following review of past medical 
history, medications, pulmonary function testing, and CT scan that patient is likely 
to be a surgical candidate and that, after considering known possible adverse events, 
delivery of intratumoral cisplatin is unlikely to adversely affect surgical feasibility   
 
3.1.8. Rapid on-site cytopathologic examination (ROSE) performed during the 
procedure returns likely NSCLC (per the determination of a trained, attending, 
cytopathologist). No research procedures will be performed if ROSE is non-
diagnostic 
 
3.1.9. A CT scan of the chest (with or without contrast) within 1 month of the screening 
visit 
 
3.1.10. Ability to understand and the willingness to sign a written informed consent 
document 
 
3.2. Exclusion criteria 
3.2.1. Use of an investigational agent within 30 days of the screening visit 
 
3.2.2. IV chemotherapy within the 30 days of the screening visit 
 
3.2.3. Pregnancy/lactation (pregnancy test to be performed by pre-op as part of standard 
of care for women of child-bearing age as defined by UVMMC Policy NPREP16) 
 
3.2.4. History of prior radiation to the study lesion 
 
3.2.5. History of allergic reaction to cisplatin or its derivatives 
 
3.2.6. Patients with uncontrolled intercurrent illness 
 
3.2.7. Physician determination that patient would not be appropriate for study  
 
 
4. TREATMENT PLAN 
4.1. Agent Administration 

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4.1.1. Treatment will be administered intraprocedurally.  Reported adverse events and 
potential risks are described in the Data and Safety Monitoring Plan.  No 
investigational or commercial agents or therapies other than those described below 
may be concomitantly administered with the intent to treat the patient's malignancy. 
 
4.1.2. The agent will be administered at 3 potential dose levels in a 3+3 design.31 
 
4.1.3. IT cisplatin 1mg/ml will be dosed with a delivered volume based on a proportion 
of the volume of the tumor. 
 
4.1.4. This volumetric dosing approach is being employed to account for the dramatic 
tumor volume differences seen in this diameter range. Prior studies have most 
commonly used an empirically derived intratumoral dose of 40mg or less (although 
have ranged to 100mg intratumorally, Appendix B).  To minimize the risk of 
extravasation of the agent from small tumors we have adopted a volumetric dosing 
strategy.  
 
4.1.4.1. 
First dose cohort: The delivered quantity of cisplatin will equal one-fourth 
(1/4th) of the total tumor volume.   
 
4.1.4.2. 
De-escalation dose cohort : The delivered quantity of cisplatin will equal 
one-eight (1/8th) of the total tumor volume This dose cohort will only be used 
if the ¼-tumor volume dose cohort is terminated due to DLT. 
 
4.1.4.3. 
Escalation dose cohort: The delivered quantity of cisplatin will equal one-
half (1/2) of the total tumor volume 
 
4.1.4.4. 
Lower or higher dose cohorts may be pursued if indicated based on the 
rate of DLT, pending formal review and approval by the appointed Data  
Safety Monitoring Committee of the UVM Cancer Center. This is a standard 
approach since the DSMC reviews all AEs and relevant data at any change in 
dose level (pre-specified or otherwise) before preceding to the next dose level.   
 
 
4.1.5. Tumor volume will be determined using automated segmentation available in the 
open-source software platform (https://chestimagingplatform.org) and manually 
verified. 
 
4.1.6. The minimum volume that is feasible to deliver is 0.5mL.  
 
 
4.1.7. This leads to the following “INITIAL” example dosing regimen for tumors of a 
specified volume, beginning at 1/4th Volumetric Dosing and assuming that < 2 of 
the first 3 participants have a dose limiting toxicity (DLT), defined as a Grade 3 by 
the CTCAE v5.0:  
 
 

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4.1.8. The following are example doses for the DE-ESCALATION cohort:  
 
 
 
 
 
4.1.9. The following are example doses for the ESCALATION cohort: 

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4.1.10. Dose escalation will be performed as follows: 
 
 
 
 
 
4.2. Duration of Study Period: 
4.2.1. There is only a single delivery of the agent, cisplatin. 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next escalation dose. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose. If this is the first dose evaluated, a 
lower dose level will be established, in concert with DSMC, 
and 3 patients enrolled to that level.   
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose escalation 
is stopped, and this dose is declared the maximally 
administered dose.  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
≤1 out of 6 at highest dose level below 
the maximally administered dose 
This will be the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose. 

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4.2.2. Primary endpoint adjudication for DLT will occur after the 2 week post-procedure 
evaluation and laboratory values are completed.   
 
4.2.3. The patient will be monitored for adverse events until surgical resection or for 30 
days after cisplatin delivery, whichever occurs first. 
 
4.3. Treatments and Evaluations by Visit: 
4.3.1. Screening Evaluation:  
4.3.1.1. 
Initial evaluation performed via face-to-face visit or televideo (standard of 
care) 
 
4.3.1.2. 
A non-contrast chest CT scan will be performed  within 30 days of the 
screening visit.   
 
4.3.1.3. 
Baseline blood draws within 14 days of bronchoscopy: 
4.3.1.3.1. 
Samples for the following laboratory tests will be sent if not 
available: 
4.3.1.3.1.1. 
Hematology Panel: WBC count, RBC count, hemoglobin, 
hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells) 
4.3.1.3.1.2. 
Chemistry Panel (serum or plasma): sodium, potassium, 
chloride, bicarbonate, glucose, creatinine, albumin (pre-op only), 
calcium, magnesium 
4.3.1.3.1.3. 
Liver panel: ALT, AST, INR, alkaline phosphatase, 
bilirubin 
 
 
 
 
 
 
 
4.3.2. Bronchoscopic Procedure: 
4.3.2.1. 
Pre-procedure SARS-CoV-2 testing will be performed prior to the 
procedure (standard of care). 
 
4.3.2.2. 
Approximately 15mL of blood for research purposes will be drawn.  
 
4.3.2.3. 
A pre-operative CXR will be performed if no chest imaging (CXR, CT, 
PET-CT) within 7 days prior to the procedure (research). 
 
4.3.2.4. 
Patients will be brought to the operating room or procedure suite. 
Anesthesia staff will be present to administer deep sedation to minimize cough. 
 
4.3.2.5. 
Standard white light bronchoscopy will be performed. (standard of care) 
 
4.3.2.6. 
The linear endobronchial ultrasound bronchoscope (EBUS) will be used to 
perform invasive mediastinal staging. (standard of care) 
 
4.3.2.7. 
For all participants, all N2 or N3 lymph nodes greater than 5mm in short 
axis by ultrasound will be aspirated via EBUS-TBNA and evaluated using 

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ROSE. Two (2) passes with lymphocytes or up to 5 non-diagnostic passes will 
be considered negative (ROSE charged to research). If ROSE is positive at an 
N2 or N3 station no agent will be delivered  and the patient will be 
discontinued from the study. 
 
4.3.2.8. 
The clinically selected bronchoscopic procedure (e.g. EBUS 
bronchoscope, electromagnetic navigation, robotic platform) will be used to 
locate the lesion of interest. The lesion will be sampled via needle aspiration. 
Rapid on-site cytopathologic examination will be used to evaluate needle 
aspirates unless the target lesion was previously sampled and diagnosed on 
final pathology as NSCLC. All aspirates necessary for clinical care will be 
obtained first. This is usually 10-20 aspirates depending on cytopathology 
requirements. (standard of care) 
 
4.3.2.9. 
After the confirmation of NSCLC on ROSE, the research portion of the 
procedure will re-start.  
 
4.3.2.10. An additional IV will be placed by anesthesiology for blood draws 
(research) 
 
4.3.2.11. Before cisplatin injection, IV ampicillin-sulbactam 3g x 1 will be 
administered.  If the patient has a beta-lactam allergy, clindamycin 900mg will 
be substituted).(research)  
 
4.3.2.12. Prior to instillation of the cisplatin, 3 needle biopsies with a 21-gauge 
needle will be obtained for research purposes.. (research) 
 
4.3.2.13. The 21-gauge needle will then be re-inserted into the tumor. The stylet 
will be removed and a syringe containing the predefined total dose of 1mg/ml 
cisplatin attached.  
 
4.3.2.14. Intraoperative cone beam CT scan will be used to verify the location. If 
the needle tip is not located within the lesion, the needle will be repositioned 
using fluoroscopy.  No agent will be delivered if the needle tip is not within the 
lesion. 
 
4.3.2.15. Injection will then be started.  If difficulty is encountered injecting with 
the 21G needle a 19G needle may be substituted. The same requirements for 
the location of the needle (4.3.2.13) will be imposed.  
 
4.3.2.16. Following delivery of the agent, a second cone-beam CT scan will be 
performed to assess for extravasation of the agent. 
 
4.3.2.17. Serial blood draws (maximum 9) for platinum levels will be drawn after 
delivery of cisplatin and continuing for up to 2 hours later. Each is 
approximately 2mL and time stamped to allow creation of a titration 
curve.(research) 

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4.3.2.18. Research time will be recorded, beginning at completion of acquisition of 
all samples necessary for clinical care and stopped following delivery of the 
agent.    
 
4.3.2.19. The patient will be extubated and transferred to the PACU. 
 
4.3.2.20. A follow up CXR will be performed (standard of care) 
 
4.3.3. 24H Post-Bronchoscopy Evaluation 
4.3.3.1. 
A follow up telephone/televideo or in-person evaluation will be performed 
by a physician, advanced practice practitioner, or nurse and will occur within 
36 hours of completion of the procedure. A standard script (Appendix) will be 
used to assess for AEs. (research) 
 
4.3.3.2. 
Blood will be drawn for an additional platinum level for patients able to 
return for an in-person visit.(research) 
 
4.3.4. 1 Week Post-Bronchoscopy Follow Up 
4.3.4.1. 
Participants will undergo an evaluation by a physician or advanced 
practice provider between 5-9 days post-procedure. Visit will occur in-person. 
The only exception would be COVID related issues. In that case, telemedicine 
and local labs will be allowed. No phone evaluations will occur unless there is 
no other option.  A standard script will be used to assess for AEs. (research)  
 
4.3.4.2. 
A blood draw to assess for AEs will be performed between 5-9 days post-
procedure.(research)     
 
4.3.4.2.1. 
 Samples for the following laboratory tests will be sent to UVMMC 
laboratories for analysis: 
4.3.4.2.1.1. 
Hematology Panel  
4.3.4.2.1.2. 
Chemistry Panel 
4.3.4.2.1.3. 
Liver Panel 
 
4.3.4.3. 
Blood will be drawn for an additional platinum level.(research) 
 
4.3.5. 2 Week Post-Bronchoscopy Follow Up 
4.3.5.1. 
Participants will undergo an evaluation by a physician or advanced 
practice provider between 12-16 days post-procedure.  Visit will occur in-
person. The only exception would be COVID related issues. In that case, 
telemedicine and local labs will be allowed. No phone evaluations will occur 
unless there is no other option.A standard script will be used to assess for AEs. 
(research)  
 
4.3.5.2. 
A blood draw to assess for AEs will be performed between 12-16 days 
post-procedure.(research)     
 

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4.3.5.2.1. 
 Samples for the following laboratory tests will be sent to UVMMC 
laboratories for analysis: 
4.3.5.2.1.1. 
Hematology Panel  
4.3.5.2.1.2. 
Chemistry Panel 
4.3.5.2.1.3. 
Liver Panel 
 
4.3.6. A Chest CT will be performed between 12 and 30 days after delivery of the 
cisplatin.(research)     
 
4.3.7. Surgical Resection, if planned, will be scheduled between 14 and 30 days after 
delivery of the cisplatin.  
 
4.3.7.1. 
Approximately 15mL of blood will be drawn for research purposes on the 
day of (prior to) the resection procedure. 
 
4.3.8. Routine Cancer Care 
4.3.8.1. 
Patients will receive additional therapy at the discretion of the 
multidisciplinary treatment team. This review generally occurs at the 
University of Vermont Lung Transdisciplinary Conference (attendance 
generally includes but is not limited to interventional pulmonary, pulmonary, 
oncology, radiation oncology, cardiothoracic surgery, pathology, and thoracic 
radiology).  
 
5. PHARMACEUTICAL INFORMATION:  
5.1. A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 10.1. 
 
5.2. Formulation of Cisplatin: Cisplatin (cis-diamminedichloroplatinum) will be purchased 
from Fresenius/APP Pharmaceuticals. Cisplatin is a heavy metal complex containing a 
central atom of platinum surrounded by two chloride atoms and two ammonia molecules 
in the cis position. It is a yellow to orange powder with the molecular formula 
PtCl2H6N2, and a molecular weight of 300.05. It is soluble in water or saline at 1 
mg/mL. It has a melting point of 207°C. Cisplatin Injection is a sterile aqueous solution 
for intravenous use, each mL containing 1 mg cisplatin and 9 mg sodium chloride. 
Hydro- chloric acid and/or sodium hydroxide added to adjust pH. The pH range of 
Cisplatin Injection is 3.8-5.9. 
 
5.3. Supply of Study Medication On-Site: Fresenius/APP Cisplatin will be stocked and 
handled in the Research Pharmacy of the University of Vermont Medical Center. It will 
be clearly labeled using standard and established protocols. The cisplatin will be 
delivered in syringes, straight drug (1mg/ml) to the OR/procedure suite. 
 
5.4. Study Drug Dispensing: Once the subject has signed the Informed Consent Form to 
participate in the study, the subject will be associated with the research study using the 
Research Flag located in the patient banner section of the EPIC. The UVMMC 
Investigational Drug Service is alerted a study drug order will be placed in the subject’s 
EMR by the principal investigator or designee. A study drug order is placed in EMR 

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using the unique study identification number, and subject’s study ID number.  
 
5.5. Drug Accountability: The UVMMC Investigation Drug Service will keep an inventory 
of all dispensed study drug. Study drug accountability logs are maintained by the IDS. 
Administration of study drug is recorded in subject’s EMR. Study drug not administered 
is returned to IDS and destroyed. 
 
 
5.6. Medication Interactions:  
 
5.6.1. No other investigational drugs will be allowed prior to surgical resection. 
 
5.7. Potential Teratogenicity: 
 
5.7.1. Enrolled participants will be counseled that chemotherapeutics including cisplatin 
could be harmful to the fetus should the patient become pregnant following 
administration of the drug.   
 
 
6. STATISTICAL CONSIDERATIONS 
6.1. Study design 
6.1.1. This is a 3+3 dose escalation protocol.   
 
6.1.2. Enrollment is staggered, and no patient will be enrolled until the prior patient has 
completed the 1 week assessment.   
  
6.1.3. The Initial dose cohort will be 1/4th tumor volume. 
 
6.1.4. The subsequent dose escalation protocol is dependent on the rate of DLT as noted 
in the Treatment Plan. 
 
6.2. Criteria for endpoint evaluation 
 
6.2.1. Primary Endpoint: Safety (DLT), as defined by CTCAE v 5.0. 
 
6.2.1.1. 
Assessment of Adverse Events: The PI will be responsible for evaluating 
all AEs at the end of the individual patient study period. CTCAE v 5.0 grade 3 
or above will be considered a DLT 
 
6.2.1.2. 
The reporting procedures to be followed are presented in the “CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements” which can be 
downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeg
uidelines.pdf).  
 
6.2.1.3. 
Adverse Laboratory Values 
6.2.1.3.1. 
Not every laboratory abnormality qualifies as an adverse event. A 

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laboratory test result must be reported as an adverse event if it meets any 
of the following criteria:  
6.2.1.3.2. 
•  Is accompanied by clinical symptoms  
6.2.1.3.3. 
•  Results in a change in study treatment (e.g., dosage 
modification, treatment interruption, or treatment discontinuation)  
6.2.1.3.4. 
•  Results in a medical intervention (e.g., potassium 
supplementation for hypokalemia) or a change in concomitant therapy  
6.2.1.3.5. 
•  Is clinically significant in the investigator’s judgment  
 
6.2.1.3.6. 
It is the investigator’s responsibility to review all laboratory 
findings. Medical and scientific judgment will be exercised in deciding 
whether an isolated laboratory abnormality should be classified as an 
adverse event.  
6.2.1.3.7. 
Any abnormality of safety laboratories (“laboratory panel”) will be 
considered an AE if is a change from baseline (based on CTCAE v5.0) 
 
 
6.2.1.4. 
Adverse Event Characteristics: 
 
6.2.1.5. 
CTCAE term (AE description) and grade:  The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.   
 
6.2.1.6. 
“Expectedness;” AEs can be “Unexpected” or “Expected” for expedited 
reporting purposes only.  
 
6.2.1.7. 
Attribution of the AE: 
  
 
Definite – The AE is clearly related to the study treatment. 
  
 
Probable – The AE is likely related to the study treatment. 
  
 
Possible – The AE may be related to the study treatment. 
  
 
Unlikely – The AE is doubtfully related to the study treatment. 
  
 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
6.2.2. Secondary and Exploratory Endpoints:  
 
6.2.2.1. 
Safety profile of intralesional cisplatin as classified by the CTCAE, v5.0 
 
6.2.2.2. 
Proportion of cisplatin-treated subjects proceeding to surgery without 
extended local injection-related delay, defined as >30 days from preplanned 
surgery date (21 days from preplanned surgical date with 7-day window to 
allow for operating room [OR] scheduling) 
 
6.2.2.3. 
Time to surgery from intralesional therapy.  
 
6.2.3. Biomarker and Surrogate Endpoints for Research Purposes: 

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6.2.3.1. 
The below assays will be performed from: 
6.2.3.1.1. 
Blood samples, pre-procedure on the date of the bronchoscopy and 
pre-procedure on the date of the surgical resection 
6.2.3.1.2. 
Three (3) needle biopsies obtained at the time of bronchoscopy 
before cisplatin delivery 
6.2.3.1.3. 
Seven (7) needle biopsies obtained from the ex-planted resection 
specimen (3 for platinated DNA, 1 for tumor organoid, 3 for other 
biomarker assessments described below) 
6.2.3.1.4. 
Approximately 20 sections of fixed tissue from the resected tumor 
(final amount to be determined by pathology following obtaining all 
necessary tissue for clinical care, including any additional candidacy for 
clinical trials) 
 
Objectives 
Endpoints 
Secondary 
 
To assess pathologic responses (PR) in the resected 
tumor following a single intra-tumoral 
administration of cisplatin in subjects with early 
stage NSCLC 
 
 
• 
Proportion of cisplatin-treated subjects with 
major pathologic response (MPR), i.e., 
≥90% reduction in viable tumor cells, at the 
time of NSCLC resection 
• 
Proportion of cisplatin-treated subjects with 
pathologic complete response (pCR), i.e., no 
residual viable tumor cells, at the time of 
NSCLC resection 
• 
Change from baseline in percent of residual 
viable tumor cells (% RVT) in cisplatin-
treated subjects at the time of NSCLC 
resection 
Exploratory 
 
 
To assess radiologic responses in the tumor 
following a single intra-tumoral administration of 
cisplatin in subjects with early stage NSCLC  
 
• 
Tumor response rate evaluation (Δ tumor size) 
according to RECIST 1.1 criteria 
To explore the change from pre-treatment 
baseline in measures of immune activation in 
the blood and tumor (eg, percentages of 
immune cell subsets, numbers of T-cell clones, 
concentrations of serum cytokine levels) 
 
 
 
 
Pre- and post-treatment in the bronchoscopic 
biopsy and surgically resected tumor samples, 
respectively: 
• 
Tissue levels of immune-related gene expression 
as measured by appropriate techniques such as 
RNA-sequencing in biopsy samples collected at 
diagnosis and time of resection 
• 
Tissue frequencies of immune cell subsets 
determined via semi-quantitative 
immunohistochemistry (IHC) analysis of 
diagnostic biopsy and surgically-resected tissue 
specimens 
• 
To assess changes in T cell clonality in blood 
by TCR-sequencing (via DNAseq) at baseline 
and after therapy, TCR repertoire sequencing 
will be performed on the tumor to profile in the 
blood 
• 
Tumor mutational burden will be assessed 

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Objectives 
Endpoints 
by next generation sequencing. 
 
Pre- and post-treatment blood: 
• 
Changes in the concentrations of immune 
activation and inflammation markers in the 
serum before and after treatment. Serum 
cytokine and inflammatory biomarker (e.g., 
hs-CRP, IL-6, TNF-a) concentrations will be 
measured by appropriate techniques such as 
Mesoscale Discovery (MSD). 
• 
Serum neutrophil-to-lymphocyte ratio (NLR): 
Defined as neutrophil count divided by 
lymphocyte count, as determined by complete 
blood count (CBC) with differential conducted at 
baseline and after treatment. 
• 
Change in frequencies of immune cell subsets in 
blood as measured by flow cytometry (eg, CD3, 
CD8, PD-1) at baseline and after treatment 
(absolute frequencies and percent change from 
baseline). 
• 
To assess changes in T cell clonality in blood by 
TCR-sequencing (via DNAseq) at baseline and 
after therapy. TCR repertoire sequencing will be 
performed on the biopsy sample of the tumor to 
ID clones specific to the tumor to profile in the 
blood. 
 
 
 
 
To evaluate cisplatin pharmacokinetic 
parameters in the blood and to confirm cisplatin 
exposure and distribution in the  
 
• 
Maximum observed serum concentration 
(Cmax), area under the concentration-time, 
half-life (T1/2), clearance of drug after 
administration (CL), volume of distribution 
(Vd) 
Cisplatin concentration in the tumor at the site of 
injection and adjacent tumor regions measured 
by an ELISA-like method that can detect 
cisplatinated DNA 
 
 
 
 
 
6.3. Sample Size 
6.3.1. The minimum sample size will be 10. Initial dose ranging will be performed in a 
3+3 fashion.  Additional patients up to a minimum of 10 patients will be enrolled at 
the recommended Phase II dose to assess for additional AEs.    
 
6.3.2.  The maximum sample size, if six patients at each of two dose levels were 
enrolled, would be 12 patients. 

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6.3.3. Accrual would be anticipated to occur over a one year time period 
 
6.4. Power:  
6.4.1. Primary endpoint: The sample size in this study is determined by the dose 
escalation protocol and is thus not driven by considerations of statistical power for 
between group comparisons.   
 
6.5. Statistical Analysis Plan 
6.5.1. Primary Endpoint: Statistical analysis will consist of descriptive summaries of the 
treated patients along with a summary of the dose-escalation sequence and 
determination of the MTD. Adverse events, including type and grade, will be 
tabulated according to dose tier. 
 
 
 
7. DATA SAFETY AND MONITORING 
7.1. Trial Safety: Identification of risks and plans to minimize risk 
Expected Risks 
Frequency 
• Renal injury/failure (reported with 
 Occurs frequently 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
systemic  administration, never reported 
with intratumoral delivery) 
• Myelosuppression (reported  with 
 Occurs frequently 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
systemic  administration, never reported 
with intratumoral delivery) 
• Neurologic side effects, including hearing 
 Occurs frequently 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
impairment (reported with systemic 
administration, never reported with 
intratumoral delivery) 
• Hepatic injury (reported with systemic 
 Occurs frequently 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
administration, never reported with 
intratumoral delivery) 
• Nausea/vomiting (known but rare 
 Occurs frequently 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
adverse event with intratumoral cisplatin) 
• Significant bleeding (defined as >100mL is 
 Occurs frequently 
 Occurs infrequently 
rarely reported with peripheral biopsies 

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23 
 
 
 
 
Other potential risks:  
1. Incorrect ROSE diagnosis is very rare, but could lead to cisplatin delivery into a 
lesion other than a NSCLC. Further, a single, resectable lesion from a metastatic 
site is also an unusual presentation.  Presentation of small cell lung cancer with a 
single peripheral nodule is also unusual.  Although cisplatin is active against 
both small cell lung cancer, and the most common metastatic lesions (bladder, 
colorectal, breast, prostate, and head and neck), injection into a tumor other than 
a NSCLC would be considered an adverse event and reported to the IRB.  
Similarly, in the extremely rare circumstance that there would be an injection 
into a lesion with a ROSE diagnosis of NSCLC, but a final diagnosis of a benign 
disease, this would also be considered an adverse event and reported to the IRB. 
 
2. Delay in surgical resection. Although not clearly documented in the setting of 
systemic neoadjuvant IV therapy for Stage I or II NSCLC this is possible.  
However, known adverse events related to a single dose of cisplatin would be 
anticipated to resolve within 30 days making this unlikely. This would also be 
considered an adverse event and reported to the IRB.         
 
7.1.1. Planned safety tests/procedures/observations to be performed as measures to 
protect participants against foreseeable risks. 
7.1.1.1. 
Pre-procedure evaluation by Cardiothoracic Surgery to insure 
resectability. 
 
7.1.1.2. 
Follow up phone call, video, or face-to-face visit performed by a 
physician, advanced practice practitioner (APP), or nurse the day after the 
bronchoscopy 
 
7.1.1.3. 
Evaluation (video/telephone or face-to-face)  by a physician or APP, 5-9 
days post-bronchoscopy 
<1.0%). Unknown if risk increases with additional 
research biopsies. 
 Occurs rarely 
 Frequency unknown 
• Lung or airway injury including 
pneumothorax.  Pneumothorax is reported 
with peripheral biopsies.  Unknown if this 
risk increases above that associated with 
performing clinically indicated biopsies 
since the lesion and needle location will be 
already established. Other risks to the 
airway or lung are possible (e.g. 
pneumonitis) but are not reported or 
expected.     
 Occurs frequently 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 

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7.1.1.4. 
Blood draw for laboratory panel at 5-9 days and 12-16 days post-
bronchoscopy 
 
7.1.1.5. 
Only experienced pathology attendings will make the ROSE determination 
during the procedure (e.g. fellows will not perform the ROSE diagnosis) 
 
7.1.2. Criteria under which an INDIVIDUAL SUBJECT’S study treatment or study 
participation would be stopped or modified: 
 
7.1.2.1. 
At subject, PI, or study team member request 
 
7.1.2.2. 
If the subject had a Serious Adverse Event (SAE) deemed related to study 
Other: specify 
 
7.1.2.3. 
During the bronchoscopy, bleeding >100mL or concern for a patient’s 
ability to continue to tolerate the bronchoscopy would result in stopping that 
procedure (regardless of whether cisplatin had been delivered into the tumor or 
not). No further intratumoral delivery would be performed. 
 
7.1.3. Criteria under which THE ENTIRE STUDY would need to be stopped. 
 
7.1.3.1. 
 A 30% or greater rate of possibly related, serious, unanticipated events 
after 6 patients, will trigger halting of the study and initiate IRB and DSMCC 
review. 
 
7.1.4. Withdrawals/dropout reporting to the IRB prior to study completion will occur at 
the IRB annual continuing renewal submission 
 
7.1.5. Plan for management of incidental findings: 
 
7.1.5.1. 
We do not anticipate incidental findings. The pre-bronchoscopy CT scan 
is obtained as part of clinical care for all patients are undergoing a clinically 
indicated bronchoscopy. Unanticipated findings on the pre-resection CT will 
be evaluated as potential AEs. 
    
7.2. Adverse Events: 
 
7.2.1. Definition of adverse events (AE) for this study: 
 
7.2.1.1. 
An adverse event (AE) will be considered any undesirable sign, symptom 
or medical or psychological condition even if the event is not considered to be 
related to the investigational drug/device/intervention. Medical 
conditions/diseases present before starting the investigational drug/intervention 
will be considered AEs only if they worsen after starting study 
treatment/intervention. An AE is also any undesirable and unintended effect of 
research occurring in human subjects as a result of the collection of identifiable 

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25 
 
 
private information under the research. AEs also include any problems 
associated with the use of an investigational device that adversely affects the 
rights, safety or welfare of subjects. 
 
7.2.2. Define of serious adverse events (SAEs): 
 
7.2.2.1. 
A serious adverse event (SAE) will be considered any undesirable sign, 
symptom, or medical condition which is fatal, life-threatening, requires or 
prolongs inpatient hospitalization, results in persistent or significant 
disability/incapacity, constitutes a congenital anomaly/ birth defect, is 
medically significant and which the investigator regards as serious based on 
appropriate medical judgment. An important medical event is any AE that may 
not result in death, be life-threatening, or require hospitalization but may be 
considered an SAE when, based upon appropriate medical judgment, it may 
jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definitions of SAEs. 
 
7.2.2.2. 
Any serious psychological and emotional distress resulting from study 
participation (suggesting need for professional counseling or intervention). 
 
7.2.3. ALL AEs above will be collected/ recorded.  
 
7.2.4. A REDCap database will be used to save and manage data.  
 
7.2.4.1. 
The database is located on the secure UVM server and is firewall 
protected. Data will be collected from source documents including but not 
limited to clinic notes, laboratory results, and other EMR available documents. 
The PI will review all AE data at the end of the study period for each patient. 
Data will be entered and managed by trained study personnel.  
 
7.2.5. AEs be classified/graded using NCI Common Toxicity Criteria for Adverse 
Events (CTCAE), Version 5.0  
 
7.2.6. The PI will determine the relationship of AEs to the study using the following 
scale:  
 
7.2.6.1. 
Definite: AE is clearly related in time and a direct association can be 
demonstrated to the study intervention. 
7.2.6.2. 
Probable: AE is reasonably related in time and is more likely explained by 
the study intervention than by other causes. 
7.2.6.3. 
Possible: AE may be reasonably related in time and the AE can be 
explained equally well by causes other than the study intervention. 
7.2.6.4. 
Unlikely: A potential relationship could exist with the study intervention, 
but the AE is most likely explained by other causes.  
7.2.6.5. 
Unrelated:AE is clearly not related to intervention and can be fully 
explained by another cause. This other cause should be provided.  
 

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7.2.7. Recording/reporting of baseline AEs will begin after the subject signs consent. 
Subsequent AEs will be recorded following initiation of the bronchoscopic 
procedure.  
 
7.2.8. Recording/reporting of AEs will end following surgical resection or 30 days after 
cisplatin delivery, whichever occurs first. 
 
7.2.9. The PI will review all AEs following the 1 week follow up visit (occurs  at  5-9  
days performed by a physician or advanced practice provider), both to assess for 
unexpected and serious AEs and to ensure that dose escalation occurs consistent 
with the statistical plan. 
 
8.  ADVERSE EVENT REPORTING: 
 
 
 
 
8.1. Unanticipated Problems and Protocol Deviations 
8.1.1. Definition of an unanticipated problem:  
 
8.1.1.1. 
An unanticipated problem is any event/experience that meets ALL 3 
criteria below: 
8.1.1.1.1. 
Unexpected (in terms of nature, severity, or frequency) given: (a) 
the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
8.1.1.1.2. 
Related or possibly related to a subject's participation in the 
research; 
8.1.1.1.3. 
Suggests that the research places subjects or others at a greater risk 
Type of Event 
To whom will it be 
reported 
Time Frame for Reporting 
How to report? 
Death of a research 
subject unless the death is 
expected (e.g. due to 
disease progression). 
UVMCC DSMC and 
UVM IRB 
DSMC: Within 24 hours 
IRB: Within 24 hours of 
knowledge of the event 
DSMC: Email 
IRB: RNI Click 
form 
Serious Adverse Event 
(SAE), regardless of 
relatedness of 
expectedness 
UVMCC DSMC. Per 
IRB 
policy, unexpected, 
related SAEs are 
reported 
DSMC: Within 10 working 
days from the time the study 
team received knowledge of 
the event. 
IRB: 24 hours 
DSMC: Email 
IRB: RNI Click 
form 
Non-serious AEs 
UVMCC DSMC and 
UVM IRB 
At quarterly DSMCC 
report. Annually at IRB 
Continuing review. 
DSMC: Email 
IRB: Click form 

Version: 7.0 03February2022 
27 
 
 
of harm (including physical, psychological, economic, or social harm) 
related to the research than was previously known or recognized. 
8.1.1.2. 
Definition of a protocol deviation: 
 
8.1.1.2.1. 
A protocol deviation is any variance from the protocol involving a 
subject or subjects that is not approved by the IRB prior to its initiation or 
implementation, and occurs when a member of the study team departs 
from the IRB-approved protocol in any way without the investigator first 
obtaining IRB approval 
 
8.1.1.3. 
Recording/reporting of Unanticipated Problems and Protocol Deviations 
will begin after the subject signs consent 
 
8.1.1.4. 
Recording/reporting of Unanticipated Problems and Protocol Deviations 
will end at surgical resection or 30 days after cisplatin delivery, whichever 
occurs first.  
 
8.1.2. Unanticipated Problem, and Protocol Deviation reporting. 
 
 
 
 
9. DATA COLLECTIONS METHODS 
 
9.1. Endpoints of the study are described in Section 6 of the protocol 
 
9.2. Endpoints will be collected/recorded using protocol-specific Case Report Forms (CRFs), 
and source documents and captured in a REDCap database 
 
9.3. The database is located on the secure UVM server and is firewall protected. 
 
9.4. Correlative sub-studies, will link specimens other research data using the following: 
 
9.4.1. All specimens (including CT scans) will be deidentified and scrubbed of HIPPA 
identifiers. A study number will be assigned. Only the PI and primary study 
coordinater will have access to the key to link study number with patient 
information. 
 
9.5. The UVMCC DSM Report will be provided to the UVMCC 
 
Type of Event 
To whom will it be 
reported 
Time Frame for Reporting 
How to report? 
Unanticipated 
Problems that are not 
AEs or protocol 
deviations. 
IRB and DSMC 
Within 7 days to both the IRB 
and DSMC 
DSMC: Email IRB: 
Click form 

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28 
 
 
9.6. The UVMCC DSMC will be responsible for overseeing the study data  
 
9.7. The PI will perform aggregate review of: 
 
9.7.1. All AEs 
9.7.2. Unanticipated Problems  
9.7.3. Protocol violations 
9.7.4. Audit results 
9.7.5. Application of dose finding escalation/de-escalation rules 
9.7.6. Application of study designed stopping/decision rules 
9.7.7. Early withdrawals 
9.7.8. Whether the study accrual pattern warrants continuation/action 
9.7.9. Endpoint data 
 
9.8. This aggregate review will occur quarterly 
 
 

CHRMS (Medical) # 
29 
 
 
1. TABLE OF STUDY VISITS AND PROCEDURES: 
 
 
 
 
Screening 
Phase 1: Intratumoral Cisplatin Protocol 
Study Visit 
Pre-
Bronchoscopy 
Bronchoscopic  
Procedure 
24H 
Followup 
1 Week 
Followup 
2 Week 
Followup 
Surgical 
Resection** 
Informed Consent 
X 
 
 
 
 
 
History and Evaluation 
X 
 
X 
X 
X 
 
 
Research Biopsies 
 
 
X 
 
 
 
 
 
 
 
Delivery of Cisplatin 
 
 
X 
 
 
 
 
 
 
 
 
Cisplatin Blood Levels 
 
 
X 
 
X 
 
X 
 
 
 
 
CXR 
X 
(pre-bronchoscopy if no 
imaging within prior 7 
days) 
 
X 
(post-procedure) 
 
 
 
 
 
 
 
24H Post-Procedure 
Follow Up 
 
 
 
 
X 
 
 
 
 
 
Hematology Panel  
 
X 
 
 
 
 
X 
 
X 
 
 
 
Chemistry Panel 
X 
 
 
X 
X 
 
 
Liver Panel 
 
X 
 
 
X 
X 
 
 
Albumin 
X 
 
 
 
 
 
Blood Draw for 
Research  
 
X 
 
 
 
X (day of 
resection) 
 
Review of Adverse 
Events and 
Concomitant 
Medications 
 
 
 
X 
 
X 
 
X 
 
 
Chest CT Scan (non-
contrast if not 
performed or 
inadequate will ordered 
for research purposes) 
X 
 
 
 
 
X 
 
 
Obtain Research 
Resected Pathology 
Specimen 
 
 
 
 
 
X (fresh and 
fixed) 
* Research biopsies will be evaluated for changes in immunocellular infiltrate vs. resection specimen 
**Surgical resection to occur 14-30 days post-procedure 

CHRMS (Medical) # 
30 
 
 
 
 
 
 
 
 
APPENDIX A: DSM REPORTING TABLE FOR ADVERSE EVENTS 
 
Expected Risks 
Number 
Frequency 
• Renal injury/failure (reported with 
systemic administration, never reported 
with EBUS-TBNI delivery) 
• Myelosuppression (reported with 
systemic administration, never reported 
with EBUS-TBNI delivery) 
• Neurologic side effects, including hearing 
impairment (reported with systemic 
administration, never reported with 
EBUS-TBNI delivery) 
• Hepatic injury (reported with systemic 
administration, never reported with 
EBUS-TBNI delivery) 
• Nausea/vomiting (known but rare 
adverse event with EBUS-TBNI cisplatin) 
• Significant bleeding (defined as >100mL is 
rarely reported with EBUS for biopsies 
<0.1%, never for EBUS-TBNI) 

CHRMS (Medical) # 
31 
 
 
 
APPENDIX B:  
NCI COMMON ADVERSE EVENTS FOR COMMONLY USED ONCOLOGY DRUGS (CAEPR) 
 
Possible Side Effects of Cisplatin (Table Version Date: November 8, 2019) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, more than 20 and up to 100 may have: 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Anemia which may cause tiredness, or may require blood transfusions 
• Kidney damage which may cause swelling, may require dialysis 
• Hearing loss including ringing in the ears 
• Nausea, vomiting 
• Confusion 
• Numbness and tingling of the arms and legs 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, from 4 to 20 may have: 
• Diarrhea  
• Change in taste 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat 
• Hair loss 
 
RARE, AND SERIOUS 
In 100 people receiving Cisplatin, 3 or fewer may have: 
• Brain damage, Posterior Reversible Encephalopathy syndrome, which may cause headache, seizure, 
blindness 
• Seizure 
• A new cancer resulting from treatment of a prior cancer 
 
 
 

CHRMS (Medical) # 
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APPENDIX C:  
SCRIPT FOR IDENTIFICATION OF ADVERSE EVENTS BASED ON NCI CAEPR 
 
 
 
A PHASE I TRIAL OF INTRATUMORAL CISPLATIN DELIVERED AT DIAGNOSIS FOR  
EARLY STAGE, RESECTABLE, NON-SMALL CELL LUNG CANCER 
 
SUBJECT NO._________________________      SUBJECT INITIALS_______________  
 
 
 
 
Follow up contact- 1 week post bronchoscpy                 /    /        
    
 
 
 
 
 
 
 
                              Date 
 
Did the subject report any adverse events?           
   Yes 
   No 
 
 
1. Do you have any health concerns since we saw you on the day of the procedure? 
 
 
 
 
2. Since the procedure, have you had: 
  
    Wheezing or shortness of breath? 
 
     Chest pain? 
 
     Fever or rash? 
 
     Easy bruising or bleeding? 
 
     Itching?  
 
     Hearing loss or ringing in your ears? 
 
     Nausea or vomiting? 
 
    Confusion? 
 
    Numbness or tingling in the arms or legs/ 
 
    Diarrhea? 

CHRMS (Medical) # 
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    Change in taste? 
 
    Swelling of the face or throat? 
 
    Headache?  
 
    Seizure? 
 
 
 
 
 
 
 
 
 
Followup Contact Conducted by: _________________________          ____/____/_____ 
                                                                                                        
 
 
 
 
 

CHRMS (Medical) # 
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